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The International Collaborative Group on hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC)
... Although most CRCs are considered sporadic, it is estimated that familial risk is involved in up to 30% of all cases. 1 However, not more than 5% to 6% are caused by known germline mutations in cancer-predisposing genes. 2 The most common form of inherited CRC is Hereditary Non-Polyposis Colorectal Cancer (HNPCC), a familial syndrome characterized by an increased susceptibility to CRC and other associated tumors as defined by the Amsterdam I and II clinical criteria. 3,4 An important fraction of HNPCC constitutes Lynch syndrome, which is caused by germline inactivating variants in the mismatch repair (MMR) genes and leads to tumors presenting microsatellite instability (MSI). However, almost half of the families that fulfill the Amsterdam criteria show microsatellite-stable, MMR-proficient tumors and have a still unknown genetic basis. ...
... 7 Therefore, identifying the different molecular mechanisms implicated in FCCTX tumorigenesis remains a challenge and a priority. Hence, in our study we conducted whole exome sequencing (WES) to look for germline genetic alterations in a FCCTX family cohort that fulfilled the Amsterdam I/II criteria, 3,4 lacked MMR germline variants and presented MMRproficient tumors. Although several candidate variants were identified in the family here presented, only the variant identified in the MMP11 gene showed a perfect segregation with the disease. ...
... The studied family was recruited at the Genetic Counseling Unit of Hospital Clínico San Carlos (Madrid, Spain) and was part of a cohort of FCCTX families that fulfilled the Amsterdam I/II criteria, 3 Table S1. Variant calling was performed using two different algorithms (VarScan and GATK), and the identified variants were annotated according to the recommendations of the HGVS. ...
Matrix metalloproteinase‐11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer‐affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.
... While the incidence of CRC seems to be decreasing in the general population over the last decades, the number of cases diagnosed at a young age has increased over the same period (1,2). Generally, young age is defined by the Amsterdam II criteria as 50 years or younger (3,4). Because the Amsterdam II criteria are very stringent, quite a number of MSI-H tumors went undetected. ...
... The findings of this study indicate that initiation of MSI screening in CRC based on clinically defined criteria bears a great risk of missing quite a large portion of potential cases with MSI-H CRC. Our findings are in line with the current literature regarding the poor performance of both the Amsterdam and the revised Bethesda criteria as selection tools for MSI screening (3,4,6). These findings should be seen as an argumentation to leave the dogma of fulfillment of clinical criteria and move on to systematic screening of colorectal neoplasia for MSI, especially since these clinical criteria were aimed at identifying individuals with possible germline mutations at risk for Lynch syndrome (17-19). ...
Background
Clinical guidelines suggest screening of colorectal cancer (CRC) for microsatellite instability (MSI). However, microsatellite instability—high (MSI-H) CRC is not rare in older patients. This study aimed to investigate the prevalence of MSI-H CRC in an unselected population in an age-based manner.
Material and methods
A retrospective analysis of data from patients undergoing radical surgery for CRC was performed. Only cases with results from MSI testing using immunochemistry (IHC) were analyzed. Age-based analyses were performed using two cut-off ages: 50 years. as stated in Amsterdam II guidelines, and 60 years. as outlined in the revised Bethesda criteria.
Results
The study population included 343 (146 female and 197 male) patients with a median age of 70 years (range 21–90 years). The prevalence of MSI-H tumors in the entire cohort was 18.7%. The prevalence of MSI-H CRC was 22.5% in the group ≤50 years vs. 18.2% in the group >50 years using the age limit in the Amsterdam II guidelines. MSI-H CRC was present in 12.6% of the group aged ≤60 years compared to 20.6% in the control group >60 years.
Conclusion
MSI screening of CRC based on age alone is associated with negative selection of a relevant number of cases. MSI-H CRC is also common in elderly patients, who may be negatively selected secondary to an age-based screening algorithm. Following the results of this study, screening based on clinical criteria should be omitted in favor of systematic screening as is already internationally practiced.
... No deceased affected individual with tumour material available for testing Note for living unaffected individuals: Where more than one family member may be eligible for unaffected testing, the residual probability of a causative pathogenic variant in the family should be considered, taking into account prior normal unaffected tests instability (MSI) or mismatch repair immunohistochemistry (IHC) was the usual first step on tumour samples. The original Amsterdam Criteria [11] were developed initially to provide a consistent diagnosis of Lynch Syndrome (previously 'HNPCC',-hereditary nonpolyposis colorectal cancer)'. Once germline genetic testing became more available in the late 1990s, the criteria were used to guide testing toward families most likely to harbour a germline variant in one of four mismatch repair genes (MMR) genes. ...
... Therefore, consensus strategies were put in place to identify those individuals and families in whom there was the greatest likelihood of detecting a causative germline variant and who would most likely benefit from genetic investigations. This is reflected in NICE guidelines for breast cancer [4] and the use of the original Amsterdam Criteria [11] to drive testing for MMR genes. ...
In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).
... In 1991, the Amsterdam I criteria were published, which were established as the minimal clinical criteria for the identification of patients and families at high risk of having LS [14,15]. These criteria were created to provide common guidelines for the selection of families for research and for the comparison of results between studies; due to this, the criteria prioritized specificity more than sensitivity. ...
... There are also patients who meet the Amsterdam criteria and do not have identifiable mutations in the MMR genes [29]. In the latter case, a Lynchlike syndrome would be suspected, in which patients may meet the Amsterdam and Bethesda criteria, and present MSI and the absence of MMR proteins; however, these patients do not have identified germline mutations in the genes that encode proteins of the MMR system, and proposed explanations of this phenotype include the presence of cryptic or rare germline mutations in MMR Table 1 Amsterdam I and II clinical criteria [14,15] Amsterdam I (1991) There must be at least three relatives with colorectal cancer; all the following criteria must be present: 1-One of the cases must be a first-degree relative of the other two 2-At least two successive generations must be affected 3-At least one case must have been diagnosed before the age of 50 4-Familial Adenomatous Polyposis must be excluded 5-Tumors must be verified by pathological examination Amsterdam II (1999) There must be at least three relatives with an HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small intestine, ureter, or renal pelvis) 1-One of the cases must be a first-degree relative of the other two 2-At least two successive generations must be affected 3-At least one must be diagnosed before the age of 50 4-Familial Adenomatous Polyposis should be excluded in cases of colorectal cancer 5-Tumors must be verified by pathological examination genes, or even pathogenic germline mutations in genes like MUTYH, POLE and POLD1, the absence of the gene products of which could affect the MMR system [30]. ...
Background
Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history.
Main body
Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis.
Conclusion
Universal screening could be an option to address the problem of underdiagnosis.
... Identification of LS families has been and still is biased. The first clinical criteria to identify affected families were constructed for research purposes to identify the causative gene(s) and reflected the misconception that we were looking for inherited CRC, not a syndrome of inherited cancer in many organs, and they primarily identified path_MLH1 families [29]. The understanding that endometrial cancer was part of the syndrome was reflected in later criteria [30] and led to more path_MSH2 and especially path_MSH6 families being recognized. ...
... Contrary to the assumptions underlying the clinical Amsterdam 1 (AMS1) [29] and Amsterdam 2 (AMS2) [30] criteria, our studies in the PLSD have shown that ovarian cancer can be grouped together with endometrial and colon cancer as the early onset cancers in carriers who are subject to colonoscopy, while rectal cancer can be grouped with the other less frequent cancers that are seen mainly in survivors of the early onset cancers. Therefore, grouping colon and rectal cancer epidemiologically as one organ, as was done by the AMS1/2 criteria might now be considered a mistake. ...
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcino-genesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metas-tasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance , aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
... Historically, before knowing the causal genes, the Amsterdam criteria were proposed, with the aim to identify patients likely to be affected by LS for research purposes (Table 1) [12]. Successively, the Bethesda guidelines were developed in order to select CRC patients to test for possible LS (Table 1) [13]. ...
... Studies assessing the response of individuals with MMRd/MSI CRC to immune checkpoint blockade found no significant differences between the study participants with germline mutation and those with sporadic MMRd/MSI CRC receiving either monotherapy or combination therapy [12,82]. Even if some data are available from subgroup analyses, to date, there have been no large prospective studies specifically addressing the efficacy of ICIs in LS patients with CRC/EC. ...
Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.
... Typically, LS families display autosomal dominant inheritance of colorectal cancer (CRC) (and various extracolonic cancers such as endometrial cancer) with a relatively young age at onset (< 50 years) (1,2). The Amsterdam criteria, used as an aid in the clinical diagnosis of LS, draws heavily on the family history of CRC, but additionally states the need for the absence of polyps to distinguish LS from familial adenomatous polyposis (FAP) (3,4). Although the cumulative lifetime adenoma burden of LS patients generally stays below ten, recent data has shown that LS may manifest with an elevated polyp count, and that individuals with pathogenic germline variants in different genes may undergo gene-specific tumorigenesis (5)(6)(7)(8)(9), creating difficulties for diagnosis. ...
Background
Lynch syndrome (LS) is an autosomal dominant multi-organ cancer syndrome with a high lifetime risk of cancer. The number of cumulative colorectal adenomas in LS does not generally exceed ten, and removal of adenomas via routine screening minimizes the cancer burden. However, abnormal phenotypes may mislead initial diagnosis and subsequently cause suboptimal treatment.
Aim
Currently, there is no standard guide for the care of multiple colorectal adenomas in LS individuals. We aimed to shed insight into the molecular features and reasons for multiplicity of adenomas in LS patients.
Methods
We applied whole exome sequencing on nine adenomas (ten samples) and three assumed primary carcinomas (five samples) of an LS patient developing the tumors during a 21-year follow-up period. We compared the findings to the tumor profiles of two additional LS cases ascertained through colorectal tumor multiplicity, as well as to ten adenomas and 15 carcinomas from 23 unrelated LS patients with no elevated adenoma burden from the same population. As LS associated cancers can arise via several molecular pathways, we also profiled the tumors for CpG Island Methylator Phenotype (CIMP), and LINE-1 methylation.
Results
All tumors were microsatellite unstable (MSI), and MSI was present in several samples derived from normal mucosa as well. Interestingly, frequent frameshift variants in RNF43 were shared among substantial number of the tumors of our primary case and the tumors of LS cases with multiple tumors but almost absent in our control LS cases. The RNF43 variants were completely absent in the normal tissue, indicating tumor-associated mutational hotspots. The RNF43 status correlated with the mutational signature SBS96. Contrary to LS tumors from the reference set with no elevated colorectal tumor burden, the somatic variants occurred significantly more frequently at C>T in the CpG context, irrespective of CIMP or LINE-1 status, potentially indicating other, yet unknown methylation-related mechanisms. There were no signs of somatic mosaicism affecting the MMR genes. Somatic variants in APC and CTNNB1 were unique to each tumor.
Conclusion
Frequent somatic RNF43 hot spot variants combined with SBS96 signature and increased tendency to DNA methylation may contribute to tumor multiplicity in LS.
... A high degree of MSI (MSI-H) is a common aspect of both the MSI and CIMP pathways (9,10). Traditionally, clinic criteria have been implemented to select patients with CRC who may require further investigation with regard to MSI (11)(12)(13). In the current German guidelines for the diagnosis and management of CRC for example (14), MSI screening is recommended in CRC patients who fulfill either the Amsterdam (13) or revised Bethesda Criteria (12). ...
Background
Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable.
Methods
We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria.
Results
The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively.
Conclusions
A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.
... Lynch syndrome, MMR, germline testing, carcinogenesis, colorectal cancer number of carefully chosen individuals with a CRC diagnosis were provided with LS testing (1). ...
... Amsterdam II The establishment of testing criteria relied on personal and family history of cancer. Amsterdam I criteria (also called 3-2-1) is the most stringent criteria and states that families should have at least three relatives with colorectal cancer (CRC) in two generations with one diagnosis under the age of 50 and one being a first-degree relative of the other two, and familial adenomatous polyposis excluded (16). Amsterdam II criteria were later established to include other Lynch-associated cancers, including endometrial, small bowel, ureter, or renal pelvis (14). ...
The presence of variants of uncertain significance (VUS) in DNA mismatch repair (MMR) genes leads to uncertainty in the clinical management of patients being evaluated for Lynch syndrome (LS). Currently, there is no platform to systematically use tumor-derived evidence alongside germline data for the assessment of VUS in relation to LS. We developed INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) to leverage information from the tumor genome to inform the potential role of constitutional VUS in MMR genes. INT²GRATE platform has two components: a comprehensive evidence-based decision tree that integrates well-established clinico-genomic data from both the tumor and constitutional genomes to help inform the potential relevance of germline VUS in LS; and a web-based user interface (UI). With the INT²GRATE decision tree operating in the backend, INT²GRATE UI enables the front-end collection of comprehensive clinical genetics and tumor-derived evidence for each VUS to facilitate INT²GRATE assessment and data sharing in the publicly accessible ClinVar database. The performance of the INT²GRATE decision tree was assessed by qualitative retrospective analysis of genomic data from 5057 cancer patients with MMR alterations which included 52 positive control cases. Of 52 positive control cases with LS and pathogenic MMR alterations, 23 had all the testing parameters for the evaluation by INT²GRATE. All these variants were correctly categorized as INT²GRATE POSITIVE. The stringent INT²GRATE decision tree flagged 29 of positive cases by identifying the absence or unusual presentation of specific evidence, highlighting the conservative INT²GRATE logic in favor of a higher degree of confidence in the results. The remaining 99% of cases were correctly categorized as INCONCLUSIVE due to the absence of LS criteria and ≥1 tumor parameters. INT²GRATE is an effective platform for clinical and genetics professionals to collect and assess clinical genetics and complimentary tumor-derived information for each germline VUS in suspected LS patients. Furthermore, INT²GRATE enables the collation of integrated tumor-derived evidence relevant to germline VUS in LS, and sharing them with a large community, a practice that is needed in precision oncology.
... [4] The inception of a prominent new organization, InSiGHT (International Society for Gastrointestinal Hereditary Tumors), stemmed from the merger of ICG-HNPCC with the Leeds Castle Polyposis Group (LCPG), carried out over several meetings, in 1999 in Lorne, Australia, in 2000 in Tiberias, Israel, and in 2001 in Venice, Italy, respectively. [10,11] These guidelines played a crucial role in pinpointing familial groups that ultimately unveiled the connection between the HNPCC syndrome and inherited mismatch repair gene mutations (MMR) [12][13][14]. However, the guidelines do not account for extracolonic cancers or apply to smaller family groups. ...
"Lynch syndrome, also known as hereditary non-polyposis cancer syndrome, represents the most common autosomal dominant genetic predisposition for the early onset development of several malignancies. Nearly three decades ago, the discovery of microsatellite instability, a distinctive feature of pathogenic variants within genes encoding mismatch repair proteins, marked a significant leap forward in understanding cancer biology and the underlying spectrum of cancers triggered by these mutations – typical of Lynch syndrome. In recent years, a new treatment paradigm, using immune checkpoint inhibitors, as well as preventive measures has drastically improved the survival rates. Identifying individuals with an inherent predisposition to cancer, through diagnostic protocols followed by personalized screening and treatment algorithms, holds the potential to mitigate premature cancer-related fatalities as well as preventable mortality. It is estimated that only a limited number of patients have been diagnosed, underscoring the importance of implementing specific screening programs for early detection of malignancies to which these patients are susceptible. This article aims to underline the importance of a national protocol tailored to guide a Western-inspired practice for Lynch syndrome patient management, the main aim of the Romanian Society for Lynch Syndrome, by providing an overview of similar initiatives throughout the world."
... proposed to define families with a strong CRC family history that meet the Amsterdam I criteria [3] where the tumors are DNA mismatch repair (MMR)-proficient/microsatellite stable and do not carry a germline pathogenic variant in one of the MMR genes (Lynch syndrome) [4,5]. The genetic factors underlying FCCTX are poorly understood and are likely to be heterogeneous involving multiple susceptibility genes [6]. ...
Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1 , a gene associated with breast and ovarian cancer and RNF43 , a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998–2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1 :c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43 :c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO ²⁰¹⁹ ) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.
... Recognizing the importance of accurate identification, guidelines such as the Amsterdam criteria and the Bethesda guidelines have been developed to aid in the diagnosis, with recommendations for universal testing of all newly diagnosed CRC patients for deficient mismatch repair or MSI to ascertain the presence of the LS. IHC analysis and polymerase-chainreaction-based testing play pivotal roles in this process, with the loss of mismatch repair proteins directing subsequent germline testing of the implicated genes [45][46][47][48]. ...
This case report presents the diagnostic journey and management of a 19-year-old female who was diagnosed with advanced colorectal cancer (CRC) associated with Lynch syndrome (LS), a hereditary nonpolyposis colorectal cancer (HNPCC). The patient initially presented with complaints of persistent abdominal pain, vomiting, and unexplained weight loss, leading to investigations revealing hypochromic microcytic anemia and the presence of an inhomogeneous pelvic mass associated with the sigmoid colon. Subsequent diagnostic procedures, including flexible sigmoidoscopy and pathology reports, confirmed the presence of an advanced rectosigmoid adenocarcinoma with high-grade dysplasia. Molecular testing and immunohistochemical staining revealed a deficiency in mismatch repair proteins, confirming the diagnosis of LS. Despite ineligibility for certain clinical trials due to lymph node infiltration, the patient demonstrated a significant positive response to pembrolizumab immunotherapy, with a notable reduction in tumor size and lymph node involvement. This case underscores the significance of genetic predisposition in the development of early-onset CRC and the potential efficacy of immunotherapy in managing advanced CRC associated with LS in young patients. Additionally, this case provides insights into the evolving landscape of CRC management and the critical role of personalized treatment strategies in optimizing patient outcomes.
... 1,4 Affected people also have an increased risk of gastric (0.7%-13%), small bowel (0.6%-12%), pancreatic (0.4%-6%) and urothelial (1.9%-15%) cancers. 3,4 Screening strategies for Lynch syndrome in people with endometrial cancer include clinical history-based criteria (e.g., Amsterdam and Bethesda criteria [5][6][7][8] ), tumour microsatellite instability (MSI) testing and tumour immunohistochemical (IHC) testing. The former identifies DNA repair failures by means of DNA sequencing. ...
Background:
Identifying people with Lynch syndrome, a genetic condition predisposing those affected to colorectal, endometrial and other cancers, allows for implementation of risk-reducing strategies for patients and their families. The goal of this study was to describe screening and testing practices for this condition among people with endometrial cancer in Nova Scotia, Canada, and to determine the prevalence of Lynch syndrome in this population.
Methods:
All patients diagnosed with endometrial cancer in Nova Scotia between May 1, 2017, and Apr. 30, 2020 were identified through a provincial gynecologic oncology database. Patients from out of province were excluded. We collected age, body mass index, tumour mismatch repair protein immunohistochemistry results, personal and family histories, and germline testing information for all patients.
Results:
We identified 465 people diagosed with endometrial cancer during the study period. Most were aged 51 years or older, and had obesity and low-grade early-stage endometrioid tumours. Tumour immunohistochemistry testing was performed in 444 cases (95.5%). Based on local criteria, 189 patients were eligible for genetic counselling, of whom 156 (82.5%) were referred to medical genetics. Of the 98 patients who underwent germline testing, 9 (9.2%) were diagnosed with Lynch syndrome.
Interpretation:
The prevalence of Lynch syndrome was at least 1.9% (9/465) in this population. Our results illustrate successful implementation of universal tumour testing; however, there remains a gap in access to genetic counselling.
... The original clinical criteria were the Amsterdam I criteria, according to which the In the past, both clinical and histopathological criteria have been used to diagnose LS [5]. The original clinical criteria were the Amsterdam I criteria, according to which the clinical diagnosis of LS could be made if the following conditions were met: the presence of three family members diagnosed with CRC in two successive generations (with one first-degree relative from the other two), at least one case of a family member with CRC before the age of 50, and the exclusion of familial adenomatous polyposis [66]. These criteria were modified in 1999 to include neoplasms of the extra-colonic district in the Amsterdam II criteria [67]. ...
Simple Summary
Lynch syndrome is an autosomal dominant hereditary disease that confers a high risk of developing various types of tumors, especially colorectal and endometrial cancer. In recent years, the molecular mechanisms underlying Lynch syndrome have generated considerable interest. Several studies have highlighted the epiphenomenon of microsatellite instability, caused by a deficit in the ability of cells to repair DNA damage, as a disease-specific feature. The discovery of microRNAs has served to clarify how these small oligonucleotide molecules may contribute to the progression of Lynch syndrome by modulating the expression of several players involved in DNA repair pathways. The purpose of this review is to analyze the management of patients with Lynch syndrome by emphasizing the importance of microRNAs as markers or therapeutics for the development of novel clinical approaches.
Abstract
Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2–3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI⁺) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine.
... Since LS is a hereditary disease, an anamnesis and an accurate family history are of pivotal importance. Several clinicopathologic criteria (Amsterdam Criteria (Amsterdam I); revised in 1997 (Amsterdam II) [39] and subsequently the Bethesda guidelines, introduced in 1996 and updated in 2004 [40,41]), have been introduced to identify patients at risk of LS. ...
Purpose
Lynch syndrome (LS) is an autosomal dominant genetic syndrome resulting in a wide spectrum of malignancies caused by germline mutations in mismatch repair genes (MMR). Gene mutations have different effects and penetrance between the two genders. The aim of this review is to offer a gender-specific evidence-based clinical guide on diagnosis, screening, surveillance, and counselling of UTUC patients with LS.
Methods
Using MEDLINE, a non-systematic review was performed including articles between 2004 and 2022. English language original articles, reviews, and editorials were selected based on their clinical relevance.
Results
Upper tract urothelial carcinoma (UTUC) is the third most common malignancy in Lynch syndrome. Up to 21% of new UTUC cases may have unrecognized LS as the underlying cause. LS-UTUC does not have a clear gender prevalence, even if it seems to slightly prefer the male gender. The MSH6 variant is significantly associated with female gender (p < 0.001) and with gynecological malignancies. Female MSH2 and MLH1 carriers have higher rates for endometrial and ovarian cancer with respect to the general population, while male MSH2 and MLH1 carriers have, respectively, higher rate of prostate cancer and upper GI tract, or biliary or pancreatic cancers. Conflicting evidence remains on the association of testicular cancer with LS.
Conclusion
LS is a polyhedric disease, having a great impact on patients and their families that requires a multidisciplinary approach. UTUC patients should be systematically screened for LS, and urologists have to be aware that the same MMR mutation may lead to different malignancies according to the patient’s gender.
... Prior to the introduction of Universal Screening, the diagnostic management of LS was mainly based on Selective Screening, which included clinical criteria based on the evaluation of family and personal history and the clinicopathological features of the tumor (Amsterdam criteria 1990 [32,33], Bethesda criteria 1997 [34], and Society of Gynecologic Oncology 20-25% and 5-10% criteria 2007 [35]). However, these have been limited in their application to clinical practice due to their complexity and the frequent lack of complete family history data. ...
This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.
... The Bethesda II guidelines criteria were met by all families [22,36]. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics and Research committee Farhat Hached University Hospital, Sousse, Tunisia, (OHRP IRB 00008931) on 10th May 2021. ...
Lynch syndrome is a heritable condition caused by a heterozygous germline inactivating mutation of the DNA mismatch repair (MMR) genes, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants, for which the clinical significance is unclear in many cases. We have identified three MLH1 missense alterations (p.(Glu736Lys), p.(Pro640Thr) and p.(Leu73Pro)) in six individuals from large Tunisian families. For none of these alterations, a classification of pathogenicity was available, consequently diagnosis, predictive testing and targeted surveillance in affected families was impossible. We therefore performed functional laboratory testing using a system testing stability as well as catalytic activity that includes clinically validated reference variants. Both p.(Leu73Pro) and p.(Pro640Thr) were found to be non-functional due to severe defects in protein stability and catalytic activity. In contrast, p.(Glu736Lys) was comparable to the wildtype protein and therefore considered a neutral substitution. Analysis of residue conservation and of the structural roles of the substituted residues corroborated these findings. In conjunction with the available clinical data, two variants fulfil classification criteria for class 4 “likely pathogenic”. The findings of this work clarify the mechanism of pathogenicity of two unclear MLH1 variants and enables predictive testing and targeted surveillance in members of carrier families worldwide.
... The clinical diagnosis of Lynch syndrome has depended on the Amsterdam I criteria developed in 1991 (9). Because its sensitivity and specificity were 60% and 70%, respectively (10-12), the Amsterdam II criteria were revised, developed in 1997, and included extracolonic malignancies with the aim to increase sensitivity (13). ...
Lynch syndrome (LS) is a genetic disorder mainly caused by germline mutations in mismatched repair (MMR) genes ( MSH2 , MLH1 , MSH6 , and PMS2 ) or deletions of the epithelial cell adhesion molecule gene ( EPCAM ). A 43-year-old Chinese male patient underwent radical surgery and was pathologically confirmed to have stage IIIB colon adenocarcinoma. After four cycles of standard adjuvant chemotherapy, the tumor reoccurred in situ with intestinal obstruction. The patient received secondary colectomy. Immunohistochemistry analysis revealed a loss of MSH2 protein expression in the surgical specimen. Noticing that the patient’s mother and grandfather all were diagnosed with LS-related cancers, we collected the patient’s and his mother’s peripheral blood for genetic testing, and the result showed a six-base deletion of MSH2 . Thus, we concluded that our patient had LS. Subsequently, the patient accepted pembrolizumab as the first-line systemic therapy after liver metastases. He achieved clinical complete response (cCR) within 2 months and remained progression-free for more than 2 years. The case report showed that MSH2 mutation (c.489_494deTGGGTA) is a likely pathogenic mutation, and immunotherapy (pembrolizumab) is effective for this patient.
... Third, at least two successive generations need to be affected. Fourth, at least, one of the relatives with CRC needs to have received the diagnosis before age 50 11 . Cancer diagnosis was confirmed by pathology reports. ...
Background/aims:
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of colorectal cancer (CRC) syndrome, in which the mutations in mismatch repair genes have been implicated in the disease etiopathogenesis. The aim of this study was to investigate the prevalence of human mutL homolog 1 (hMLH1) gene point mutations in patients with HNPCC in Northwest of Iran
Methodology:
In this study, 30 patients with HNPCC were selected who fulfilled the Amsterdam II criteria. Moreover, 30 subjects were selected as the control group. Total RNA was extracted from peripheral blood sample, and complementary DNA (cDNA) was synthesized using specific primers. Screening of germline mutations within the hMLH1 gene was performed by direct cDNA sequencing. Functional evaluation was conducted through real-time polymerase chain reaction mRNA expression using the TaqMan Gene Expression Assay.
Results:
In this study, c.655A >G polymorphism was found in 13.3% of patients and 10% of the control group, while c.1959G > T polymorphism was found in only one of the patients. Two novel variants, including c.973C > A and c.1086C > A, were found in 13.3% and 20% of patients, respectively, that were identified for the 1st time in this study. Moreover, the mRNA expression of hMLH1 gene in patients carrying the c.973C > A and c.1086C > A mutations showed no statistically significant difference in comparison to patients with no mutation and healthy controls.
Conclusions:
This study establishes that the frequency and type of mutations do not follow a similar pattern in other populations due to genetic and geographical differences.
... Amsterdam I criteria (1991) [58] All the following criteria: 1. At least three relatives with colorectal cancer 2. One should be a first-degree relative of the other two 3. ...
Objective
Lynch syndrome (LS) is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene. From a clinical perspective, LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population. We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS, focusing on incidence, diagnosis, clinical features, therapeutic strategies, and screening protocols.
Methods
Previous literature was assessed through Medline, Scopus, and Google Scholar databases. A narrative review of the most relevant articles on urological manifestations of LS was provided.
Results
In the LS tumor spectrum upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy, and the first most common cancer in the urological field, with an approximately 14-fold increased risk of developing UTUC compared to general population. LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process, including (i) clinical criteria, (ii) molecular testing, and (iii) genetic testing to confirm the hereditary disorder. The current European Association of Urology (EAU) guidelines recommend to perform molecular testing among UTUC patients <65 years old, or UTUC patients with personal history of LS-related tumor, or UTUC patients with one first-degree relative with LS-related tumor <50 years old, or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset. Newly diagnosed LS patients should be referred to a multidisciplinary management, including gastroenterologists and gynecologists. Finally, considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy may be a valuable therapeutic alternative. Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.
Conclusion
Considering the strict association between UTUC and LS, we believe that the urologist should recognize patients at increased risk for hereditary disease according to current EAU clinical criteria and address them to a comprehensive diagnostic algorithm, including molecular evaluation and genetic testing. To date, literature lacks clear evidence regarding the role of LS in developing bladder cancer, prostate cancer, or renal cell carcinoma, and current data are still inconclusive, highlighting the urgent need for further studies.
... Heredity is estimated to contribute to ~ 20% of colorectal cancers (CRC) and covers a complex genetic landscape (Valle 2017) but only ~ 5% of CRC cases have been explained by a high-risk pathogenic germline variant. The clinical Amsterdam I criteria (Vasen et al. 1991) were established to identify families with a high risk of germline variants resulting in autosomal dominant hereditary CRC. However, the later detection of the mismatch repair (MMR) genes MLH1, MSH2/EPCAM, MSH6 and PMS2 has dichotomized the Amsterdam I positive families into two groups: those with MMR-deficient tumors linked to Lynch Syndrome (LS) and those with MMR-proficient Familial Colorectal Cancer Type X (FCCTX) syndrome with unknown genetic causes (Carethers and Stoffel 2015). ...
The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
Lynch syndrome, also called hereditary non‐polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes—resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34‐year‐old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology‐Oncology MDT meeting—management options including fertility‐sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo‐oophorectomy was performed with pathology results consistent with well‐differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2‐yearly colonoscopic surveillance.
"Chemotherapy is an important treatment in oncological disease, with a vast number of side effects. The cardiotoxicity of several chemotherapeutic agents and appropriate risk stratification and patient follow-up must be ensured by a multidisciplinary team which must include an oncologist and a cardiologist. Lynch syndrome is associated with younger-onset malignant tumors of various localizations, requiring aggressive chemotherapy. FOLFOX chemotherapy which is frequently used in Lynch syndrome-associated colorectal cancer has several cardiotoxic effects with mechanisms ranging from increased reactive oxidative species to Krebs cycle blockade or coronary vasospasm. These complex effects on the cardiovascular system have varied clinical effects, such as heart failure, arrhythmias, or acute ischemic events"
(1) Background: The human MutS homolog, hMSH2, is known to be involved in DNA
mismatch repair and is responsible for maintaining the stability of the genome. When DNA damage
occurs, MSH2 promotes cell apoptosis via the regulation of ATR/Chk2/p53 signal transduction,
and MSH2 deficiency is also related to accelerated telomere shortening in humans. MSH2 missense
mutations are involved in a defective DNA reparation process, and it can be implied in carcinogenesis,
as it is already involved in well-known cancer-related syndromes such as Lynch syndrome. Human
MSH6, which stands for mutS homolog 6, is a member of the MMR family that is responsible for the
repair of post-replicative mismatched DNA bases. It is also one of the proteins with gene mutations
that are associated with a high risk of developing Lynch syndrome, leading to a large series of tumors.
(2) Methods: Patients and their clinical and pathological features were selected from the database
of the project GRAPHSENSGASTROINTES and used accordingly, with ethics committee approval
no. 32647/2018 awarded by the County Emergency Hospital from Targu-Mures. Analyses were
conducted on whole blood, saliva, urine, and tumoral tissue samples using a stochastic method with
stochastic microsensors. (3) Results: The results obtained using stochastic sensors were correlated
with a series of macroscopic and microscopic pathological features for each sample type. Criteria or
relationships were established for tumor location, vascular and perineural invasions, lymph node
metastases, the presence of tumor deposits, and the presence of a mucus compound in the tumor
mass. (4) Conclusions: The correlation between the concentrations of MSH2 in the four types of
samples and the pathological features allowed for the fast characterization of a tumor, which can
help surgeons and oncologists choose personalized treatments. Also, the colorectal tumor location
was correlated with the concentration of MSH2 in whole blood, urine, and saliva. MSH6, which
stands for mutS homolog 6, is not only useful in immunohistochemistry but in pathology practice as
well. In this paper, the relationships between MSH6 levels in four biological fluids—whole blood,
saliva, urine, and tissues—and tumor locations among the colorectal area, gross features, presence of
a mucinous compound, molecular subtype, stroma features, and vascular invasions are presented.
Simple Summary
Approximately 20% of colorectal cancer (CRC) cases are diagnosed in individuals under 40, with a severe prognosis due to germline variant accumulation. Many of these variants have been classified as hereditary cancer causative, while others remain poorly researched. The identification of germline variants across different populations is critical for accurate prognosis, treatment, and follow-up. We aimed to identify and predict the functional implications of germline variants using whole-genome sequencing of a Tunisian pedigree with Lynch syndrome CRC risk. Two SNPs/indels were identified in genes with CRC association (MLH1 and PRH1-TAS2R14) and four in genes with non-CRC cancer association (PPP1R13B, LAMA5, FTO, and NLRP14). Three structural variants overlapped genes associated with non-CRC digestive cancer (RELN, IRS2, and FOXP1) and one overlapped RRAS2 with non-CRC cancer associations. This study provides further evidence of genetic predisposition according to the risk clustering of variants based on their functional implications and risk mechanisms within the same pedigree.
Abstract
Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three “variant risk clusters” shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different “variant risk clusters” can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.
سرطان نوعی اختلال مولكولی و ژنتیكی است كه در آن كنترل تزاید سلولی از دست رفته است. مكانیسم پایه در تمام سرطانها جهش در ردهی زایا و یا به طور شایعتر در سلولهای پیكری میباشد.
پاتولوژی مولکولی سرطان، اطلاعات جامعی در زمینههای مختلفی از جمله تشخیص بیماری، مراقبت سلامت بیمار، انتخاب درمان، پایش نتایج درمان، پیش آگهی، پیشبینی خطر بیماری، استراتژیهای پیشگیری، تعیین بیمار و نمونه، و اپیدمیولوژی بالینی را فراهم میکند. با توجه به پیشرفت دانش پاتولوژی مولكولی، داشتن اطلاعاتی در زمینه انجام تستهای تشخیصی بهتر و آسانتر، جهشهای ژنی برای کاربرد بالینی، تفسیر نتایج و نکات مهم برای انجام تستها، مهم میباشند.
جراحان، متخصصین گوارشی، انكولوژیستها، اندوكرینولوژیستها، متخصصین نورولوژی و پاتولوژیستها و بسیاری از رشتههای دیگر پزشكی باید از این بیماریها به صورت كامل آگاهی داشته باشند و تستهای مولكولی مربوط به هر كدام از آنها را به طور كامل بشناسند و زمان استفاده و موارد كاربرد این تستها را بدانند و اینكه چگونه بیمارانی كه دچار سندرمهای سرطان ارثی هستند و یا فامیل آنها كه مستعد ایجاد سرطان هستند را مدیریت نمایند.
این كتاب به مفهوم پایه و اساس پاتولوژی مولكولی سرطان و در نهایت سندرمهای شایع ارثی سرطان و مدیریت بالینی آنها میپردازد و هدف اصلی، كمك به پزشكان در مدیریت این بیماران در بالین میباشد و محتمل است كه بینش جدید به نقش بنیادی تغییرات DNA در ایجاد سرطان در آیندهی نزدیك، به ایجاد روشهای بهتر واختصاصیتر تشخیص زود هنگام، پیشگیری و درمان بیماریهای بدخیم منجر گردد.
The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes. Despite the guidelines now available, determining the pathogenicity of rare variants remains challenging, as the clinical significance of a genetic variant could be uncertain, but it may represent a disease-associated variation in the aforementioned genes. In this case report we will describe the case of a 47 years-old female affected by endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic, and a family history consistent with LS.
Lynch syndrome (LS), caused by germline mutations in the mismatch repair genes, is the most common hereditary colorectal cancer. While LS is also associated with various cancers, early detection of the proband is meaningful for tumor prevention, treatment, and familial management. It has been a dramatic shift on the screening approaches for LS. As the rapid development of the molecular biological methods, a comprehensive understanding of the LS screening strategies will help to improve the clinical care for this systematic disease. The current screening strategies have been well validated but mainly by evidence derived from western population, lacking consideration of the ethnic heterogeneity, which hampers the universality and clinical application in China. Hence, this review will focus on the Chinese experience in LS screening, aiming to help better understand the ethnic diversity and further optimize the screening strategies.
A 56-years-old male presented at our hospital due to the symptoms of anemia, liver disfunction and colon polyps. He had resected rectal cancer at the ages of 41 and has no family history of colorectal cancer. A thorough examination for anemia resulted in detection of multiple colon cancer and cancer on ampulla of Vater. We performed total colectomy with dissection of regional lymph nodes and pancreaticoduodenectomy with dissection of regional lymph nodes. Immunohistochemical analysis showed a lack of MSH2 and MSH6 protein in the colon cancer and cancer on ampulla of Vater, and germline mutation of hMSH2 gene was recognized. Therefore, we diagnosed the case as Lynch syndrome.
Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in man and accounts for some 3% of unselected patients with colorectal or endometrial cancer and 10-15% of those with DNA mismatch repair (MMR)-deficient tumors. Previous studies have established the genetic basis of LS predisposition, but there have been significant advances recently in the understanding of the molecular pathogenesis of LS tumors, which has important implications in clinical management. At the same time, immunotherapy has revolutionized the treatment of advanced cancers with MMR defects. We aim to review the recent progress in the LS field and discuss how the accumulating epidemiological, clinical, and molecular information have contributed to a more accurate and complete picture of LS, resulting in genotype- and immunological subtype-specific strategies for surveillance, cancer prevention, and treatment.
Objective
To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories.
Design
Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years’ missing data.
Results
Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed.
Conclusion
The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
Cancer is one of the most common causes of death worldwide. A strong predisposition to cancer is generally only observed in colorectal cancer (5% of cases) and breast cancer (2% of cases). Colorectal cancer is the most common cancer with a strong genetic predisposition, but it includes dozens of various syndromes. This group includes familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, NTHL1-associated polyposis, Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome, and Muir–Torre syndrome. The common symptom of all these diseases is a very high risk of colorectal cancer, but depending on the condition, their course is different in terms of age and range of cancer occurrence. The rate of cancer development is determined by its conditioning genes, too. Hereditary predispositions to cancer of the intestine are a group of symptoms of heterogeneous diseases, and their proper diagnosis is crucial for the appropriate management of patients and their successful treatment. Mutations of specific genes cause strong colorectal cancer predispositions. Identifying mutations of predisposing genes will support proper diagnosis and application of appropriate screening programs to avoid malignant neoplasm.
El objetivo de este trabajo fue caracterizar demográfica y molecularmente las familias con diagnóstico de síndrome de Lynch en base a estudios genéticos. Se utilizó la base prospectiva del Registro de Epidemiología Molecular de Cáncer Colorrectal (REM-CCR) del Hospital Italiano de Buenos Aires (Clinical trials.gov NCT02781337). El criterio de inclusión fue que tuvieran hecho un estudio genético entre 1996 y 2017 (secuenciación y/o determinación de grandes rearreglos de al menos un gen reparador de error de apareamiento). Se analizaron 50 familias con los criterios de Amsterdam. En 23 (46%) se identificaron variantes patogénicas (n=19) y probablemente patogénicas (n=2). El 28.6% de las variantes patogénicas fueron originalmente descritas en esta serie, entre ellas la variante c.1911del en el exón 12 de MSH2 identificada en una familia con agregación de cáncer de mama. Fue identificada una mutación fundadora de Piamonte, Italia (c.2252_2253del). Los genes afectados incluyeron MSH2 (13 variantes)MLH1 (9 variantes) y PMS2 (1 variante). La tasa de detección de mutaciones fue del 46%. Entre las familias con mutación identificada (n=23), se detectó una edad mediana de inicio del cáncer menor (46 vs. 50 años, p=0.02) y mayor incidencia de tumores extra-colorrectales (90.5% vs. 45.8%, p <0.01), que las 27 sin mutaciones. La implementación de estudios genéticos permitió caracterizar variables demográficas en base a la identificación de mutaciones germinales asociadas al síndrome de Lynch, identificándose dos grupos diferenciados por la edad de afectación y la incidencia de tumores extracolónicos.
Background
Lynch syndrome (LS) is the first cause of inherited colorectal cancer (CRC), being responsible for 2–4% of all diagnoses. Identification of affected individuals is important as they have an increased lifetime risk of multiple CRC and other neoplasms, however, LS is consistently underdiagnosed at the population level. We aimed to evaluate the yield of LS screening in CRC in a single-referral centre and to identify the barriers to its effective implementation.
Methods
LS screening programme included individuals with CRC < 70 years, multiple CRC, or endometrial cancer at any age. Mismatch repair (MMR) protein immunohistochemistry (IHC) analysis was performed in routine practice on the surgical specimen and, if MLH1 IHC was altered, MLH1 gene promoter methylation was analysed. Results were collected in the CRC multidisciplinary board database. LS suspected individuals (altered MMR IHC without MLH1 promoter methylation) were referred to the Cancer Genetic Counselling Unit (CGCU). If accepted, a genetic study was performed. Two checkpoints were included: review of the pathology data and verification of patient referral by a genetic counsellor.
Results
Between 2016 and 2019, 381 individuals were included. MMR IHC analysis was performed in 374/381 (98.2 %) CRC cases and MLH1 promoter methylation in 18/21 (85.7 %). Seventeen of the 20 LS suspected individuals were invited for referral at the CGCU. Two cases were not invited and the remaining patient died of cancer before completion of tumour screening. Fifteen individuals attended and a genetic analysis was performed in 15/20 (75 %) LS suspected individuals. Ten individuals were diagnosed with LS, in concordance with the IHC profile (2.7 % of the total cohort). This led to cascade testing in 58/75 (77.3 %) of the available adult relatives at risk, identifying 26 individuals with LS.
Conclusions
Establishing a standardized institutional LS screening programme with checkpoints in the workflow is key to increasing the yield of LS identification.
PURPOSE
This study aims to review and evaluate available informatics platforms for research and management purposes of Lynch syndrome (LS) to identify gaps and needs for future development.
METHODS
LS informatics tools were identified through literature search in four publication databases (1 and Scopus). First, the LS and functional elements of every informatics tools for LS were introduced. Then, current existing LS informatics tools were reviewed and explained.
RESULTS
A detailed review of implemented studies shows that many types of informatics platforms are available for LS management (ie, prediction model, clinical decision support system, database website, and other tools for research and management purposes of LS). Moreover, several dimensions of existing LS informatics tools were discussed and features and positive findings were reported.
CONCLUSION
Reviewing the literature reveals that several LS informatics tools were focused on gene-specific estimate, cancer risk prediction, identifying/screening patients, supporting personalized care of individuals with LS, and storing mismatch repair mutations information. Nevertheless, these platforms do not fully cover the care and research purposes. For instance, future developments of LS tools require more attention to dynamic knowledgebase, extra-colonic lynch–related cancers on the basis of precision medicine, variants of unknown significance, and support from diagnosis to surveillance for patient follow-up. Insights and recommendations provided in this study could help researchers and developers to meet the existing challenges in future developments.
Part of the Cambridge Illustrated Surgical Pathology series, this book provides a comprehensive account of the experienced gynecologic pathologists' diagnostic approach to uterine pathology. Discussion is built around major pathologic entities in the uterus and cervix while highlighting the diverse and complex spectrum of alterations encountered in daily practice. Emphasizing clear description, diagnostic algorithms and problem solving, the book's primary goal is to lay the foundation for diagnostic accuracy, reproducibility, and relevance. It also dispels common misconceptions and encourages an intelligent and thoughtful approach to diagnostic problems using all the tools available to the modern physician. The book is richly illustrated, with more than 700 color photomicrographs, all of which are also found in downloadable format on the accompanying CD-ROM.
Part of the Cambridge Illustrated Surgical Pathology series, this book provides a comprehensive account of the experienced gynecologic pathologists' diagnostic approach to uterine pathology. Discussion is built around major pathologic entities in the uterus and cervix while highlighting the diverse and complex spectrum of alterations encountered in daily practice. Emphasizing clear description, diagnostic algorithms and problem solving, the book's primary goal is to lay the foundation for diagnostic accuracy, reproducibility, and relevance. It also dispels common misconceptions and encourages an intelligent and thoughtful approach to diagnostic problems using all the tools available to the modern physician. The book is richly illustrated, with more than 700 color photomicrographs, all of which are also found in downloadable format on the accompanying CD-ROM.
Part of the Cambridge Illustrated Surgical Pathology series, this book provides a comprehensive account of the experienced gynecologic pathologists' diagnostic approach to uterine pathology. Discussion is built around major pathologic entities in the uterus and cervix while highlighting the diverse and complex spectrum of alterations encountered in daily practice. Emphasizing clear description, diagnostic algorithms and problem solving, the book's primary goal is to lay the foundation for diagnostic accuracy, reproducibility, and relevance. It also dispels common misconceptions and encourages an intelligent and thoughtful approach to diagnostic problems using all the tools available to the modern physician. The book is richly illustrated, with more than 700 color photomicrographs, all of which are also found in downloadable format on the accompanying CD-ROM.
Expression of DNA mismatch repair (MMR) protein (MLH1, PMS2, MSH2, and MSH6) in upper tract urothelial carcinoma (UTUC) has been explored in Western cohorts, but it is rarely reported in Eastern cohorts. We aimed to assess the loss of MMR protein expression among Chinese UTUC patients and study its clinicopathological implications. We enrolled 175 UTUC patients at our center and tested the expression of MMR proteins by immunohistochemistry. Then, we explored these patients’ clinicopathological characteristics. We found loss of MMR proteins in 19 (10.9%) of 175 patients in our cohort (6 MSH2 and MSH6, 2 MSH6 alone, 6 MSH2 alone, 3 MLH1 and PMS2, and 2 PMS2 alone). Loss of MMR proteins was not a significant prognostic factor of relapse-free survival for these patients. In addition, patients with lower T stage or with bladder cancer history were more likely to have loss of MMR protein expression. At last, two metastatic patients (MSH2 and MSH6 loss; MSH2 loss) with loss of MMR protein experienced tumor recession after several cycles of anti-PD-1 immunotherapy. In conclusion, this is the largest Chinese UTUC cohort study to date that explores the loss of MMR protein expression. The rate of MMR loss observed was comparable to that in the Western UTUC cohort, supporting universal UTUC screening in China. Furthermore, a subset of advanced UTUCs with MMR protein loss are probably immunogenic, for whom single or combined immunotherapy may be potential therapeutic options in the future.
This chapter will review the history of cancer genetics and describe updates in hereditary cancer risk assessment pertinent to the gynecologic oncologist.
Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.
p>To study cytochrome P4502C subfamily gene polymorphisms in the polyp and non-polyp population of the Imperial Cancer Research Fund flexible sigmoidoscopy screening trial and establish any association with adenomatous polyps of the colon.
The vast majority of environmental compounds are inert requiring activation to become carcinogens by xenobiotic metabolising enzymes. Individuals exhibiting different expression patterns of these enzymes, possibly due to generic polymorphisms, vary in their susceptibility to the effects of environmental factors. The CYP2C subfamily enzymes are known to be involved in the metabolism of several commonly used drugs, notably, omeprazole, warfarin, non-steroidal anti-inflammatories, tolbutamide & diazepam, as well as a number of environmental mutagens such as benz[a]pyrene (3)
DNA based polymerase chain reaction and restriction fragment length polymorphism methods were used to determine the frequency of CYP2C8, 9, 18 and 19 polymorphisms (Table 17) in individuals attending the ICRF screening trail.
For CYP2C8 there is a reported base pair change a to c at position 390. The c base is the wild type (WT) and an allele is very rare and may not exist at all. For CYP2C18 a reported t to c base pair change at position 1154 did not appear to exist. Allele frequencies in a UK population for CYP2C9, CYP2C18 and CYP2C19 polymorphisms have been established. There was no statistically significant difference for any of the polymorphisms studied between those with adenomas and controls. There were more heterozygotes and homozygotes combined in the adenoma group for the polymorphism termed CYP2C 9 . This did not reach significance (p=0.064). There is evidence that this polymorphism has a dominant effect and is involved in benz[a]pyrene metabolism, a smoking carcinogen. Smoking has been shown to predispose to colorectal adenomas.
None of the CYP2C subfamily polymorphism studied were shown to predispose to adenomatous polyps of the distal colon and rectum. CYP2C 9 warrants further investigation.</p
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