Sara González

Catalan Institute of Oncology; L'Hospitalet, Spain · Hereditary Cancer Program

Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch-like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in 15–95% LLS-associated tumors. However, translating tumor testing results into patient manageme...

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testin...

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...

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers. Up to 90% of classical FAP are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novo cases, usually linked to milder phenotypic manifestations. To explore the prevalence of mosaicism in 11...

Introduction Germline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest. Methods and r...

RNA analyses are a potent tool to identify spliceogenic effects of DNA variants, although they are time-consuming and cannot always be performed. We present splicing assays of 20 variants that represent a variety of mutation types in 10 hereditary cancer genes and attempt to incorporate these results into American College of Medical Genetics and Ge...

Background: CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification....

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA gen...

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location a...

Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized pre‐defined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of...

Importance Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestatio...

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors including CRC and carcinomas of the ovary and breast. Whole exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in...

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient heredit...

Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer (CRC) are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent l...

Next generation sequencing panels have been developed for hereditary cancer, although there is some debate about their cost-effectiveness compared to exome sequencing. The performance of two panels is compared to exome sequencing. Twenty-four patients were selected: ten with identified mutations (control set) and fourteen suspicious of hereditary c...

Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define th...

In the article by Sanz-Pamplona and colleagues ([1][1]), functionally relevant mutations in AMER1 were identified in approximately 10% of stage II colorectal tumors, reinforcing its role as a driver gene in colorectal cancer, as occurs with APC , KRAS , or TP53 . AMER1 codifies a membrane protein

Background and aims: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lync...

Ma et al 1 comprehensively assessed the association of previously reported genetic variants with colorectal cancer (CRC) risk. The meta-analyses revealed strong evidence for association with rare MUTYH variants, even when excluding cases with MUTYH-associated polyposis. An article by Nieuwenhuis et al 2 accurately defined the phenotypical features...

Next generation sequencing (NGS) has revolutionized genomic research and is set to have a major impact on genetic diagnostics thanks to the advent of benchtop sequencers and flexible kits for targeted libraries. Among the main hurdles in NGS are the difficulty of performing bioinformatic analysis of the huge volume of data generated and the high nu...

Germline mutations in DNA polymerase ε (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not...

3629 Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component...

Next-generation sequencing (NGS) is changing genetic diagnosis due to its huge sequencing capacity and cost-effectiveness. The aim of this study was to develop an NGS-based workflow for routine diagnostics for hereditary breast and ovarian cancer syndrome (HBOCS), to improve genetic testing for BRCA1 and BRCA2. A NGS-based workflow was designed usi...

Background and objetive: Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorecta...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL One of the emerging Next Generation Sequencing (NGS) applications is amplicon resequencing, which can be applied to screen for mutations in defined genes with diagnostic value. However, in this scenario, methods and protocols are still poorly developed. To address this n...

The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic alg...

The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrie...

Classical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. We screened the APC and MUTYH genes for mutations and evaluated the genotype-phenotype correlation in 136 Spanish classical FAP families. APC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detec...

The Yin-Yang haplotype is defined as two mismatched haplotypes (Yin and Yang) representing the majority of the existing haplotypes in a particular genomic region. The human adenomatous polyposis coli (APC) gene shows a Yin-Yang haplotype pattern accounting for 84% of all of the haplotypes existing in the Spanish population. Several association stud...

MUTYH-associated polyposis (MAP) is a disorder caused by bi-allelic germline MUTYH mutation, characterized by multiple colorectal adenomas. In order to identify mutations in MUTYH gene we applied High Resolution Melting (HRM) genotyping. HRM analysis is extensively employed as a scanning method for the detection of heterozygous mutations. Therefore...

Menéndez M, Castellví-Bel S, Pineda M, de Cid R, Muñoz J, González S, TeuléÀ, Balaguer F, Ramón y Cajal T, Maria Reñé J, Blanco I, Castells A, Capellà G. Founder effect of a pathogenic MSH2 mutation identified in Spanish families with Lynch syndrome. Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS...

Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/beta-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included....

Germline mutations in the APC gene cause of most cases of familial adenomatous polyposis (FAP) and a lesser proportion of attenuated FAP (AFAP). Systematic analysis of APC at the RNA level could provide insight into the pathogenicity of identified mutations and the molecular basis of FAP/AFAP in families without identifiable mutations. Here, we ana...

There are two major hereditary colorectal cancer syndromes: Adenomatous Polyposis, secondary to APC germline alterations (FAP, Familial Adenomatous Polyposis) or secondary to MUTYH germline alterations (MAP, MUTYH associated Polyposis), and Lynch syndrome, associated with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2). The...

e22037 Background: About 13% of Familial Adenomatous Polyposis (FAP) families and 70% of Attenuated FAP families remain with unknown molecular pathogenic cause after APC and MYH mutational analyses. Also, mutations can affect specific allele expression (ASE) at the germline level. The aim of the study was to determine the presence of germline ASE i...

e22046 Background: APC mutations are believed to constitutively activate the wnt pathway in colorectal tumors. Our goal was to comprehensively characterize Wnt signaling components in a set of APC-associated FAP tumors both at the DNA and RNA levels. Methods: Sixty adenomas from FAP cases harboring pathogenic APC mutations were included (10 adenoma...

Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are d...

Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to...

approximately 20% of classic familial adenomatous polyposis (FAP) cases and 70% to 80% of attenuated FAP (AFAP) cases are negative for the APC/MUTYH point mutation. Quantitative multiplex PCR of short fluorescent fragments (QMPSF), a technique for detecting copy number alterations, has been successfully applied to several cancer syndrome genes. We...

22226 Background: Hereditary colorectal cancer (CRC) has been related to mutations in APC, mismatch repair genes and base excision repair genes, but little is known about the risk of developing CRC associated to common polymorphisms in these genes. We conducted a case control study to assess the risk of common polymorphisms in DNA repair genes in r...

11091 Background: Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the Adenomatous Polyposis Coli (APC) gene. FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyp...

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal disorder caused by mutations in DNA mismatch repair (MMR) genes. Tumors of the HNPCC-spectrum are associated with microsatellite instability (MSI) and loss of MMR protein expression. Lymphomas are not considered to be HNPCC-related tumors. We report and analyze a case of an HNPCC pat...

We identified the APC N1026S variant of unknown malignant potential in the adenomatous polyposis coli (APC) gene in a Spanish attenuated familial adenomatous polyposis (AFAP) family. The variant was located in the first of the 4 highly conserved 15-amino acid (AA) repeats within the beta-catenin union domain. Our aim was to determine its functional...

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing to colorectal cancer and affects 1 in 5-10,000 births. Inheritance of a mutant allele of the adenomatous polyposis coli (APC) gene is the cause of approximately 80% of FAP and 20-30% of an attenuated form of FAP (AFAP), whereas mutations in MUTYH account for a small...

Familial adenomatous polyposis is a rare genetic disease characterized by the development of more than a hundred adenomatous polyps in the colorectal area, as well as by extracolonic manifestations. Without treatment, this inherited disease, usually transmitted by autosomal dominant inheritance, predisposes to colorectal cancer. Treatment must be p...

Familial adenomatous polyposis is a rare genetic disease characterized by the development of more than a hundred adenomatous polyps in the colorectal area, as well as by extracolonic manifestations. Without treatment, this inherited disease, usually transmitted by autosomal dominant inheritance, predisposes to colorectal cancer. Treatment must be p...

We have undertaken a comprehensive study of common polymorphisms in genes of DNA repair, exploring both the risk of developing colorectal cancer and the prognosis of patients. Subjects from a case-control study (377 cases and 329 controls) designed to assess gene-environment interactions were genotyped by use of an oligonucleotide microarray and th...

The incidence of familial adenomatous polyposis (FAP) is approximately 7.4 per 100,000 inhabitants. APC gene mutations have been found in 60-70% of all FAP families, codons 1309 (20%) and 1061 (8%) being known hot-spots. We searched for mutations in the APC gene in a population-based registry of FAP from the Spanish Balearic Islands. Fifty-one memb...

Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the genome integrity, allowing the...

Cancer cells progress through the accumulation of genetic alterations. Familial adenomatous polyposis (FAP) tumors provide an excellent model to unravel the molecular steps underlying malignant transformation. Global genomic damage was assessed in 56 adenomas and 3 carcinomas from six FAP patients and compared with that of sporadic adenomas and car...

Colorectal cancer (CRC) is one of the most common malignant neoplasms in western countries.1 Hereditary non-polyposis colorectal cancer (HNPCC) is thought to represent the most common form of familial colorectal carcinoma and may account for approximately 1-6% of all colorectal cancers.2 The clinical phenotype of HNPCC is variable, and there is no...

Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways. We have d...

Germ-line mutations in the tumor suppressor gene APC are associated with hereditary familial adenomatous polyposis (FAP), and somatic mu- tations are common in sporadic colorectal tumors. We now report that methylation in the promoter region of this gene constitutes an alternative mechanism for gene inactivation in colon and other tumors of the gas...

Malignant transformation of the cell is accompanied and characterized by disruption of genetic material and aberrant expression of multiple genes. Systematic analysis of differential gene expression in human tumor samples may provide an estimate of the degree of genetic and epigenetic deregulation in neoplastic cells. We have assessed, by means of...

Hepatitis B and hepatitis D viral genomes were tested by nested polymerase chain reaction in the serum and liver of 69 hepatitis B surface antigen (HBsAg) negative, anti-hepatitis C virus (HCV) positive patients (47 with HCV RNA and 22 without HCV RNA). Serum hepatitis B virus (HBV) DNA-was detected in 49% of the patients with HCV-RNA and in 64% of...

We studied the long-term outcomes of 43 patients with chronic hepatitis C treated with one or two interferon cycles, in relation to hepatitis C virus RNA in serum and peripheral-blood mononuclear cells. After the first interferon cycle, 15 (35%) patients had normal transaminase levels, although only five of them had normal levels throughout follow-...