[Show abstract][Hide abstract] ABSTRACT: At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a non-coding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell specific loss of Cdkn2a causes hyperplasia whilst overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched controls. Compared with controls, carriers displayed increased insulin secretion, impaired insulin sensitivity and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A-loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrate that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region.
[Show abstract][Hide abstract] ABSTRACT: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. Polyps are most common in the colorectum (98 % of patients) and the stomach (14 %). Causative mutations for JPS have been identified in two genes to date, SMAD4 and BMPR1A. SMAD4 mutations are associated with a higher incidence of gastric polyposis. In this case report, we describe two patients with massive gastric polyposis associated with a SMAD4 mutation. Both presented with anaemia and both had colonic polyps. Initial endoscopic findings revealed giant rugal folds suggestive of Ménétrier disease. However, as other possible gastropathies could not be differentiated on the basis of histology, a definitive diagnosis of JPS required additional mutation analysis. In patients with polyposis predominant in or limited to the stomach, establishing a diagnosis based solely on the pathological features of polyps can be challenging due to difficulties in differentiating JPS from other hypertrophic gastropathies. Mutation analysis should be considered early in the diagnostic process in cases of suspected juvenile polyposis, thus facilitating rapid diagnosis and adequate follow-up.
Familial Cancer 07/2015; 14(4). DOI:10.1007/s10689-015-9822-z · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.
Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.
No significant association with pancreatic cancer was found for any of the seven SNPs.
Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.
BMC Research Notes 06/2015; 8(1):264. DOI:10.1186/s13104-015-1235-4
[Show abstract][Hide abstract] ABSTRACT: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.
European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.
Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.
PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med advance online publication 25 June 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.83.
Genetics in medicine: official journal of the American College of Medical Genetics 06/2015; DOI:10.1038/gim.2015.83 · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.
We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.
Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).
In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.
Journal of the National Cancer Institute 05/2015; 107(5). DOI:10.1093/jnci/djv033 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dear Editor, We read with interest the paper by Canto and coworkers recently published in Gut that provided guidelines for the management of individuals with a high risk for pancreatic ductal adenocarcinoma (PDAC).1 Although indications for surgery are discussed, no recommendations are given regarding the extent of surgery, that is, partial pancreatectomy (PP) or total pancreatectomy (TP), in cases with a small screen-detected PDAC. This is an important issue because it seems very likely that a hereditary background increases the risk for a second primary cancer of the pancreas. Here, we describe two high-risk individuals who developed a second primary tumour after a PP of an early-stage cancer. Patient 1 is a 62-year-old woman with the common Dutch ‘p16-Leiden’ founder mutation in the CDKN2A gene and a medical history of melanoma at age 56. This patient was enrolled … [Full text of this article]
Gut 04/2015; 64(8). DOI:10.1136/gutjnl-2015-309568 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Colonoscopic surveillance is recommended for individuals with familial colorectal cancer (CRC). However, the appropriate screening interval has not yet been determined. The aim of this randomized trial was to compare a 3-year with a 6-year screening interval.
Patients and methods:
Individuals between ages 45 and 65 years with one first-degree relative with CRC age < 50 years or two first-degree relatives with CRC were selected. Patients with zero to two adenomas at baseline were randomly assigned to one of two groups: group A (colonoscopy at 6 years) or group B (colonoscopy at 3 and 6 years). The primary outcome measure was advanced adenomatous polyps (AAPs). Risk factors studied included sex, age, type of family history, and baseline endoscopic findings.
A total of 528 patients were randomly assigned (group A, n = 262; group B, n = 266). Intention-to-treat analysis showed no significant difference in the proportion of patients with AAPs at the first follow-up examination at 6 years in group A (6.9%) versus 3 years in group B (3.5%). Also, the proportion of patients with AAPs at the final follow-up examination at 6 years in group A (6.9%) versus 6 years in group B (3.4%) was not significantly different. Only AAPs at baseline was a significant predictor for the presence of AAPs at first follow-up. After correction for the difference in AAPs at baseline, differences between the groups in the rate of AAPs at first follow-up and at the final examination were statistically significant.
In view of the relatively low rate of AAPs at 6 years and the absence of CRC in group A, we consider a 6-year surveillance interval appropriate. A surveillance interval of 3 years might be considered in patients with AAPs and patients with ≥ three adenomas.
[Show abstract][Hide abstract] ABSTRACT: High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations Astrid A. Out • Ivonne J. H. M. van Minderhout • Nienke van der Stoep • Lysette S. R. van Bommel • Irma Kluijt • Cora Aalfs • Marsha Voorendt • Rolf H. A. M. Vossen • Maartje Nielsen • Hans F. A. Vasen • Hans Morreau • Peter Devilee • Carli M. J. Tops • Frederik J. Hes Abstract Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colo-rectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6 % for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6 %) of the patients and pathogenic mosaic variants in 2 (1 %). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leuko-cyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7 % of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.
Familial Cancer 01/2015; 14(2). DOI:10.1007/s10689-015-9780-5 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hereditary factors are involved in the development of a substantial proportion of all cases of colorectal cancer. Inherited forms of colorectal cancer are usually subdivided into polyposis syndromes characterized by the development of multiple colorectal polyps and nonpolyposis syndromes characterized by the development of few or no polyps. Timely identification of hereditary colorectal cancer syndromes is vital because patient participation in early detection programmes prevents premature death due to cancer. Polyposis syndromes are fairly easy to recognize, but some patients might have characteristics that overlap with other clinically defined syndromes. Comprehensive analysis of the genes known to be associated with polyposis syndromes helps to establish the final diagnosis in these patients. Recognizing Lynch syndrome is more difficult than other polyposis syndromes owing to the absence of pathognomonic features. Most investigators therefore recommend performing systematic molecular analysis of all newly diagnosed colorectal cancer using immunohistochemical methods. The implementation in clinical practice of new high-throughput methods for molecular analysis might further increase the identification of individuals at risk of hereditary colorectal cancer. This Review describes the clinical management of the various hereditary colorectal cancer syndromes and demonstrates the advantage of using a classification based on the underlying gene defects.
[Show abstract][Hide abstract] ABSTRACT: Lynch syndrome (LS) accounts for 2 - 4 % of all colorectal cancers. Affected family members have a germline mutation in one of the DNA mismatch repair genes MLH1, PMS2, MSH2, or MSH6, and a lifetime risk for development of colorectal cancer of 25 - 75 %. Current guidelines recommend annual to biannual surveillance colonoscopy in mutation carriers. Several factors may predict failure to prevent interval cancer in LS: more lesions in the right colon; more flat ("non polypoid") and lateral growing polyps; small adenomas may already harbor high grade dysplasia or a high percentage of villous component and become advanced adenomas; there is a short duration of the adenoma - carcinoma sequence; synchronous lesions have high prevalence; patients are younger and less tolerant to colonoscopy (need more sedation); and repeated colonoscopies are needed for lifelong surveillance (patient experience is important for compliance). In order to prevent cancer in LS patients, surveillance colonoscopy should be performed in an endoscopic unit experienced with LS, every 1 - 2 years, starting at age 20 - 25 years, or 10 years younger than the age of first diagnosis in the family (whichever is first), and yearly after the age of 40 years. Colonoscopy in LS patients should be a very meticulous and precise procedure (i. e. taking sufficient withdrawal time, documentation of such warranted), with removal of all of the polyps, special attention to the right colon and alertness to flat lesions. Following quality indicators such as successful cleansing of the colon and removal of every polyp will probably improve prevention of interval cancers. At this moment, none of the new endoscopic techniques have shown convincing superiority over conventional high resolution white light colonoscopy.
[Show abstract][Hide abstract] ABSTRACT: The p16-Leiden germline variant in the CDKN2A gene is associated with a high risk of melanoma and pancreatic cancer. The aims of this study were to assess the risk of developing other cancers and to determine whether tobacco use would alter cancer risk in carriers of such a variant. We therefore prospectively evaluated individuals with a p16-Leiden germline variant, participating in a pancreatic surveillance programme, for the occurrence of cancer (n=150). Tobacco use was assessed at the start of the surveillance programme. We found a significantly increased risk for melanoma (relative risk (RR) 41.3; 95% confidence interval (CI) 22.9-74.6) and pancreatic cancer (RR 80.8; 95% CI 44.7-146). In addition, increased risks were found for cancers of the lip, mouth and pharynx (RR 18.8; 95% CI 6.05-58.2) and respiratory tumours (RR 4.56; 95% CI 1.71-12.1). Current smokers developed significantly more cancers of the lip, mouth and pharynx, respiratory system and pancreas compared with former and never-smokers. In conclusion, this study shows that carriers of a p16-Leiden variant have an increased risk of developing various types of cancer, and smoking significantly increases the risk of frequently occurring cancers. Smoking cessation should be an integral part of the management of p16-Leiden variant carriers.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.187.
European journal of human genetics: EJHG 09/2014; 23(5). DOI:10.1038/ejhg.2014.187 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE).
Design After obtaining informed consent, asymptomatic proven gene mutation carriers aged 35–70 years were included in this prospective multicentre study in the Netherlands. Patients with previous small-bowel surgery were excluded. After bowel preparation, VCE was performed. The videos were read by two independent investigators. If significant lesions were detected, an endoscopic procedure was subsequently performed to obtain histology and, if possible, remove the lesion.
Results In total, 200 patients (mean age 50 years (range 35–69), M/F 88/112), with proven mutations were included. These concerned MLH1 (n=50), MSH2 (n=68), MSH6 (n=76), PMS2 (n=3) and Epcam (n=3) mutation carriers. In 95% of the procedures, caecal visualisation was achieved. Small-bowel neoplasia was detected in two patients: one adenocarcinoma (TisN0Mx) and one adenoma, both located in the duodenum. In another patient, a duodenal cancer (T2N0Mx) was diagnosed 7 months after a negative VCE. This was considered a lesion missed by VCE. All three neoplastic lesions were within reach of a conventional gastroduodenoscope. All patients with neoplasia were men, over 50 years of age and without a family history of small-bowel cancer.
Conclusions The prevalence of small-bowel neoplasia in asymptomatic patients with LS was 1.5%. All neoplastic lesions were located in the duodenum and within reach of conventional gastroduodenoscopy. Although VCE has the potential to detect these neoplastic lesions, small-bowel neoplasia may be missed.
Trial registration number NCT00898768.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given their high lifetime risk of developing neoplasms. The role of MTHFR C677T genotype in modifying these relationships in LS individuals is also unclear. We investigated associations between dietary intakes of folate, vitamins B2, B6, B12, and methionine and CRT development in a prospective cohort study of 470 mismatch repair gene mutation carriers.
Dietary intakes were assessed by food frequency questionnaire. Cox regression models with robust sandwich covariance estimation, adjusted for age, sex, physical activity, number of colonoscopies during person-time, NSAID use, and mutual vitamins were used to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Analyses were also stratified by MTHFR C677T genotype.
During a median person-time of 28.0 months, 131 persons developed a CRT. Fifty-one of these persons developed an incident colorectal adenoma, while there were four persons who developed an incident colorectal carcinoma. Compared to the lowest tertile of intake, adjusted HRs (95 % CIs) for CRT development in the highest tertile were 1.06 (0.59-1.91) for folate, 0.77 (0.39-1.51) for vitamin B2, 0.98 (0.59-1.62) for vitamin B6, 1.24 (0.77-2.00) for vitamin B12, and 1.36 (0.83-2.20) for methionine. Low vitamin B2 and low methionine intake were statistically significantly associated with an increased risk of CRT in MTHFR 677TT individuals compared to a combined reference of persons with low intake and CC genotype.
There was no suggestion that intake of any dietary B vitamin or methionine was associated with CRT development among those with LS.
Cancer Causes and Control 06/2014; 25(9). DOI:10.1007/s10552-014-0412-4 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family.
Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2014-102284 · 6.34 Impact Factor