Background & Aims MUTYH -associated polyposis (MAP) is characterized by a lifetime risk of colorectal cancer of up to 100%. However, no systematic evaluation of extracolonic manifestations has been ...reported. Methods A large cohort of MAP patients was recruited from a European multicenter study. Data were collected on 276 cases from 181 unrelated families. Information on extracolonic tumor spectrum and incidence were evaluated to determine cumulative lifetime risk, which was compared with that of the general population to obtain standardized incidence ratios (SIRs). Results Duodenal polyposis occurred in 17% of cases; the relative risk (SIR) of duodenal cancer was 129 (95% confidence interval CI: 16–466), whereas the lifetime risk was 4%. The incidence of extraintestinal malignancies among cases was almost twice that of the general population (SIR: 1.9; 95% CI: 1.4–2.5), with a lifetime risk of 38%. We observed a significant increase in the incidence of ovarian, bladder, and skin cancers (SIR: 5.7, 7.2, and 2.8, respectively) and a trend of increased risk of breast cancer among cases. The median ages of onset of these 4 malignancies ranged from 51 to 61 years. In contrast to familial adenomatous polyposis, no desmoid tumors were observed, but sebaceous gland tumors, characteristic of the Muir-Torre variant of Lynch syndrome, occurred in 5 patients. Conclusions The relative risks for several extraintestinal malignancies increased in patients with MAP, but based on the spectrum of cancers (which overlaps with that of Lynch syndrome) and the relatively advanced age at onset, intensive surveillance measures other than frequent endoscopy are unlikely to be helpful to patients with MAP.
Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to ...provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6.
Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk.
The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers.
The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
Background Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer ...predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer. Methods Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families). Results We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair. Conclusion Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes. Keywords: Pancreatic cancer, Genetic predisposition, Whole exome sequencing, DNA damage repair genes
Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, ...occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.
Abstract
Context
Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal ...and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series.
Objective
To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT.
Design
Nationwide retrospective Dutch cohort study.
Setting
Tertiary referral center.
Patients
We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers.
Investigation
Germline CDC73 mutation analysis.
Mean Outcome
CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance.
Results
Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism–jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers.
Conclusions
Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.
Germline CDC73 mutations were frequently found in young patients with primary hyperparathyroidism and those presenting with parathyroid carcinoma and/or a positive family history.
Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, ...MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.
The switch/sucrose non-fermentable (SWI/SNF) subunit ARID1A (AT-rich interactive domain 1A gene) has been recently postulated as a novel tumor suppressor of gynecologic cancer and one of the driver ...genes in endometrial carcinogenesis. However, specific relationships with established molecular alterations in endometrioid endometrial cancer (EEC) are currently unknown. We analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry) and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), we included a 'Lynch syndrome set'. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in EECs in 31% (40/130) of the EEC cases. No loss of expression of the other subunits of the SWI/SNF complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P=0.0004). In contrast to Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14%) of the 'Lynch syndrome set' as compared with 24 cases (75%, P<0.0001) of the sporadic microsatellite-unstable tumors showed loss of ARID1A. These observations suggest that ARID1A is a causative gene, instead of a target gene, of microsatellite instability by having a role in epigenetic silencing of the MLH1 gene in endometrial cancer.
Background & Aims Surveillance of high-risk groups for pancreatic cancer might increase early detection and treatment outcomes. Individuals with germline mutations in p16-Leiden have a lifetime risk ...of 15% to 20% of developing pancreatic cancer. We assessed the feasibility of detecting pancreatic cancer at an early stage and investigated the outcomes of patients with neoplastic lesions. Methods Individuals with germline mutations in p16-Leiden (N = 79; 31 male; mean age, 56 years; range, 39–72 years) were offered annual surveillance by magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP). Those found to have neoplastic lesions were offered options for surgery or intensive follow-up. Individuals found to have possible neoplastic lesions were examined again by MRI/MRCP within 2 to 4 months. Results After a median follow-up period of 4 years (range, 0–10 years), pancreatic cancer was diagnosed in 7 patients (9%). The mean age at diagnosis was 59 years (range, 49–72 years). Three of the tumors were present at the first examination, and 4 were detected after a negative result in the initial examination. All 7 patients had a resectable lesion; 5 underwent surgery, 3 had an R0 resection, and 2 had lymph node metastases. Possible precursor lesions (ie, duct ectasias, based on MRCP) were found in 9 individuals (11%). Conclusions MRI/MRCP detects small, solid pancreatic tumors and small duct ectasias. Although surveillance increases the rate of resectability, carriers of a p16-Leiden mutation develop agressive tumors.
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10–40% of melanoma‐prone families. In our study we comprehensively characterized 488 ...melanoma cases from 451 non‐CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom‐designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1‐families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88–4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non‐CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.
What's new?
Germline mutations in CDKN2A are major contributors to familial melanoma. These mutations, however, are responsible for only 10 to 40 percent of genetic susceptibility in melanoma‐prone families. In this study, 30 established and candidate melanoma susceptibility genes were investigated for associations with the disease in patients from 451 non‐CDKN2A/CDK4 melanoma families. From the candidate gene panel, (likely) pathogenic variants in BAP1 and MITF were identified in several families, and potentially deleterious variants were identified in the shelterin complex genes ACD and TERF2IP. These genes appear to play a significant role in familial melanoma predisposition and are therefore promising candidates for incorporation into comprehensive genetic tests.
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