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  • 1
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    Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis (2013)
    BMJ Publishing Group
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    Publication Date: 2013-12-19
    Description: Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH . However, in about 20–30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with 〉10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with 〉10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had 〉100 adenomas. Only two index patients (1%), both with 〉100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC , MUTYH , POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
    Keywords: Colon cancer
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
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    Functional analysis of MSH2 unclassified variants found in suspected Lynch syndrome patients reveals pathogenicity due to attenuated mismatch repair (2014)
    BMJ Publishing Group
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    Publication Date: 2014-03-18
    Description: Background Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome. Methods The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions. Results We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T〉G), MSH2-Q690E (c.2068C〉G) and MSH2-M813V (c.2437A〉G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects. Conclusions Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.
    Keywords: Molecular genetics, Colon cancer, Ethics
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 3
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    Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas (2012)
    BMJ Publishing Group
    Details
    Publication Date: 2012-06-19
    Description: Background CDKN2A -mutation carriers run a high risk of developing melanomas and have an increased risk of developing pancreatic cancer (PC). Familial PC (FPC) patients with a personal history or family history of melanomas are therefore offered CDKN2A -mutation analysis. In contrast, CDKN2A testing in FPC families without a history of melanomas is not generally recommended. The aim of this study was to evaluate the frequency of CDKN2A -mutations in FPC families without melanomas. Methods Data were gathered from PC family registers. FPC families were defined as families with clustering of PC without meeting diagnostic criteria of familial cutaneous malignant melanoma (familial CMM) or other inherited cancer syndromes. Blood samples were obtained for DNA isolation from PC patients or first degree relatives and analysed for CDKN2A -mutations. Results Among 40 FPC families, DNA analyses were carried out in 28 families (70%), leading to identification of CDKN2A -mutations in six families (21%). None of the CDKN2A -mutation-positive families fulfilled the diagnostic criteria for familial CMM and in three CDKN2A families no melanomas were observed. Two CDKN2A -mutations were found; the Dutch founder mutation p16-Leiden (c.225_243del, p.Ala76fs) and the c.19_23dup, p.Ser8fs-mutation. After disclosure of the CDKN2A -mutation in one of the families, a curable melanoma was diagnosed at dermatological surveillance in a 17-year-old family member. Conclusion CDKN2A -mutation can be found in a considerable proportion of families with FPC. CDKN2A -mutation analysis should therefore be included in genetic testing in FPC families, even in the absence of reported melanomas. This strategy will enhance the recognition of individuals at risk for PC and facilitate the early detection of melanomas.
    Keywords: Pancreas and biliary tract, Skin cancer, Screening (oncology), Dermatology
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
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    Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance (2012)
    BMJ Publishing Group
    Details
    Publication Date: 2012-12-14
    Description: Background Although Peutz-Jeghers syndrome (PJS) is known to be associated with pancreatic cancer (PC), estimates of this risk differ widely. This hampers counselling of patients and implementation of surveillance strategies. We therefore aimed to determine the PC risk in a large cohort of Dutch PJS patients. Methods PJS was defined by diagnostic criteria recommended by the WHO, a proven LKB1 mutation, or both. All patients with a presumptive diagnosis of pancreatic, ampullary or distal bile duct cancer were identified. Cases were reviewed clinically, radiologically and immunohistochemically. Cumulative PC risks were calculated by Kaplan-Meier analysis and relative risks by Poisson regression analysis. Results We included 144 PJS patients (49% male) from 61 families (5640 person years follow-up). Seven (5%) patients developed PC at a median age of 54 years. Four patients (3%) were diagnosed with distal bile duct (n=2) or ampullary cancer (n=2) at a median age of 55 years. The cumulative risk for PC was 26% (95% CI 4% to 47%) at age 70 years and relative risk was 76 (95% CI 36 to 160; p〈0.001). The cumulative risk for pancreatico-biliary cancer was 32% (95% CI 11% to 52%) at age 70 years, with a relative risk of 96 (95% CI 53 to 174; p〈0.001). Conclusions PJS patients have a highly increased risk for pancreatico-biliary cancer. Therefore, patients are eligible for surveillance within well defined research programmes to establish the benefit of such surveillance.
    Keywords: Pancreas and biliary tract, Dermatology, Epidemiology
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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