Biallelic MUTYH mutations can mimic Lynch syndrome

Morak, Monika; Heidenreich, Barbara; Keller, Gisela; Hampel, Heather; Laner, Andreas; Chapelle, Albert de la; Holinski‐Feder, Elke

doi:10.1038/ejhg.2014.15

Cited by 93 publications

(78 citation statements)

References 31 publications

(45 reference statements)

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“…Eight of the eleven POLE-mutated tumours showed additional MSH6 somatic mutations, and of these, five cases also showed MSH2 mutations. 12 Moreover, MSI tumours with two somatic MSH2 mutations, lacking MSH2 and MSH6 protein expression, 22 or with loss of MLH1 protein staining in the tumour, [23][24][25] have also been reported for patients with bi-allelic variants in the base excision repair gene MUTYH. Similarly to POLE germline variants, MUTYH missense variants can also induce somatic mutations in MMR genes, although the mechanism behind the co-occurrence of mutations in the different DNA repair defects remains elusive.…”

Section: Resultsmentioning

confidence: 99%

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

et al. 2014

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Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C4G, p.(Leu424Val) and POLD1 c.1433G4A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant. INTRODUCTIONFaithful DNA replication and the repair of errors are both essential for the maintenance of genomic stability and suppression of carcinogenesis. 1 Duplication of genomes with high accuracy is achieved through three mechanisms: the high selectivity of DNA polymerases; exonucleolytic proofreading; and post replication mismatch repair. 2 The DNA polymerases ε (POLε) and δ (POLδ) are required for the efficient genome replication in the eukaryotic replication fork. 3 Their major component proteins, encoded by POLE and POLD1, respectively, possess an intrinsic 3′-5′ proofreading domain that removes incorrectly inserted nucleotides during DNA synthesis. [4][5][6][7][8][9] Studies in the yeast have shown that mutations in the proofreading domains of POLε or POLδ increase spontaneous mutation rates. 8,9 In addition, somatic mutations in the proofreading domains of POLD1 and POLE have been identified in microsatellite instable (MSI) and hypermutated subgroups of colorectal cancers (CRCs). [10][11][12] Recently, Palles et al reported that heterozygous germline variants in the proofreading domain of the DNA polymerases POLE and POLD1 predispose, with a high penetrance, to multiple colorectal adenomas, early onset CRC (OMIM #114500) and endometrial cancer (OMIM #608089). These variants were found by whole-genome sequencing and linkage analysis in three large families with a dominant pattern of CRC and multiple adenomas. 13 Subsequent screening of 3805 CRC patients revealed that these variants are relatively rare: POLE

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Section: Resultsmentioning

confidence: 99%

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

et al. 2014

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“…1, 8–12 Furthermore, there is increasing recognition that the wide phenotypic spectrum of LS cancers can overlap with other hereditary cancer syndromes. 13–16 Thus, traditional, criteria-based genetic testing may not be the ideal hereditary cancer risk assessment strategy in individuals with suspected LS.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome

et al. 2015

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Background & Aims Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. Methods We performed germline analysis with a 25-gene next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All subjects had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain significance (VUS). We also analyzed data on patients’ personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Results Of the 1260 subjects, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%–90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%−10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%−7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P=.0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. Four hundred seventy-nine individuals had ≥1 VUS (38%; 95% CI, 35%–41%). Conclusions In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients’ histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.

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“…The term, "Lynch syndrome mimic" (50) or "Lynch syndrome-like" (51) seems to be a synonym of "Lynch-like syndrome." It is also possible that LLS patients may represent a heterogeneous group between sporadic MMR-deficient CRC patients and true LS patients.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population

Chika

Eguchi

Kumamoto

et al. 2016

Japanese Journal of Clinical Oncology

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Objective: We investigated the prevalence of Lynch syndrome and Lynch-like syndrome among Japanese colorectal cancer patients, as there have been no credible data from Japan. Methods: Immunohistochemical analyses for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were carried out in surgically resected, formalin-fixed paraffin-embedded specimens obtained from 1,234 newly diagnosed colorectal cancer patients between March 2005 and April 2014. The presence/absence of the BRAF V600E mutation and hypermethylation of the MLH1 promoter was analyzed where necessary. Genetic testing was finally undertaken in patients suspected as having Lynch syndrome. Results: By the universal screening approach with immunohistochemical analysis for mismatch repair proteins followed by analyses for the BRAF V600E mutation and MLH1 promoter methylation status, 11 (0.9%) of the 1,234 patients were identified as candidates for genetic testing. Out of the 11 patients, 9 (0.7%) were finally diagnosed as having Lynch syndrome; the responsible genes included MLH1 (n = 1), MSH2 (n = 4), EPCAM (n = 1) and MSH6 (n = 3). The remaining two patients (0.2%) were regarded as having Lynch-like syndrome, since biallelic somatic deletion of the relevant mismatch repair genes was detected in the absence of germline mismatch repair alterations. None of the cases was identified as having germline MLH1 epimutation. Conclusions: The prevalence of Lynch syndrome among all newly diagnosed cases of colorectal cancer in Japan is in the same range as that recently reported by studies in Western population. The prevalence of Lynch-like syndrome seems to be extremely low.

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Biallelic MUTYH mutations can mimic Lynch syndrome

Cited by 93 publications

References 31 publications

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome

Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population

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