MSI and IHC analysis are highly concordant in endometrial cancer. This holds true for cases with subclonal loss of MMR protein expression. Discordant MMR-proficient/MSI-high cases (<1%), may be explained by POLE-EDM variants.
Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.
Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPVnegative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P ¼ 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV þ , HPV À /p53wt, HPV À /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV þ , 16.3% for HPV À /p53wt and 22.6% for HPV À /p53abn tumors (P ¼ 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P ¼ 0.020).Conclusions: HPV À and HPV þ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV À /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV þ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.
Graphical Abstract Highlights d Biallelic germline NTHL1 mutations predispose to a multitumor syndrome d Biallelic germline NTHL1 mutation carriers are at risk for breast cancer d Tumors from NTHL1-deficient patients reveal a cross-cancer NTHL1-associated signature d Mutational signature analyses can assist to identify germline DNA repair defects
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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