Key points are not available for this paper at this time.
See editorial on page 20. See editorial on page 20. Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome and is caused by pathogenic constitutional variants in 1 of the mismatch repair (MMR) genes, including MLH1, MSH2 (EPCAM), MSH6, and PMS2. Although generally referred to as 1 entity, LS exhibits a highly heterogeneous phenotype, exemplified by major differences in cancer penetrance between MMR gene variant carriers.1Helderman N.C. et al.Crit Rev Oncol Hematol. 2021; 163103338Crossref PubMed Scopus (10) Google Scholar These differences imply that the quality of colonoscopy, optimal surveillance intervals, treatment, preventive strategies, and other aspects of care likely differ between LS subgroups. Nevertheless, in most countries all (newly) diagnosed LS patients are subject to identical screening and treatment regimes. The study of LS CRC molecular profiles will improve our understanding of phenotypic heterogeneity and may in turn stimulate the development of gene-specific guidelines. Because previous molecular studies focused predominantly on MLH1-, MSH2-, and PMS2-associated CRCs, our study aimed to define the molecular profile of MSH6-associated CRCs relative to other LS CRCs. The study included 106 confirmed LS CRCs, of which 44 (25 MSH6-, 5 MLH1-, 5 MSH2-, and 9 PMS2-associated CRCs) were analyzed by whole exome sequencing (WES) and 62 (24 MLH1-, 18 MSH2-, and 20 PMS2-associated CRCs) by a cancer hotspot panel (CHP) described previously.2Ten Broeke S.W. et al.Gastroenterology. 2018; 155: 844-851Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar For a full description of the materials and methods used, refer to the Supplementary Methods. A description of the total cohort, consisting of both WES and CHP cohorts, is presented in Supplementary Table 1. A full description of all available histologic and molecular characteristics (including constitutional MMR and somatic variants) for each analyzed LS CRC is presented in Supplementary Table 2. Although the overall variant spectra of MSH6-, MLH1-, MSH2-, and PMS2-associated CRCs look similar, notable differences exist. These include the higher (P 1:7 between both strands were not considered. Finally, variants were classified according to the American College of Medical Genetics and Genomics recommendations for variant interpretation using Franklin.13https://franklin.genoox.com/clinical-db/homeGoogle Scholar,14Richards C.S. et al.Genet Med. 2008; 10: 294-300Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar Variants reported in this study classify as variants of unknown significance, likely pathogenic or pathogenic, and in addition have a combined annotation-dependent depletion score higher than 20, indicating they are considered to be in the top 1% of possibly pathogenic variants.15Rentzsch P. et al.Nucleic Acids Res. 2019; 47: D886-D894Crossref PubMed Scopus (1829) Google Scholar LOH of the MMR genes was manually curated with the use of Integrative Genomics Viewer.12Robinson J.T. et al.Nat Biotechnol. 2011; 29: 24-26Crossref PubMed Scopus (8762) Google Scholar LOH was considered when the variant allele frequency of the germline MMR variant differed ≥20% between tumor and normal tissue or when at least 4 of 10 randomly assessed single-nucleotide polymorphisms, located both upstream and downstream of the MMR variant, showed a variant allele frequency difference of ≥20% between tumor and normal tissue. Mutational signatures were extracted from the WES data to score the overall contribution of dMMR to the total number of variants in each LS CRC of the WES cohort, using SigProfiler and the SigProfiler reference mutational signatures.16Alexandrov L.B. et al.Nature. 2020; 578: 94-101Crossref PubMed Scopus (1568) Google Scholar The SNV mutational signatures SBS6, SBS15, SBS20, SBS21, SBS26, and SBS44 and the INDEL mutational signatures ID1, ID2, and ID7 were considered dMMR signature-associated. SBS1, SBS5, and SBS40 were considered to be L.B. et al.Nature. 2020; 578: 94-101Crossref PubMed Scopus (1568) Google Scholar, L.B. et al.Nature. PubMed Scopus Google Scholar, 2020; of Genomes PubMed Scopus Google Scholar, et al.Nucleic Acids Res. 2019; 47: PubMed Scopus Google Scholar, M. et Cancer Res. 2021; PubMed Scopus Google Scholar For each gene with at least 5 variants in the combined WES and CHP cohorts, we the of dMMR signature-associated variants to the of mutational SNVs were considered dMMR signature-associated when they involved at or with L.B. et al.Nature. 2020; 578: 94-101Crossref PubMed Scopus (1568) Google Scholar, L.B. et al.Nature. PubMed Scopus Google Scholar, 2020; of Genomes PubMed Scopus Google Scholar, et al.Nucleic Acids Res. 2019; 47: PubMed Scopus Google Scholar, M. et Cancer Res. 2021; PubMed Scopus Google Scholar INDELs were considered dMMR signature-associated if they involved single-nucleotide INDELs sequences with ID1, ID2, and L.B. et al.Nature. 2020; 578: 94-101Crossref PubMed Scopus (1568) Google Scholar, L.B. et al.Nature. PubMed Scopus Google Scholar, 2020; of Genomes PubMed Scopus Google Scholar, et al.Nucleic Acids Res. 2019; 47: PubMed Scopus Google Scholar, M. et Cancer Res. 2021; PubMed Scopus Google Scholar were performed using for and for are presented as and were compared using the test or test are presented as and were compared using test or test were compared between MSH6-associated CRCs vs MLH1-, MSH2-, or PMS2-associated CRCs, and P were for the number of comparisons and using & for In the combined WES and CHP data variants observed in the WES cohort were if the was in the The latter not for the gene-based signature analysis. P in this are and considered when P < Cancer for cancer (CRC) was of to be and the of events involved in the and progression of CRC are well in and data have to an to molecular of CRC in including instability and PDF Lynch A Cancer or by syndrome is the most common of hereditary cancer 1 in This to cancer is caused by or germline pathogenic in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In constitutional of MLH1 or MSH2 to an is also the specific patients with Lynch syndrome identical clinical management in most PDF
Helderman et al. (Wed,) studied this question.