{"doi":"10.1053/j.gastro.2023.06.032","title":"Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes","abstract":"An important subset of colorectal cancer (CRC) is caused by rare pathogenic variants in more than 20 high-risk genes,1Huyghe J.R. Bien S.A. Harrison T.A. et al.Nat Genet. 2019; 51: 76-87Crossref PubMed Scopus (265) Google Scholar, 2Seifert B.A. McGlaughon J.L. Jackson S.A. et al.Genet Med. 2019; 21: 1507-1516Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 3Belhadj S. Terradas M. Munoz-Torres P.M. et al.Hum Mutat. 2020; 41: 1563-1576Crossref PubMed Scopus (23) Google Scholar The National Comprehensive Cancer Network clinical practice guidelines (2022) recommend that physicians consider multigene panel testing for these high-risk genes in all newly diagnosed CRC patients2Seifert B.A. McGlaughon J.L. Jackson S.A. et al.Genet Med. 2019; 21: 1507-1516Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,3Belhadj S. Terradas M. Munoz-Torres P.M. et al.Hum Mutat. 2020; 41: 1563-1576Crossref PubMed Scopus (23) Google Scholar to identify carriers of pathogenic variants and promote testing of family members who may also be carriers and would benefit from increased screening for CRC prevention. However, clinical challenges remain, such as (1) understanding the risk of CRC associated with individual variants within high-risk genes and (2) for recessively inherited CRC genes, where both alleles of the gene are defective (biallelic) because of the same pathogenic variant (homozygous carriers) or 2 different pathogenic variants (compound heterozygote carriers), understanding if CRC risk is increased if only 1 pathogenic variant is present (monoallelic carriers). Research addressing these challenges will improve clinical actionability regarding the intensity of screening and surveillance for carriers. We combined genetic data from 58,998 CRC-affected individuals and 71,171 control individuals of European ancestry from 3 major CRC consortia, namely, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Cancer Transdisciplinary Study (CORECT), and the Colon Cancer Family Registry (CCFR)1Huyghe J.R. Bien S.A. Harrison T.A. et al.Nat Genet. 2019; 51: 76-87Crossref PubMed Scopus (265) Google Scholar (Supplementary Table 1). To enable analysis of rare genetic variants in this dataset, we used the largest available imputation panel based on whole-genome sequencing data from 97,256 samples in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) study4Consortium G.P. Abecasis G.R. Altshuler D. et al.Nature. 2010; 467: 1061-1073Crossref PubMed Scopus (6069) Google Scholar to impute variants into genome-wide array data for CRC-affected case and control individuals. We examined the association of variants with a minor allele frequency (MAF) of <0.001 in 22 moderate- to high-penetrance CRC genes.2Seifert B.A. McGlaughon J.L. Jackson S.A. et al.Genet Med. 2019; 21: 1507-1516Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar For the recessive CRC genes MUTYH, NTHL1, MSH3, and MBD4, we assessed the risk of CRC associated with biallelic or monoallelic carriers. If different variants within a gene increase CRC risk, testing all variants simultaneously can be more powerful; therefore, we conducted gene-based tests using the set-based Mixed-Effects Score Test (MiST).5Sun J. Zheng Y. Hsu L. Genet Epidemiol. 2013; 37: 334-344Crossref PubMed Scopus (91) Google Scholar Detailed methods are provided in the Supplementary Material. We investigated the association of single variants with CRC by modeling the variants as a log-additive effect, which is a more general model. Two significant variants were identified, the APC c.3920T>A:p.Ile1307Lys variant (odds ration [OR], 1.82; P =1.62 × 10–14), which is more common in the Ashkenazi Jewish population,6Stern H.S. Viertelhausen S. Hunter A.G. et al.Gastroenterology. 2001; 120: 392-400Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar and the c.1187G>A:p.Gly396Asp pathogenic variant in MUTYH (","journal":null,"year":2023,"id":354008,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9462,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":841821,"name":"Minta Thomas","orcid":"0000-0001-9337-7015","position":1,"is_corresponding":false},{"id":251137,"name":"Conghui Qu","orcid":"0000-0003-1927-6245","position":2,"is_corresponding":false},{"id":331257,"name":"Xiaoliang Wang","orcid":"0000-0001-5184-2935","position":3,"is_corresponding":false},{"id":90056,"name":"Jeroen R. 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