{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:46:46Z","timestamp":1792043206058,"version":"4.4.0"},"reference-count":62,"publisher":"Harborside Press, LLC","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Most mismatch repair\u2013deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic <jats:italic>MLH1<\/jats:italic> methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of <jats:italic>MLH1<\/jats:italic> methylation in MMRd tumors to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional <jats:italic>MLH1<\/jats:italic> methylation (epimutation), a poorly recognized mechanism for LS. We aimed to assess the frequency and age distribution of constitutional <jats:italic>MLH1<\/jats:italic> methylation among incident CRC cases with MMRd, <jats:italic>MLH1<\/jats:italic>-methylated tumors. <jats:bold>Methods:<\/jats:bold> In retrospective population-based studies, we selected all CRC cases with MMRd, <jats:italic>MLH1<\/jats:italic>-methylated tumors, regardless of age, prior cancer, family history, or <jats:italic>BRAF<\/jats:italic> V600E status, from the Columbus-area HNPCC study (Columbus) and Ohio Colorectal Cancer Prevention Initiative (OCCPI) cohorts. Blood DNA was tested for constitutional <jats:italic>MLH1<\/jats:italic> methylation by pyrosequencing and real-time methylation-specific PCR, then confirmed with bisulfite-sequencing. <jats:bold>Results:<\/jats:bold> Results were achieved for 95 of 98 Columbus cases and all 281 OCCPI cases. Constitutional <jats:italic>MLH1<\/jats:italic> methylation was identified in 4 of 95 (4%) Columbus cases, ages 34, 38, 52, and 74 years, and 4 of 281 (1.4%) OCCPI cases, ages 20, 34, 50, and 55 years, with 3 showing low-level mosaic methylation. Mosaicism in blood and normal colon, plus tumor loss of heterozygosity of the unmethylated allele, demonstrated causality in 1 case with sample availability. Age stratification showed high rates of constitutional <jats:italic>MLH1<\/jats:italic> methylation among younger patients. In the Columbus and OCCPI cohorts, respectively, these rates were 67% (2 of 3) and 25% (2 of 8) of patients aged &lt;50 years but with half of the cases missed, and 75% (3 of 4) and 23.5% (4 of 17) of patients aged \u226455 years with most cases detected. <jats:bold>Conclusions:<\/jats:bold> Although rare overall, a significant proportion of younger patients with <jats:italic>MLH1<\/jats:italic>-methylated CRC had underlying constitutional <jats:italic>MLH1<\/jats:italic> methylation. Routine testing for this high-risk mechanism is warranted in patients aged \u226455 years for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimizing additional testing.<\/jats:p>","DOI":"10.6004\/jnccn.2023.7020","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T19:48:35Z","timestamp":1689104915000},"page":"743-752.e11","source":"Crossref","is-referenced-by-count":34,"title":["Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair\u2013Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger"],"prefix":"10.6004","volume":"21","author":[{"given":"Megan P.","family":"Hitchins","sequence":"first","affiliation":[{"name":"Bioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California"},{"name":"Department of Medicine (Oncology), Stanford University, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela","family":"D\u00e1maso","sequence":"additional","affiliation":[{"name":"Department of Medicine (Oncology), Stanford University, Stanford, California"},{"name":"Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), ONCOBELL Program, L\u2019Hospitalet de Llobregat, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Bioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zhou","sequence":"additional","affiliation":[{"name":"Bioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Medicine (Oncology), Stanford University, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcio A.","family":"Diniz","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Research Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Pineda","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), ONCOBELL Program, L\u2019Hospitalet de Llobregat, Barcelona, Spain"},{"name":"Consortium for Biomedical Research in Cancer \u2013 CIBERONC, Carlos III Institute of Health, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Capella","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), ONCOBELL Program, L\u2019Hospitalet de Llobregat, Barcelona, Spain"},{"name":"Consortium for Biomedical Research in Cancer \u2013 CIBERONC, Carlos III Institute of Health, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Pearlman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ohio State University, Columbus, Ohio"},{"name":"The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Hampel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ohio State University, Columbus, Ohio"},{"name":"The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio"},{"name":"Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"B1","series-title":"Cell","first-page":"1227","article-title":"Hypermutability and mismatch repair deficiency in RER+ tumor cells","volume":"75","author":"Parsons R","year":"1993","unstructured":"Parsons R, Li GM, Longley MJ,  Hypermutability and mismatch repair deficiency in RER+ tumor cells. 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