{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMLH1 is a critical component of the DNA mismatch repair (MMR) system that preserves genomic stability by recognizing and repairing base–base mismatches and small insertion–deletion loops. Its proper function is essential not only for the correction of replication errors but also for initiating cell‐cycle arrest in response to DNA damage. Loss of MLH1 activity by germline mutations or by promoter hypermethylation thereby leads to microsatellite instability, a hallmark of Lynch syndrome and a variety of sporadic tumors, ultimately predisposing affected individuals to colorectal, endometrial, and several other malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its repair function, aberrant regulation of MLH1 through epigenetic mechanisms such as promoter hypermethylation plays a pivotal role in tumorigenesis and influences treatment response. Epigenetic silencing of MLH1 has been demonstrated as both a somatic event in sporadic cancers and, in rare cases, as a constitutional or mosaic germline epimutation that phenocopies genetic defects. The loss of MLH1 expression is frequently used as a biomarker in molecular screening strategies of Lynch syndrome, where its inactivation correlates with microsatellite instability, altered drug sensitivity (notably to agents such as cisplatin), and impaired recruitment in DNA damage response pathways. Furthermore, MLH1’s interaction with other repair partners—notably the helicase FANCJ—underscores its broader role in coordinating repair processes and shaping the tumor microenvironment, including immune responses elicited via cytosolic DNA sensing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its molecular role in DNA repair and epigenetic regulation, MLH1 status is central to clinical risk assessment, genetic testing, and the management of patients predisposed to cancer. Systematic screening for MLH1 mutations and promoter methylation facilitates the identification of Lynch syndrome and related “Lynch‐like” cases, thereby informing surveillance protocols for colorectal, endometrial, gastric, ovarian, urinary tract, and even breast cancers. Genetic and epigenetic alterations in MLH1 are further associated with variable penetrance and diverse tumor spectra, emphasizing its utility as a predictive biomarker for both inherited susceptibility and acquired tumor behavior. Studies also highlight the significance of aberrant splicing and rare missense variants in MLH1 that contribute to disease, underscoring the gene’s multifaceted role in carcinogenesis and the tailoring of personalized therapeutic approaches."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}, {"type": "fg_fs", "start_ref": "30", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Valérie Bonadona, Bernard Bonaïti, Sylviane Olschwang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JAMA (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/jama.2011.743"}], "href": "https://doi.org/10.1001/jama.2011.743"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21642682"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21642682"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Heather Hampel, Wendy Frankel, Jenny Panescu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-1114"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-1114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16885385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16885385"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Fay Kastrinos, Bhramar Mukherjee, Nabihah Tayob, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Risk of pancreatic cancer in families with Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JAMA (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/jama.2009.1529"}], "href": "https://doi.org/10.1001/jama.2009.1529"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19861671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19861671"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Rebecca A Barnetson, Albert Tenesa, Susan M Farrington, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa053493"}], "href": "https://doi.org/10.1056/NEJMoa053493"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16807412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16807412"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "H F Vasen, A Stormorken, F H Menko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2001.19.20.4074"}], "href": "https://doi.org/10.1200/JCO.2001.19.20.4074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11600610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11600610"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "E Domingo, P Laiho, M Ollikainen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2004.020651"}], "href": "https://doi.org/10.1136/jmg.2004.020651"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15342696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15342696"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Aung Ko Win, Joanne P Young, Noralane M Lindor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2011.39.5590"}], "href": "https://doi.org/10.1200/JCO.2011.39.5590"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22331944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22331944"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "E Barrow, L Robinson, W Alduaij, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2008.01125.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2008.01125.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19215248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19215248"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Petr Cejka, Lovorka Stojic, Nina Mojas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylation-induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/emboj/cdg216"}], "href": "https://doi.org/10.1093/emboj/cdg216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12727890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12727890"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Joy C Lin, Shinwu Jeong, Gangning Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2007.10.014"}], "href": "https://doi.org/10.1016/j.ccr.2007.10.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17996647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17996647"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "M Koopman, G A M Kortman, L Mekenkamp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficient mismatch repair system in patients with sporadic advanced colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6604867"}], "href": "https://doi.org/10.1038/sj.bjc.6604867"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19165197"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19165197"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Catherine M Suter, David I K Martin, Robyn L Ward "}, {"type": "b", "children": [{"type": "t", "text": "Germline epimutation of MLH1 in individuals with multiple cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1342"}], "href": "https://doi.org/10.1038/ng1342"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15064764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15064764"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Shuji Ogino, Takako Kawasaki, Gregory J Kirkner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Diagn (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/jmoldx.2007.060170"}], "href": "https://doi.org/10.2353/jmoldx.2007.060170"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17591929"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17591929"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "J M Cunningham, C Y Kim, E R Christensen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/323658"}], "href": "https://doi.org/10.1086/323658"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11524701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11524701"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Elena Stoffel, Bhramar Mukherjee, Victoria M Raymond, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2009.07.039"}], "href": "https://doi.org/10.1053/j.gastro.2009.07.039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19622357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19622357"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Arjen R Mensenkamp, Ingrid P Vogelaar, Wendy A G van Zelst-Stams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2013.12.002"}], "href": "https://doi.org/10.1053/j.gastro.2013.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24333619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24333619"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jörg Felsberg, Niklas Thon, Sabina Eigenbrod, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.26083"}], "href": "https://doi.org/10.1002/ijc.26083"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21425258"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21425258"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Michael T Parsons, Daniel D Buchanan, Bryony Thompson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmedgenet-2011-100714"}], "href": "https://doi.org/10.1136/jmedgenet-2011-100714"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22368298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22368298"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "C Zeller, W Dai, N L Steele, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2011.611"}], "href": "https://doi.org/10.1038/onc.2011.611"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22249249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22249249"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Gillian Gifford, Jim Paul, Paul A Vasey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-03-0732"}], "href": "https://doi.org/10.1158/1078-0432.CCR-03-0732"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15240532"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15240532"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Changzheng Lu, Junhong Guan, Steve Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2020.11.006"}], "href": "https://doi.org/10.1016/j.ccell.2020.11.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33338425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33338425"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Kentaro Yamashita, Tomoko Dai, Yuichi Dai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetics supersedes epigenetics in colon cancer phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1535-6108(03)00190-9"}], "href": "https://doi.org/10.1016/s1535-6108(03"}, {"type": "t", "text": "00190-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12957287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12957287"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Min Peng, Rachel Litman, Jenny Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7601754"}], "href": "https://doi.org/10.1038/sj.emboj.7601754"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17581638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17581638"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Francesco Perri, Rosa Cotugno, Ada Piepoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Gastroenterol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1572-0241.2007.01284.x"}], "href": "https://doi.org/10.1111/j.1572-0241.2007.01284.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17509026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17509026"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Renée C Niessen, Robert M W Hofstra, Helga Westers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20678"}], "href": "https://doi.org/10.1002/gcc.20678"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19455606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19455606"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "J P Terdiman, J R Gum, P G Conrad, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/gast.2001.20874"}], "href": "https://doi.org/10.1053/gast.2001.20874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11208710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11208710"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Megan Hitchins, Rachel Williams, Kayfong Cheong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2005.09.003"}], "href": "https://doi.org/10.1053/j.gastro.2005.09.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16285940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16285940"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "C F Taylor, R S Charlton, J Burn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.10291"}], "href": "https://doi.org/10.1002/humu.10291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14635101"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14635101"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Megan P Hitchins, Robert W Rapkins, Chau-To Kwok, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.07.003"}], "href": "https://doi.org/10.1016/j.ccr.2011.07.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21840485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21840485"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Heikki J Järvinen, Laura Renkonen-Sinisalo, Katja Aktán-Collán, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2009.23.7784"}], "href": "https://doi.org/10.1200/JCO.2009.23.7784"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19720893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19720893"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "James G Dowty, Aung K Win, Daniel D Buchanan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cancer risks for MLH1 and MSH2 mutation carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.22262"}], "href": "https://doi.org/10.1002/humu.22262"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23255516"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23255516"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Melissa C Southey, Mark A Jenkins, Leeanne Mead, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2005.04.671"}], "href": "https://doi.org/10.1200/JCO.2005.04.671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16116158"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16116158"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Hans F A Vasen, Mohamed Abdirahman, Richard Brohet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2010.02.053"}], "href": "https://doi.org/10.1053/j.gastro.2010.02.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20206180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20206180"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Daniel D Buchanan, Yen Y Tan, Michael D Walsh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2013.51.2129"}], "href": "https://doi.org/10.1200/JCO.2013.51.2129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24323032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24323032"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "María Rodríguez-Soler, Lucía Pérez-Carbonell, Carla Guarinos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Risk of cancer in cases of suspected lynch syndrome without germline mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2013.01.044"}], "href": "https://doi.org/10.1053/j.gastro.2013.01.044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23354017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23354017"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Lisette G Capelle, Nicole C T Van Grieken, Hester F Lingsma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2009.10.051"}], "href": "https://doi.org/10.1053/j.gastro.2009.10.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19900449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19900449"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Nicola S Fearnhead, Jennifer L Wilding, Bruce Winney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0407187101"}], "href": "https://doi.org/10.1073/pnas.0407187101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15520370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15520370"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Kristina Lagerstedt Robinson, Tao Liu, Jana Vandrovcova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Natl Cancer Inst (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jnci/djk051"}], "href": "https://doi.org/10.1093/jnci/djk051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17312306"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17312306"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Tasha R Smith, Edward A Levine, Rita I Freimanis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgn193"}], "href": "https://doi.org/10.1093/carcin/bgn193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18701435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18701435"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "R S van der Post, L A Kiemeney, M J L Ligtenberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2010.076992"}], "href": "https://doi.org/10.1136/jmg.2010.076992"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20591884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20591884"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Isabelle Tournier, Myriam Vezain, Alexandra Martins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.20796"}], "href": "https://doi.org/10.1002/humu.20796"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18561205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18561205"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Henry T Lynch, Murray Joseph Casey, Carrie L Snyder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molonc.2009.02.004"}], "href": "https://doi.org/10.1016/j.molonc.2009.02.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19383374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19383374"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Brandie Heald, Thomas Plesec, Xiuli Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2012.45.1674"}], "href": "https://doi.org/10.1200/JCO.2012.45.1674"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23401454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23401454"}]}]}]}