{"doi":"10.1002/ijc.11415","title":"<i>MSH6</i> germline mutations are rare in colorectal cancer families","abstract":"<jats:title>Abstract</jats:title><jats:p>Germline mutations in <jats:italic>MSH6</jats:italic> can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease‐causing mutations of <jats:italic>MSH6</jats:italic> may or may not exhibit MSI. We used D‐HPLC to screen for germline mutations in the promoter region, the coding region and the 3′‐UTR of <jats:italic>MSH6</jats:italic>. Eighty‐four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC‐like families), were tested for MMR gene mutations; 27 families had a disease‐causing mutation in <jats:italic>MLH1</jats:italic> or <jats:italic>MSH2</jats:italic>, and the remaining 57 families were tested for mutations in <jats:italic>MSH6</jats:italic>. Two protein‐truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early‐onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease‐causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease‐causing germline mutations of <jats:italic>MSH6</jats:italic> are rare in HNPCC and HNPCC‐like families. © 2003 Wiley‐Liss, Inc.</jats:p>","journal":"International Journal of Cancer","year":2003,"id":595313,"datarank":0.5983476069846413,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.0,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":90710,"name":"Khedoudja Nafa","orcid":null,"position":1,"is_corresponding":false},{"id":1524352,"name":"Gabriel S. Lerman","orcid":null,"position":2,"is_corresponding":false},{"id":1524353,"name":"Emily Glogowski","orcid":null,"position":3,"is_corresponding":false},{"id":239557,"name":"Jinru Shia","orcid":"0000-0002-4351-2511","position":4,"is_corresponding":false},{"id":1524354,"name":"Tian Z. Ye","orcid":null,"position":5,"is_corresponding":false},{"id":239547,"name":"Arnold J. Markowitz","orcid":"0000-0002-5449-9623","position":6,"is_corresponding":false},{"id":239555,"name":"José G. Guillem","orcid":"0009-0002-3510-8276","position":7,"is_corresponding":false},{"id":1524355,"name":"Prema Kolachana","orcid":null,"position":8,"is_corresponding":false},{"id":1524356,"name":"Jeffrey A. Boyd","orcid":null,"position":9,"is_corresponding":false},{"id":108795,"name":"Kenneth Offit","orcid":"0000-0002-2180-2032","position":10,"is_corresponding":false},{"id":452934,"name":"Nathan A. Ellis","orcid":"0000-0003-4231-502X","position":11,"is_corresponding":false},{"id":374541,"name":"Paolo Peterlongo","orcid":"0000-0001-6951-6855","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<i>MSH6</i> germline mutations are rare in colorectal cancer families","abstract":"<jats:title>Abstract</jats:title><jats:p>Germline mutations in <jats:italic>MSH6</jats:italic> can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease‐causing mutations of <jats:italic>MSH6</jats:italic> may or may not exhibit MSI. We used D‐HPLC to screen for germline mutations in the promoter region, the coding region and the 3′‐UTR of <jats:italic>MSH6</jats:italic>. Eighty‐four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC‐like families), were tested for MMR gene mutations; 27 families had a disease‐causing mutation in <jats:italic>MLH1</jats:italic> or <jats:italic>MSH2</jats:italic>, and the remaining 57 families were tested for mutations in <jats:italic>MSH6</jats:italic>. Two protein‐truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early‐onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease‐causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease‐causing germline mutations of <jats:italic>MSH6</jats:italic> are rare in HNPCC and HNPCC‐like families. © 2003 Wiley‐Liss, Inc.</jats:p>","is_dataset_classified":null,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"14520694","pmcid":null,"openalex_id":"https://openalex.org/W2058843235","authors":[],"funders":[],"total_grants":0,"fwci":4.1874,"citation_percentile":0.94060606,"influential_citations":0,"citation_trend":[{"year":2012,"count":1},{"year":2013,"count":2},{"year":2014,"count":1},{"year":2015,"count":1},{"year":2016,"count":1},{"year":2017,"count":3},{"year":2023,"count":1}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.11415","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.11415","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fijc.11415","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.11415","host_type":"publisher"},{"url":"https://doi.org/10.1002/ijc.11415","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/14520694","host_type":"repository"}],"fields_of_study":["Genetic factors in colorectal cancer","Colorectal Cancer Screening and Detection","Cancer Genomics and Diagnostics","Adult","Chromatography, High Pressure Liquid","Colorectal Neoplasms, Hereditary Nonpolyposis","DNA Mutational Analysis","DNA Primers","DNA Repair","DNA-Binding Proteins","Endometrial Neoplasms","Exons","Family","Female","Genetic Linkage","Germ-Line Mutation","Humans","Immunoenzyme Techniques","Male","Middle Aged","MutS Homolog 2 Protein","Pedigree","Polymerase Chain Reaction","Proto-Oncogene Proteins"],"mesh_terms":["Adult","Chromatography, High Pressure Liquid","Colorectal Neoplasms, Hereditary Nonpolyposis","DNA Mutational Analysis","DNA Repair","DNA-Binding Proteins","Exons","Family","Female","Humans","Immunoenzyme Techniques","Genetic Linkage","Male","Middle Aged","Pedigree","Proto-Oncogene Proteins","Polymerase Chain Reaction","Endometrial Neoplasms","DNA Primers","Germ-Line Mutation","MutS Homolog 2 Protein"],"keywords":["MSH6","MSH2","MLH1","Germline mutation","Germline","Biology","Lynch syndrome","Cancer research","Genetics","Mutation","Colorectal cancer","Cancer","Medicine","DNA mismatch repair","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T17:11:06.951828Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}