title: Mismatch repair deficiency testing in clinical practice.
abstract: Lynch syndrome, an autosomal dominant inherited disorder, is caused by inactivating mutations involving DNA mismatch repair (MMR) genes. This leads to profound genetic instability, including microsatellite instability (MSI) and increased risk for cancer development, particularly colon and endometrial malignancies. Clinical testing of tumor tissues for the presence of MMR gene deficiency is standard practice in clinical oncology, with immunohistochemistry and PCR-based microsatellite instability analysis used as screening tests to identify potential Lynch syndrome families. The ultimate diagnosis of Lynch syndrome requires documentation of mutation within one of the four MMR genes (MLH1, PMS2, MSH2 and MSH6) or EPCAM, currently achieved by comprehensive sequencing analysis of germline DNA. In this review, the genetic basis of Lynch syndrome, methodologies of MMR deficiency testing, and current diagnostic algorithms in the clinical management of Lynch syndrome, are discussed.
authors.affiliation: a Department of Pathology, School of Medicine , Yale University , New Haven , CT , USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.affiliation: b Genentech Inc ., San Francisco , CA , USA.
authors.forename: James
authors.initials: J
authors.lastname: Ziai
authors.affiliation: a Department of Pathology, School of Medicine , Yale University , New Haven , CT , USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003110:Colonic Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D051718:MutS Homolog 2 Protein / Q000235:genetics
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: Colorectal and Endometrial cancers; DNA mismatch repair gene; Lynch syndrome; Microsatellite instability