title: Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families.
abstract: Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant.
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.|Centre for Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: Bente A
authors.initials: BA
authors.lastname: Talseth-Palmer
authors.affiliation: CSIRO Digital Productivity, Sydney, New South Wales, Australia.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Bauer
authors.affiliation: Department of Laboratory Medicine Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Sjursen
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.|Centre for Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Evans
authors.affiliation: Hunter Area Pathology Service, Pathology North, Hunter New England Area Health, Newcastle, New South Wales, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: McPhillips
authors.affiliation: Hunter Centre for Gynaecological Cancer, Hunter New England Area Health, Newcastle, New South Wales, Australia.|School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Proietto
authors.affiliation: Hunter Centre for Gynaecological Cancer, Hunter New England Area Health, Newcastle, New South Wales, Australia.|School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Otton
authors.affiliation: Hunter Family Cancer Service, Hunter New England Area Health, Newcastle, New South Wales, Australia.|St Vincent's Hospital Clinical School, University of NSW and Hospital Cancer Genetics Clinic, The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Spigelman
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.|Centre for Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|Hunter Area Pathology Service, Pathology North, Hunter New England Area Health, Newcastle, New South Wales, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D000328:Adult; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D055088:Early Detection of Cancer / Q000379:methods; D016889:Endometrial Neoplasms / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007438:Introns / Q000235:genetics; D008875:Middle Aged; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm
keywords: Cancer genetics; colorectal cancer; inherited cancer
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