Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families
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.
|ISBN||2045-7634 (Electronic) 2045-7634 (Linking)|
|Authors||Talseth-Palmer, B. A.; Bauer, D. C.; Sjursen, W.; Evans, T. J.; McPhillips, M.; Proietto, A.; Otton, G.; Spigelman, A. D.; Scott, R. J.;|
|Publisher Name||Cancer Medicine|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26811195|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13991|