Abstract
Germline variants inactivating the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome that implies an increased cancer risk, where colon and endometrial cancer are the most frequent. Identification of these pathogenic variants is important to identify endometrial cancer patients with inherited increased risk of new cancers, in order to offer them lifesaving surveillance. However, several other genes are also part of the MMR pathway. It is therefore relevant to search for variants in additional genes that may be associated with cancer risk by including all known genes involved in the MMR pathway. Next-generation sequencing was used to screen 22 genes involved in the MMR pathway in constitutional DNA extracted from full blood from 199 unselected endometrial cancer patients. Bioinformatic pipelines were developed for identification and functional annotation of variants, using several different software tools and custom programs. This facilitated identification of 22 exonic, 4 UTR and 9 intronic variants that could be classified according to pathogenicity. This study has identified several germline variants in genes of the MMR pathway that potentially may be associated with an increased risk for cancer, in particular endometrial cancer, and therefore are relevant for further investigation. We have also developed bioinformatics strategies to analyse targeted sequencing data, including low quality data and genomic regions outside of the protein coding exons of the relevant genes.
Highlights
Cancer is a life-threatening disease, with 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018 [1]
These low-quality data were not suitable for identification of copy number variants, and CNV calling was not included in the final analysis
In this study we found 35 significant variants (22 exonic, 4 UTR, 9 intronic), with 15 variants in the 4 mismatch repair (MMR) genes known to cause Lynch syndrome (LS) (MLH1, MSH2, MSH6, PMS2) and 20 in the additional MMR genes included in this study (MSH3, POLD1, RFC1, RFC3, RFC4, LIG1, EXO1, RPA1, RPA3)
Summary
Cancer is a life-threatening disease, with 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018 [1]. There is an increasing number of cases every year, and it has become an enormous burden to society. With longer life span, increased population and changed lifestyle, we can expect to have even more cases of cancer in the future. Targeted sequencing of genes associated with endometrial cancer funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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