Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer
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Published:2022-05-13
Issue:4
Volume:297
Page:965-979
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ISSN:1617-4615
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Container-title:Molecular Genetics and Genomics
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language:en
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Short-container-title:Mol Genet Genomics
Author:
Skopelitou Diamanto, Srivastava Aayushi, Miao Beiping, Kumar Abhishek, Dymerska Dagmara, Paramasivam Nagarajan, Schlesner Matthias, Lubinski Jan, Hemminki Kari, Försti Asta, Reddy Bandapalli ObulORCID
Abstract
AbstractAbout 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.
Funder
European Cooperation in Science and Technology Bundesministerium für Bildung und Forschung H2020 European Research Council Deutsches Krebsforschungszentrum (DKFZ)
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,General Medicine
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