Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer
1
Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, 08036 Barcelona, Spain
2
Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
3
Institut de Recerca Biomedica (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
4
Pathology Department, Hospital Clínic, 08036 Barcelona, Spain
5
Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
6
Centre Nacional d’Anàlisi Genòmica-Centre de Regulació Genòmica (CNAG-CRG), Parc Científic de Barcelona, 08028 Barcelona, Spain
7
Gastroenterology Department, Hospital Donostia-Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Basque Country University (UPV/EHU), 20014 San Sebastián, Spain
8
Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitaria Galicia Sur, 32005 Ourense, Spain
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 362; https://doi.org/10.3390/cancers11030362
Received: 25 January 2019 / Revised: 8 March 2019 / Accepted: 9 March 2019 / Published: 13 March 2019
Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson’s two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.
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Keywords:
colorectal cancer; whole-exome sequencing; predisposition to disease; germline–tumor analysis; mutational signatures; computational genomics
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MDPI and ACS Style
Díaz-Gay, M.; Franch-Expósito, S.; Arnau-Collell, C.; Park, S.; Supek, F.; Muñoz, J.; Bonjoch, L.; Gratacós-Mulleras, A.; Sánchez-Rojas, P.A.; Esteban-Jurado, C.; Ocaña, T.; Cuatrecasas, M.; Vila-Casadesús, M.; Lozano, J.J.; Parra, G.; Laurie, S.; Beltran, S.; EPICOLON Consortium; Castells, A.; Bujanda, L.; Cubiella, J.; Balaguer, F.; Castellví-Bel, S. Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer. Cancers 2019, 11, 362.
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