FCCC LOGO Faculty Publications
Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma
Mol Genet Genomic Med. 2019 Mar;7(3) :e556
PMID: 30680959    PMCID: PMC6418363    URL: https://www.ncbi.nlm.nih.gov/pubmed/30680959
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BACKGROUND: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. METHODS: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole-exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members. RESULTS: This work identified multiple predicted protein-damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband. CONCLUSION: Together, these data suggest the possibility of risk associated with interaction of two or more variants.
2324-9269 Nicolas, Emmanuelle Demidova, Elena V Iqbal, Waleed Serebriiskii, Ilya G Vlasenkova, Ramilia Ghatalia, Pooja Zhou, Yan Rainey, Kim Forman, Andrea F Dunbrack, Roland L Jr ORCID: http://orcid.org/0000-0001-7674-6667 Golemis, Erica A Hall, Michael J Daly, Mary B Arora, Sanjeevani ORCID: http://orcid.org/0000-0002-8273-589X R01 DK108195/GF/NIH HHS/United States P30 CA006927/BC/NCI NIH HHS/United States R35 GM122517/GF/NIH HHS/United States R01 DK108195/DK/NIDDK NIH HHS/United States T32 CA009035/BC/NCI NIH HHS/United States R35 GM122517/GM/NIGMS NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States Russian Government to Kazan Federal University T32 CA009035/CA/NCI NIH HHS/United States Journal Article United States Mol Genet Genomic Med. 2019 Mar;7(3):e556. doi: 10.1002/mgg3.556. Epub 2019 Jan 24.