Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma

Abstract

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.

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

“…We performed WES on lymphocyte DNA from the 22 eoRCC probands, detecting candidate PGVs based on a candidate gene list that was developed in our prior studies ( (10); see (Supplementary Table 1) and Supplementary Materials and Methods). Briefly, the candidate gene list was developed by a comprehensive hypothesis-driven framework with the following assumptions: 1) genes involved in genome stability (using Gene Ontology terms such as DNA repair, DNA replication, DNA damage checkpoints, cell cycle, mitotic machinery, replication stress, DNA damage response, chromatin remodeling) would be important for hereditary cancer risk (5,(11)(12)(13); and 2) an expanded network of genes relevant to renal biology (such as cellular metabolism) and genes somatically mutated in RCC that might be relevant for eoRCC-predisposition (5,11,13).…”

Application Areas of Traditional Molecular Genetic Methods and NGS in relation to Hereditary Urological Cancer Diagnosis

“…is enables possible determination of a causative mutation in the minor candidate gene not described earlier or identification of combinations of germline mutations in several of these genes in families with a history of renal carcinoma. For example, sequencing of an exome from siblings in a family with papillary thyroid cancer and clear cell RCC revealed a combination of the SDHA heterozygous mutation along with mutations in the TGFB2 and PARP1 genes [58]. In another family, hereditary renal carcinoma with areas of angioleiomyomatous stroma was described as an atypical variant of the manifestation of the TSC2 missense mutation [59].…”

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

“…Likewise, TRAP1 appears to be protective in genetic models of neurodegeneration such as Parkinson’s disease [ 27 , 28 , 39 ] where protein quality control in mitochondria plays a critical role [ 40 ]. TRAP1 was also shown to be mitoprotective in models of kidney fibrosis and renal cell carcinoma [ 41 , 42 ]. Finally, loss-of-function TRAP1 mutations have been identified in the brain of a patient with Parkinson’s disease [ 43 ], Leigh syndrome [ 44 ], and chronic functional symptomatology including pain, fatigue, and gastrointestinal dysmotility [ 45 ], and in congenital abnormalities associated with the kidney (CAKUT) [ 46 ].…”