Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma

Carlo, Maria I.; Mukherjee, Semanti; Mandelker, Diana; Vijai, Joseph; Kemel, Yelena; Zhang, Liying; Knežević, Andrea; Patil, Sujata; Ceyhan‐Birsoy, Ozge; Huang, Kuo‐Cheng; Redzematovic, Almedina; Coskey, Devyn Taylor; Stewart, Carolyn; Pradhan, Nisha; Arnold, Angela G.; Hakimi, A. Ari; Chen, Ying-Bei; Coleman, Jonathan; Hyman, David M.; Ladanyi, Marc; Cadoo, Karen A.; Walsh, Michael F.; Stadler, Zsofia K.; Lee, Chung-Han; Feldman, Darren R.; Voss, Martin H.; Robson, Mark E.; Motzer, Robert J.; Offit, Kenneth

doi:10.1001/jamaoncol.2018.1986

Cited by 139 publications

(140 citation statements)

References 52 publications

(68 reference statements)

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“…These include two different variants in POLE in two different tumors; two different variants in CHEK2 in two 6 different tumors; one variant in BRIP1 and PTCH1 both in a single tumor; and additional rare variants, one per tumor (e.g., TP53, MET, EGFR, among others, Table S7). This is consistent with a report on the relatively high frequency of germline mutations in cancer susceptibility genes in non-clear cell renal cell carcinomas 16 .…”

Section: Mutation Rates Frequency Of Driver Mutations and Germline supporting

confidence: 93%

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Zhu¹,

Poeta

Costantini

et al. 2018

Preprint

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We investigated intratumor heterogeneity and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enabled phylogenetic analysis of spatial features of clonal expansion, which showed congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of clear cell renal cell carcinoma, in pRCC driver gene mutations and most arm-level somatic copy number alterations (SCNAs) were clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and targeting largescale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displayed near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes had numerous SVs, which should be pursued for prognostic significance. WebsitesPicard tools

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Section: Mutation Rates Frequency Of Driver Mutations and Germline supporting

confidence: 93%

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Zhu¹,

Poeta

Costantini

et al. 2018

Preprint

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“…Of the 243 clear cell cases in this cohort, 13.6% (33/243) had a PV, of which 2.9% were RCassociated PVs. Similar findings were observed for the cases described as renal cell carcinoma, 13.1% (22/168) had a PV, of which 2.4% were RC-associated. DDR gene PVs were found in 24/243 (~10%) of clear cell cases, and in 16/168 (9.52%) of renal cell cases.…”

Section: Correlation Of Renal Histologies With Pvs In Specific Genessupporting

confidence: 87%

“…This population is particularly likely to be interested in evaluation of genetic risk. Further, germline PVs in some DDR genes have been observed in RC, including the DNA mismatch repair (Lynch syndrome) genes MSH2 and MLH1 in renal urothelial carcinoma, and CHEK2 in advanced renal cell carcinoma (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). To address the hypothesis that PVs in DDR genes may contribute to the missing heritability of eoRC, we analyzed germline sequencing data from a cohort of 844 eoRC, many of whom had additional non-RC primary tumors or a family history of non-RC cancers.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Hartman

Demidova

Lesh

et al. 2020

Preprint

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Purpose: Pathogenic variants (PVs) in a number of genes are known to increase the risk of hereditary renal cancer (hRC). However, many early-onset RC (eoRC) patients undergoing genetic testing lack PVs in hRC genes; thus, their genetic risk remains undefined. To determine if PVs in DNA damage response (DDR) genes are enriched in a convenience sample of eoRC patients undergoing genetic testing. Materials and Methods: Retrospective review of results for 844 unselected eoRC patients, undergoing genetic testing with a multi-gene cancer panel by Ambry Genetics [between July 2012 and December 2016]. The patients were tested with CancerNext and/or CancerNext Expanded panels for a variety of indications. Identified PVs were compared with patient characteristics.Results: Mean age of RC diagnosis was 48 years [range 24-60]. In addition to eoRC, 57.9% patients tested reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). PVs in cancer risk genes were identified in 12.8% of patients-3.7% in RC-specific genes, and 8.55% in DDR genes. DDR gene PVs were most commonly identified in CHEK2, BRCA1/2, and ATM. Among the 2.1% of patients with a BRCA1/2 PV, <50% reported a personal history of hereditary breast/ovarian-associated cancer.No association between age of RC diagnosis, and prevalence of PVs in RC-specific or DDR genes was observed. Conclusions:Multi-gene panel testing including DDR genes may provide a more comprehensive risk assessment in unselected eoRC patients, and their families. Validation in larger datasets is needed to characterize the association with eoRC.

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“…SDH‐deficient renal carcinomas were first identified in 2004 (Vanharanta, et al, ) and accepted as a unique subtype of renal tumor in 2016 (Moch, Cubilla, Humphrey, Reuter, & Ulbright, ). Two recent studies have identified the variant SDHA p.Arg31stop, previously defined as the most prevalent mutation observed in SDH‐deficient (GISTs) (Miettinen & Lasota, ), in renal cancer patients (Carlo, et al, ; McEvoy, et al, ). Association of SDHx germline variants with thyroid cancer risk has also been described (Neumann, et al, ; Ni, et al, ), of particular relevance to the proband in this study.…”

Section: Resultsmentioning

confidence: 99%

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

Nicolas

Demidova

Iqbal

et al. 2019

Molec Gen & Gen Med

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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.

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Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma

Cited by 139 publications

References 52 publications

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

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

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