8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness
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8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness Jeanette E. Eckel‑Passow1*, Huihuang Yan1, Matthew L. Kosel1, Daniel Serie2, Paul A. Decker1, Robert B. Jenkins3, Brian Costello4, Bradley Leibovich4, Thai H. Ho5 and Alexander Parker2
Abstract Background: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggres‑ siveness are unknown. Methods: We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. Results: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some ger‑ mline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. Conclusions: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggres‑ siveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression. Keywords: Kidney, GWAS, Subtype, Hi-C Background The majority (> 90%) of kidney cancer is classified as renal cell carcinoma (RCC) and approximately 85% of RCCs are further classified as the clear cell subtype (ccRCC). The etiology of ccRCC has been extensively studied and smoking, obesity and hypertension are recognized environmental risk factors that increase the risk of developing ccRCC. Additionally, genome-wide *Correspondence: [email protected] 1 Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Full list of author information is available at the end of the article
association studies (GWAS) have to date identified 14 germline variants that are associated with risk of RCC [1–5]. The value of these germline genetic explorations notwithstanding, the functional impact of the germline variants associated with RCC and ccRCC specifically remains largely unknown. Furthermore, the association of germline genetics with tumor genetics and tumor aggressiveness are largely unknown. In some cancers investigators have reported that germline variants are associated with specific molecularly-defined tumor subtypes, and in some cases the association is large enough to suggest clinical relevance (e.g., rs55705857 has an odds ratio > 6 in IDH-mutated glioma) [6–8]. To date,
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