The distribution of mutations across tumor size in ccRCC and their prognostic importance in small masses.

Abstract

479 Background: Substantial efforts have been made to delineate mutational pathways to progression in ccRCC and the prognostic importance of key mutations, yet the distribution of these mutations across tumor size remains unknown. We hypothesized that VHL and PBRM, as more truncal mutations, would be roughly equally prevalent across tumor sizes, while mutations associated with aggressive disease - SETD2, BAP1, and CDKN2a copy-number loss - would be predominantly observed in larger tumors. We further hypothesized that SETD2, BAP1, and CDKN2a copy-number loss mutations, when present in smaller (≤7 cm) ccRCC tumors, would portend worse prognosis. Methods: We assessed a combined cohort of 333 ccRCC tumors from TCGA-KIRC and TRACERx Renal for the distribution of mutations across tumor size. Logistic regression was used to model the presence of each mutation against tumor size. We assessed a subset of 194 tumors ≤7cm for associations of key mutations with clinical outcomes while controlling for size. In small masses, logistic regression was used to model the presence of metastatic disease and invasive disease, and Cox proportional hazards was used to model overall survival, against SETD2, BAP1, CDKN2a copy-number loss, and tumor size. Results: On logistic regression an increase in one centimeter of tumor size was associated with SETD2, BAP1, and CDKN2a loss at odds ratios of 1.16, 1.11, 1.19 (p<0.05); whereas no significant association was observed between tumor size and both VHL and PBRM1 (p=0.18, p=0.65). Among 194 tumors ≤7 cm, SETD2 and CDKN2a loss were associated with metastatic disease at odds ratios of 3.86 and 3.84 (p<0.05); CDKN2a loss was associated with worse overall survival at hazard ratio 2.19 (p<0.05), all while controlling for tumor size. Conclusions: SETD2 mutations, BAP1 mutations, and CDKN2a copy-number loss are rare in small ccRCC and are increasingly common in larger tumors, whereas VHL and PBRM1 are fairly evenly distributed across tumor sizes. In tumors≤7 cm, SETD2 mutation and CDKN2a loss were associated with metastatic disease and CDKN2a loss was associated with worse overall survival. SETD2 mutations and CDKN2a loss may help risk stratify ccRCC in biopsied and resected tumors. [Table: see text]