Background: Substantial efforts have been made to delineate mutational pathways to progression in ccRCC and the prognostic importance of key mutations. We hypothesized that VHL and PBRM1, as truncal mutations, would be roughly equally prevalent across tumor sizes, while more prognostic mutations - SETD2, BAP1, and CDKN2a copy-number loss - that portend aggressive disease would be predominantly observed in larger tumors. We further hypothesized that SETD2, BAP1, and CDKN2a loss mutations, when present in cT1 ccRCC, would portend worse prognosis.
Methods: Our cohort included 227 TCGA and 106 TRACERx ccRCC tumors. Logistic regression was used to model the presence of each mutation as a binary outcome against tumor size as a continuous variable. A subset of the combined cohort with tumors ≤ 7cm was used to assess the association between clinical outcomes and SETD2, BAP1, and CDKN2a copy-number loss. We modeled the presence of metastatic disease and overall survival against SETD2, BAP1, and CDKN2a copy-number.
Results: On logistic regression an increase in one centimeter of tumor size was associated with SETD2, BAP1, and CDKN2a 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 were associated with metastatic disease on logistic regression while controlling for tumor size at odds ratios of 3.86 and 3.84 (p < 0.05). CDKN2a was associated with worse overall survival on Cox proportional hazards while controlling for tumor size at hazard ratio 2.19 (p < 0.05).
Conclusions: In this exploratory work, we observe SETD2, BAP1 mutations, and CDKN2a copy-number loss are rare in small ccRCC tumors and grow increasingly common with size. . In tumors ≤7 cm, SETD2 mutation and CDKN2a loss, although rare, were associated with metastatic disease and CDKN2a loss was associated with worse overall survival.
