Differences in mutations across tumour sizes in clear-cell renal cell carcinoma

Abstract

Objective: To assess the distribution of key mutations across tumour sizes in clear-cell renal cell carcinoma (ccRCC), and secondarily to examine the prognostic impact of aggressive mutations in smaller ccRCCs.

Patient and methods: The distribution of mutations (VHL, PBRM1, SETD2, BAP1 and CDKN2A loss) across tumour sizes was assessed in 1039 ccRCCs treated with nephrectomy in cohorts obtained from the Tracking Cancer Evolution (TRACERx), The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) projects. Logistic regression was used to model the presence of each mutation against size. In our secondary analysis, we assessed a subset of ccRCCs ≤7 cm for associations of key aggressive mutations (SETD2, BAP1, and CDKN2A loss) with metastasis, invasive disease and overall survival, while controlling for size. A subset of localised tumours ≤7 cm was also used to assess associations with recurrence after nephrectomy.

Results: On logistic regression, each 1-cm increase in tumour size was associated with aggressive mutations, SETD2, BAP1, and CDKN2A loss, at odds ratios (ORs) of 1.09, 1.10 and 1.19 (P < 0.001), whereas no significant association was observed between tumour size and PBRM1 (OR 1.02; P = 0.23). VHL was mildly negatively associated with a 1-cm increase in size (OR 0.95; P = 0.01). Among tumours ≤7 cm, SETD2 and CDKN2A loss were associated with metastatic disease at ORs of 3.86 and 3.84 (P < 0.05) while controlling for tumour size. CDKN2A loss was associated with worse overall survival, with a hazard ratio (HR) of 2.19 (P = 0.03). Among localised tumours ≤7 cm, SETD2 was associated with worse recurrence-free survival (HR 2.00; P = 0.03).

Conclusion: Large and small ccRCCs are genomically different. Aggressive mutations, namely, SETD2, BAP1, and CDKN2A loss, are rarely observed in small ccRCCs and are observed more frequently in larger tumours. However, when present in tumours ≤7 cm, SETD2 mutations and CDKN2A loss were still independently associated with invasive disease, metastasis, worse survival, and recurrence after resection, after controlling for size.

Keywords: bap1; cdkn2a; clear‐cell renal cell carcinoma; genomics; renal cell carcinoma; setd2; survival; tcga; tracerx; tumour size.

Fig. 1

The proportion of tumours with given mutations within each cohort among cT1a, cT1b, and cT2 size thresholds. Copy number and CDKN2A loss were not available for Cancer Genomics of the Kidney (CAGEKID). Within Tracking Cancer Evolution (TRACERx), the grey‐outlined segment represents the proportion each mutation that was clonal‐ i.e. detected in every biopsied region.

Fig. 2

(a, b) Tumour size, mutational status, grade, and metastatic status at presentation among clear‐cell RCC tumours in Tracking Cancer Evolution (TRACERx) and The Cancer Genome Atlas (TCGA) sorted by tumour size. Clonal mutations are outlined in bold for TRACERx tumours when a mutation was present in all biopsies.