# Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition

## TL;DR

This study shows that specific genetic mutations in kidney cancer can predict cancer recurrence and guide treatment with immune checkpoint inhibitors.

## Contribution

The study identifies non-VHL mutations as prognostic markers for recurrence and potential response to adjuvant immunotherapy in clear cell renal cell carcinoma.

## Key findings

- Non-VHL mutations in ccRCC tumors are associated with larger tumor size and higher stage.
- Patients with non-VHL mutations had a higher risk of recurrence compared to those with VHL-only or no mutations.
- Non-VHL mutations in TCGA ccRCC patients correlated with significantly shorter disease-free survival.

## Abstract

Background: The risk of recurrence after nephrectomy for primary clear cell renal cell carcinoma (ccRCC) is estimated in daily practice solely based on clinical criteria. The aim of this study was to assess the prognostic relevance of common somatic mutations with respect to tumor aggressiveness and outcomes of ccRCC patients after definitive treatment.

Methods: Primary tumors from 37 patients with ccRCC who underwent radical nephrectomy were analyzed for presence of somatic mutations using a 15-gene targeted next-generation sequencing (NGS) panel. Associations to histopathologic characteristics and outcomes were investigated in the study cohort (n=37) and validated in The Cancer Genome Atlas (TCGA) ccRCC cohort (n=451).

Results:
VHL was the most frequently mutated gene (51%), followed by
PBRM1 (27%),
BAP1 (13%),
SETD2 (13%),
KDM5C (5%),
ATM (5%),
MTOR (5%), and
PTEN (3%). One-third of patients did not have any somatic mutations within the 15-gene panel. The vast majority of tumors harboring no mutations at all or VHL-only mutations (51%) were more frequently of smaller size (pT1-2) and earlier stage (I/II), whereas presence of any other gene mutations in various combinations with or without
VHL was enriched in larger (pT3) and higher stage tumors (III) (p=0.02). No recurrences were noted in patients with unmutated tumors or
VHL-only mutations as opposed to three relapses in patients with non-
VHL somatic mutations (p=0.06). Presence of somatic mutations in
PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or
PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01).

Conclusions: Preliminary findings from this ongoing study support the prognostic value of non-
VHL mutations including
PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and
PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant immune checkpoint inhibition.