# Clinical and genetic features of multiple primary tumours cohorts with a renal cell carcinoma: Implications for molecular genetic investigations

## TL;DR

The study finds that a significant percentage of patients with multiple primary tumors involving kidney cancer have genetic mutations, suggesting updated guidelines for genetic testing.

## Contribution

The study provides new insights into the genetic basis of multiple primary tumors involving renal cell carcinoma and proposes revised testing criteria.

## Key findings

- Germline pathogenic variants in cancer susceptibility genes were found in 9.4% of MPRT cases and 10.4% of MPT:RCC + X cases with RCC diagnosed before age 66.
- Excluding environmentally linked cancers increased diagnostic yield in MPT:RCC + X to 12.9%.
- Almost half of the cases with RCC-related pathogenic variants did not have typical extrarenal tumors.

## Abstract

Multiple primary tumours (MPT) is a risk factor for an underlying predisposition to cancer. Renal cell carcinoma (RCC) occurs in several hereditary cancer disorder syndromes, and RCC‐related MPT comprise individuals with multiple primary renal tumours (MPRT) and those with RCC plus a non‐renal tumour (MPT:RCC + X). Excluding rare syndromic causes, knowledge of the genetic architecture of MPRT/MPT:RCC + X is limited. To inform diagnostic approaches to MPRT/MPT:RCC + X, we present the findings of comprehensive genomic analysis in 534 individuals. The presence/absence of variants in cancer susceptibility genes (CSGs) from exome/genome sequencing was then correlated with data on age, sex, tumour types, and RCC histopathology in 93 participants with MPRT and 441 with MPT:RCC + X. 7.5% of participants with MPRT and 6.1% in participants with MPT:RCC + X had germline CSG pathogenic variants, and the diagnostic yields increased to 9.4% and 10.4%, respectively, in cases with RCC <66 years. Excluding participants with environmental carcinogen‐linked cancers increased the diagnostic yield in MPT:RCC + X to 12.9%. Pathogenic variants were mostly in CSGs known to predispose to RCC, but in almost half of these cases, typical extrarenal tumours were not present. In conclusion, our findings support amended eligibility criteria for diagnostic testing in MPRT and wider eligibility criteria for testing in MPT:RCC + X, with RCC <66 years.

Current knowledge of the genetic architecture underlying the development of renal cell carcinoma‐related multiple primary tumours is limited. The authors comprehensively analysed the results of exome/genome sequencing cohorts including 534 patients to better define genotype–phenotype correlations. A germline pathogenic variant in a cancer susceptibility gene was observed in 9.4% of the patients with a renal cell carcinoma diagnosed before the age of 66 with other primary renal tumours and 10.4% of those who also developed another primary tumour type. The authors suggest new eligibility criteria for genetic testing in patients with multiple primary tumours including a renal cell carcinoma.