Investigation of the genetic basis of multiple primary renal tumours

Abstract

Multiple primary tumours (MPT) is a risk factor for an underlying predisposition to cancer. Renal cell carcinoma (RCC) occurs in several hereditary cancer disorders 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 variant 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 tumour 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 and with RCC <66 years.