Expanding the phenotype of hereditary renal cell carcinoma syndromes: Implications for surveillance and management

Approximately 5% of renal cell carcinoma (RCC) occurs in the setting of a hereditary RCC syndrome, but accurate phenotype and cancer risk estimates remain limited by ascertainment bias in reported series.

We analyzed 32,728 cancer patients who underwent paired tumor-normal sequencing with MSK-IMPACT for germline pathogenic variants (PVs) in RCC hereditary syndrome genes VHL, FLCN, BAP1, MET, SDHB, FH, and proposed RCC risk variants MITF E318K and FH K477dup. We integrated clinical, tumor immunohistochemistry, and genomic data. We performed burden testing across tumor types and, using case-control analysis, validated novel gene-cancer associations with UK Biobank data.

Germline PVs diagnostic of hereditary RCC syndromes were identified in 109 of 32,728 patients (0.33%), including 3.6% of RCC cases. Only 61.5% of carriers met clinical criteria for their syndromes and most patients were undiagnosed prior to testing. Using burden testing, we confirm and suggest novel cancer associations, including BAP1 PVs in hepatobiliary cancers and FLCN in colorectal cancer. We independently validated in the UK Biobank the association of FLCN and colorectal cancer, but analysis of BAP1 and hepatobiliary was limited by small numbers. Tumor analyses demonstrated biallelic inactivation in syndromic tumors and supported pathogenic roles for BAP1 in hepatobiliary cancers and FLCN in colorectal cancers. The FH K477dup pathogenic variant appears to lack association with RCC risk and there was weak evidence for association of MITF E318K.

Using large, unselected pan-cancer cohorts and integrated tumor and genomic analysis can help refine the phenotype of rare cancer predisposition syndromes.