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

Germline pathogenic variants in VHL, FLCN, BAP1, MET, SDHB and FH, with biallelic inactivation demonstrated in syndromic tumours.

About 5% of renal cell carcinomas arise within a hereditary syndrome, but phenotype and risk estimates remain limited by ascertainment bias in published series. The authors analysed 32,728 cancer patients who underwent paired tumour-normal MSK-IMPACT sequencing for germline pathogenic variants in VHL, FLCN, BAP1, MET, SDHB and FH, together with the proposed risk variants MITF E318K and FH K477dup, integrating clinical, tumour immunohistochemistry and genomic data. A germline pathogenic variant diagnostic of a hereditary syndrome was found in 109 of 32,728 patients (0.33%), including 3.6% of renal cell carcinoma cases; only 61.5% of carriers met clinical criteria for their syndrome and most were undiagnosed before testing. Burden testing pointed to new associations, notably BAP1 with hepatobiliary cancers and FLCN with colorectal cancer, the latter independently replicated in the UK Biobank while the BAP1-hepatobiliary analysis was limited by small numbers. The FH K477dup variant appeared not to be associated with renal cell carcinoma risk, and evidence for MITF E318K was weak.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The most useful figure for the clinic is not the overall 0.33% but the fact that only 61.5% of carriers met the criteria for their own syndrome: selecting on clinical criteria misses a substantial share of diagnoses, a concrete argument for broad germline testing in patients with renal cell carcinoma. The phenotypic extensions rest on uneven evidence — FLCN and colorectal cancer is replicated in an independent cohort, BAP1 and hepatobiliary cancer rests on small numbers — and no age-specific absolute risks are given, so neither colorectal nor hepatobiliary screening can yet be added to surveillance protocols. Conversely, the negative signal for FH K477dup is directly usable in avoiding intensive renal surveillance based on that variant alone.

Analysis by Dr Thibaut Benquey