Fanconi anemia complementation group C gene (FANCC) association with hereditary and sporadic renal tumors

BACKGROUND: Inactivating genomic alterations (GA) of the FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency. Here, we evaluated the incidence of FANCC GA in renal tumors (RT). METHODS: A total of 463 546 clinically advanced cancer (CAC) cases underwent hybrid capture-based comprehensive genomic profiling using the FDA-approved F1CDx assay to detect all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity, prediction of germline status, and genomic signature were determined with algorithm-based analysis. RESULTS: Clinically advanced cancers (0.43% of 1993) featured FANCC GA; 27 of these FANCC-mutated tumors (20 males, mean age 57) were RT (0.35% of 7668 RT). The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph nodes, 4 soft tissues, 3 brains, 2 livers, 1 each lung, adrenal, eye, bone). Only 1 of 25 tested FANCC-mutated RT was MSI-high; 4 cases (15%) featured TMB ≥10 mutations/Mb. The genomic signature could be assessed in 5 cases: 4 were MMR-deficient. The FANCC mutations included inactivating short variant mutations in 24 cases (10 nonsense, 10 frameshift, 2 non-frame, and 2 splice-site mutations) and 3 truncating rearrangements (FANCC: SUSD3, FANCC: FANCC, and FANCC: C20orf24). Interestingly, 14 (52%) of the FANCC-mutated RT were predicted to be germline. CONCLUSIONS: Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at a similar rate to other cancers, and the genomic landscape does not appear to be different from RT with wild-type FANCC. Germline testing is warranted, as we see a high frequency of germline FANCC mutations. PATIENT SUMMARY: Our study highlights the rate of FANCC mutation in kidney cancer, which may be a therapeutic target and awaits further assessment and drug development. Also, it shows that FANCC mutations are more germline, requiring further genetic testing.