Abstract Background Inactivating genomic alterations (GA) of FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency (HRD). Here, we evaluated the incidence of FANCC GA in RT. Methods 463,546 clinically advanced cancers (CAC) underwent hybrid capture-based comprehensive genomic profiling using the FDA-approved F1CDx assay to detect all classes of GA. MSI status, TMB, gLOH, prediction of germline status, and genomic signature were determined with algorithm-based analysis. Results 1,993 (0.43%) CAC featured FANCC GA. 27 of these FANCC-mutated tumors (20 male, mean age 57) were RT (0.35% of 7,668 RT). The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph node, 4 soft tissues, 3 brain, 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 mut/Mb. 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, 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 similar rate to other cancers, and genomic landscape does not appear to be different from RT with wild-type FANCC. Germline testing is warranted, as we see 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 mutation are more germline, requiring further genetic testing.
Desai et al. (Fri,) studied this question.