Fanconi anemia complementation group C (<i>FANCC</i>) gene association with hereditary and sporadic renal tumors (RT).
Authors: Rebecca A Sager, Devashish Desai, Michael Basin, Joseph M Jacob, Alina Basnet, Gloria Joan Morris, Philippe E. Spiess, Roger Li, Liang Cheng, Andrea Necchi, Ashish M. Kamat, Petros Grivas, Karthikeyan Murugesan, Dean C. Pavlick, Hanan Goldberg, Mehdi Mollapour, Douglas I. Lin, Jeffrey S. Ross, Gennady Bratslavsky, Michael A Daneshvar
Journal: Journal of Clinical Oncology (2024)

450 Background: Inactivating genomic alterations (GA) of FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency (HRD). FANCC GA are most frequently associated with colon, lung, breast, and prostate cancers (0.5% frequency) with germline FANCC mutations linked to familial breast cancer. FANCC GA have been rarely associated with RT and are not currently linked to any hereditary renal cancer predisposition syndromes. We evaluated the incidence of FANCC GA and other genomic features across cancer types. 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, tumor mutation burden (TMB), gLOH, prediction of germline status, genomic ancestry, and genomic signature were determined with algorithm-based analysis. PD-L1 expression was tested by IHC (Dako 22C3 tumor proportional score; low positive (LP) 1-49%). 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): 13 clear cell, 3 sarcomatoid, 3 urothelial, 3 chromophobe, 2 squamous cell, 2 medullary renal carcinomas (RCC), and 1 Wilm’s tumor. The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph node, 4 soft tissue, 3 brain, 2 liver, 1 each lung, adrenal, eye, bone). Only 1 of 25 tested FANCC-mutated RT was MSI-high. The mean TMB was 5.7 mut/Mb while the median TMB was 2.5 mut/Mb, and 4 cases (15%) featured TMB ≥10 mut/Mb. 2 of 4 FANCC-mutated RT that were tested for PD-L1 were LP. The mean gLOH was 7.5%. Genomic ancestry evaluation revealed 21 EUR, 4 AFR, and 2 AMR patients. 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. Additional GA in the FANCC-mutated RT included VHL, TP53, CDKN2A, ARID1A, PBRM1, TERT, PTEN, and SETD2. Conclusions: Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at similar rate to other cancers. RT with inactivated FANCC do not appear to have a different GA landscape from RT with wild-type FANCC. The high frequency of predicted germline status during somatic testing with FANCC alterations suggests the importance of further workup with confirmatory germline testing as it may affect counseling for other family members. Limitations of this study include lack of clinical and therapy data annotation.