Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Abstract

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC. Renal cancer (RC) often develops with no signs or symptoms and is referred to as the "silent disease" 1. While factors including smoking, environment, obesity, and race have been linked to increased risk of RC, inherited factors are the most well-validated source of increased risk 2-4. Hereditary RC syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance 'RC-specific' genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 5-7. A previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene 7. However, for most eoRC patients a PV in an RC-specific gene is not identified, leaving many eoRC genetically undefined. Thus, there is a need to identify additional genes related to eoRC risk. Currently, there are no National Comprehensive Cancer Network (NCCN) guidelines for detection, prevention, or risk reduction in individuals who present with an eoRC but lack a PV in a defined RC-specific gene 8 .

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing

“…Our overall cohort had a high proportion of patients with advanced RCC. This may account for the higher prevalence of FH and SDH mutations associated with aggressive disease compared to prior germline sequencing studies in RCC [5,7]. We previously reported that the overall frequency of germline mutations was also higher among patients with advanced RCC [8].…”

“…A study of 190 Chinese patients with RCC diagnosed at the age of 45 yr found that 9.5% had germline pathogenic/likely pathogenic (P/LP) variants, of which two-thirds were in RCC predisposition genes and one-third were in cancer predisposition genes that have not been linked to RCC risk, such as BRCA1/2 [4]. In the USA, another study of 844 patients with RCC diagnosed at the age of 60 yr found germline mutations in 12.8% of patients, but only 3.7% had mutations in RCC predisposition genes [5].…”

“…Beyond the recognition of well-defined hereditary RCC syndromes, the genetic landscape and clinical characteristics of patients with early-onset RCC are not well characterized. Prior large-scale germline sequencing studies of RCC lacked central pathology review to confirm diagnostic accuracy and detailed clinical annotations to provide information on the characteristics of patients with germline mutations [5,7]. Owing to limited and conflicting data on the genetics of patients with early-onset RCC and the rising incidence of RCC among younger patients, we sought to determine the germline variants, associated clinical characteristics, and tumor histology in a large cohort of patients with early-onset RCC who underwent genetic testing.…”

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…Consistently, 7/229 (3.1%) mutation carriers with germline CHEK2 variants were identified among metastatic clear cell renal cancer patients by Ged and colleagues [ 217 ]. CHEK2 germline mutations were also the most frequent alterations found in 19/844 (2.25%) patients with early onset RCC developed before the age of 60 [ 218 ]. Notably, among these, second primary cancers (breast, thyroid, colon, blood, and ovarian) were reported in 13 (68%) individuals.…”

From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma

“…DNA repair deficiencies lead to a hypermutable state resulting in increased formation of neo-antigens, and may serve as a biomarker of ICI efficacy [78,79]. In RCC, DNA repair gene alterations have been documented at frequencies of approximately 19-25% [80,81], with CHEK2, ATM, and BRCA1, and BRCA2 most commonly implicated [80,82]. Up to 26 DNA repair genes have displayed differential expression in ccRCC compared to benign tissue, six of which were identified as potential prognostic biomarkers (ISG15, RAD51AP1, SFRP2, SLFN11 as high-risk genes; SPATA18, VAV as low risk genes).…”