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.

Figure 1

Patient characteristics. (A) Age range of individuals diagnosed with RC ≤ 60 years in SEER cohort compared to the study cohort (n = 746; of the remaining individuals in the study, 26 were diagnosed < 19 years, 33 were diagnosed at 60 years, and 39 were excluded from the calculations as their age was reported as a wide range of years). (B) Percentage of males and females diagnosed with RC ≤ 60 years in SEER compared to the study cohort (n = 844). (C) The percentages of reported RC histology up to age 60 years in the SEER data (n = 97,805) compared to the study cohort (n = 844); not all histological subtypes reported in SEER were reported in the study cohort. (D) The percentage of cancer incidence (at ≤ 60 years) in the general SEER population versus the study cohort. The SEER data reflect individuals reporting the indicated cancer type, not individuals with RC in addition to the indicated cancer type. (E) Percentage of different primary cancers reported (≤ 60 years) in SEER (n = 97,795) versus the study cohort (n = 844). Less than 0.4% not reported for figure clarity.

Figure 2

Enrichment of PVs in DDRR genes. (A) Cases with germline PVs in the entire cohort (n = 844). (A) Red bars; DDRR genes, yellow bars; other-cancer associated genes; blue bars; RC genes. APC variants identified in this study were all the moderate risk c.3920T>A, p.I1307K variant, and 5 of the 19 CHEK2 variants were the moderate risk c.470T>C, p.I157T variant. *The individual with MUTYH was a compound heterozygote with two PVs. The data is presented as percent rather than ‘n’ due to the fact that not all 49 genes were tested for all patients in the full study cohort of 844 individuals. The percent adjusts for the number of individuals that were tested for each gene. The ‘n’ values are listed in Supplemental Table 3. (B,C) Odds of finding PVs in ATM (pink circle), BRCA1 (black circle), BRCA2 (orange circle), and CHEK2 (blue circle) from study cohort versus control population, ExAc (B) and gnomAD (C). Data is presented as log10 odds ratio (OR), and log10 confidence intervals. Dotted black line; association with outcome i.e. OR > 0 is enrichment in study cohort, OR = 0 no difference in cohorts. PVs not found in gnomAD or ExAc are indicated by the absence of any data or PVs not listed from Supplemental Table 4 were not found in the control population. Note: Computation of proportion or burden of individuals with all PVs in a specific gene(s) in the control population cannot be accurately performed as all PVs have not been defined, and while there is some agreement on which variants in a specific gene(s) are currently considered PVs, this is not true for all variants in that gene (as referenced in ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/). (D) Cases with germline PVs in the cohort tested for all genes in the study (n = 491, 49 genes). The total ‘n’ is listed in Supplemental Table 6. (E) Individuals with germline PVs who were diagnosed with only RC (n = 230/491). The total ‘n’ is shown above the bar as PV per gene. (F) Individuals with germline PVs who were diagnosed with RC plus at least one additional primary cancer type (n = 61/491). The total ‘n’ shown above the bar as PV per gene. The color scheme as in (A). In (D–F), to remain consistent between graphs, the data is presented as percent rather than ‘n’ even though all 49 genes were tested for all individuals represented in these graphs.

Figure 3

Identified PVs compared to age of RC diagnosis, and histology of RC. (A) Statistical comparison of PVs in all genes, RC-specific genes, non-RC and DDRR genes in younger individuals (< 48) versus older individuals (≥ 48). N = 485, these cases were tested for all 49 genes; all cases with Wilms tumor were removed. The results were non-significant (p > 0.05) using two-sided Fisher’s exact tests. (B) Counts of PVs by RC histology: clear cell (blue bar) and renal cell (orange bar) carcinoma in the study cohort. The' renal cell' subtype, is likely clear cell, but this cannot be confirmed. (C) Counts of PVs by all RC histology observed in the study cohort. DDRR genes (maroon bars), other-cancer associated genes (yellow bars), RC-specific genes (blue bars). The total number of individuals with a PV and percent PVs per gene category is shown above the bar. (B,C) Includes counts from both homozygous and heterozygous carriers of MUTYH, and carriers of a FH variant that is currently considered to be pathogenic only in the compound heterozygous or homozygous state.