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.
Highlights
Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer
We considered that PVs in damage response and repair (DDRR) genes were most likely to impact repair of DNA damage induced during cell replication, leading to genetic instability and cancer; given renal cells turn over much less frequently than colon cells, we hypothesized that it may take longer for cancers associated with PVs in DDRR genes to manifest in Renal cancer (RC), causing us to select a cut-off of ≤ 60 years old for assessment
For analysis comparing outcomes for RCspecific genes versus genes not typically associated with RC, we focused our statistical comparison on only those individuals who had CancerNext Expanded panel version 2 testing which analyzes all 49 genes including the RC-specific genes. 491 individuals who had the CancerNext Expanded version 2 test were used for this statistical comparison
Summary
Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). Many eoRC patients lack PVs in RC-specific genes; their genetic risk remains undefined. We determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. 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 BAP15–7. DNA damage response and repair genes (DDRR) play an important role in maintaining genome integrity, and when mutated in the germline can increase cancer risk for several types of cancers, including breast, colorectal, ovarian, and others[9].
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