Faulty DNA repair (DR) impacts cancer development and sensitivity to radiotherapy. Therefore, we intend to investigate association of polymorphisms impacting DR with overall survival (OS) to assist in early cancer detection and response prediction. Standard of care (SOC) treatment for locally advanced rectal cancer (LARC) includes chemoradiation (nCRT) and surgery. Recent trials show benefits and the possibility of non-operative management in those with complete response (CR) to nCRT. Yet, limited tools exist to determine response likelihood, thereby exposing many to toxicity without benefit. There is critical need to identify biomarkers to help predict response and determine treatment.
In-house whole exome sequencing of LARC patients revealed conserved single nucleotide polymorphisms (SNPs) within coding regions of genes involved in DR were associated with radiation response. Specifically, enrichment of SNPs in JMJD1C and NSD1 were significantly associated with CR, a proposed surrogate for OS in previous studies. Population analysis of US patients found Black race, rural location and uninsured status correlated with poor treatment response. Aggregate exome sequencing using gnomAD revealed lower allele frequency of the JMJD1C SNP in patients of African, Latino, or East Asian compared to European ancestry.
Our preliminary data induce three research inquiries. First, we hypothesize the UKB cohort will reveal similar demographic distribution of SNPs impacting DR compared to the US. We aim to investigate associations between identified SNPs and OS utilizing an international dataset. Second, we hypothesize socio-environmental factors mediate SNP-OS associations. We aim to investigate the extent of this effect modification. Third, we hypothesize SNPs impairing DR are associated with younger age of cancer diagnosis compared to the general population. We aim to use sex and histology-matched controls to investigate association of age at cancer diagnosis with SNP presence.
