Abstract 322P
Background
Despite declines in the absolute number of colorectal cancer (CRC) cases, incidence rates among adults age<50 (early-onset, EOCRC) have climbed over the last two decades across Western countries, with causes poorly understood. While EOCRC cases more often have a familial component compared to older counterparts, >80% of EOCRC patients do not carry a germline mutation associated with cancer predisposition. Thus, there exists an urgent need to elucidate etiologies underlying the EOCRC epidemic.
Methods
We utilized a well-characterized cohort of CRC patients recruited across the Oncology Research Information Exchange Network (ORIEN) across cancer centers in the U.S. to identify enriched somatic variations in early-onset sporadic CRC patients. We leveraged clinical and paired germline/tumor whole exome sequencing data from 484 sporadic CRC patients (n=130 EOCRC; 24.8%) to conduct a genome-wide investigation of somatic mutation patterns distinct to early-onset sporadic CRC. Bioinformatics analyses utilized a series of best practice containerized workflows for quality control and variant identification. Genomic patterns unique to EOCRC were analyzed using logistic regression, accounting for multiple comparisons.
Results
A total of 141 genes with statistically significant differences (p<0.05) in mutation rates between EOCRC and late-onset CRC cases were identified from models adjusted for race/ethnicity, sex, CRC site and stage, and center. Variant effects IPA core analysis of this gene set revealed that genes with differential mutation rates in EOCRC were significantly enriched in Granzyme B signaling—a pathway related to reactive oxygen species formation. Indeed, one in every 8 genes involved in Granzyme B signaling harbored differential mutation rates in EOCRC versus late-onset cases (p=0.004). Leptin signaling in obesity was also a significantly enriched pathway for genes with differential mutation rates in EOCRC.
Conclusions
Pathways related to oxidative stress and obesity may distinguish EOCRC from late-onset CRC. This is consistent with our prior multi-omics study of early-onset sporadic CRC (Holowatyj et al. Gastroenterology. 2021) that demonstrated oxidative stress as a potential central pathway to EOCRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
M2Gen (contributed staff time).
Disclosure
M.J. Reilley: Other, Personal, Advisory Board: BMS, Helsinn. M. Churchman: Financial Interests, Personal, Full or part-time Employment: M2GEN. All other authors have declared no conflicts of interest.