Abstract C014: Unexplained familial early-onset colorectal cancer: Determining a shared etiology by tumor mutational signature profiling

Abstract Introduction: Identifying the causes of early-onset colorectal cancer (EOCRC) is integral to reducing its rising global burden. Approximately 25% of EOCRC cases have a first degree relative (FDR) who has also developed CRC. Determining if familial EOCRC is the result of shared hereditary or environmental factors or chance familial aggregation has important implications for clinical management and cancer prevention. We investigated the similarity of tumor mutational and experimental signature profiles from EOCRC cases and their EOCRC-affected FDRs to identify evidence of common hereditary or environmental etiologies. Methods: We identified 13 people with a mismatch repair proficient (MMRp) EOCRC who had at least one FDR with a MMRp EOCRC with tumor tissue available (familial EOCRC pairs). To calibrate mutational signature profile “similarity”, a reference group of CRCs from FDR pairs with known hereditary cancer syndromes were included (hereditary CRCs: Lynch syndrome (n=4), biallelic MUTYH (n=1), biallelic NTHL1 (n=1), BRCA1 (n=1) ). In addition, a group of 254 MMRp EOCRC cases were analyzed to assess the prevalence of any familial signatures. All participants were recruited through the ANGELS and CCFR studies. COSMIC v3. 4 tumour mutational signatures (TMS) and COSMIC v1. 0 experimental mutational signatures (EMS) were calculated from whole exome sequencing. Spearman’s rank correlation coefficient was calculated across tumours against which familial EOCRCs and hereditary CRCs were assessed for similarity. Hierarchical clustering with bootstrap resampling (pvclust, R) was applied to correlation-based distances, supporting clusters with an approximately unbiased (AU) value ≥95% as significant. Results: Hereditary CRCs had a Spearman’s correlation range of 0. 34-0. 84, derived from TMS and EMS. Of the 13 familial EOCRC pairs, five (38%) shared a TMS/EMS profile (Spearman’s correlation range 0. 37-0. 94). One familial EOCRC pair exhibited a dominant EMS related to n-nitrosopyrrolidine (NPYR) exposure (correlation=0. 94). This familial EOCRC pair, a mother and daughter, were diagnosed within a year of each other at ages 49 and 18 years, respectively. Hierarchical bootstrap clustering identified 11 EOCRCs (11/254 or 4%) with a dominant EMS profile related to NPYR exposure, two of which had a CRC-affected FDR. Conclusions: TMS and EMS profiling of unexplained familial EOCRC-affected FDR pairs showed heterogeneity with regards to shared mutational processes among the FDR pairs. Only 38% of familial EOCRC pairs demonstrated evidence of similar mutational processes in their EOCRCs that were suggestive of a shared etiology. One experimental signature related to NPYR exposure, a carcinogen found in food, tobacco smoke and occupational settings, was present as a dominant mutational process in 4% of the EOCRCs tested, highlighting the potential utility of mutational signature analysis for elucidating the etiology of EOCRC. Citation Format: Alysha Prisc, Peter Georgeson, Jihoon E. Joo, Romy Walker, Mark Clendenning, Julia Como, Natalie Diepenhorst, Julie McDonald, Steven Gallinger, Robert C. Grant, Dylan E. O'Sullivan, Darren R. Brenner, Finlay A. Macrae, Christophe Rosty, Mark A. Jenkins, Ingrid M. Winship, Daniel D. Buchanan. Unexplained familial early-onset colorectal cancer: Determining a shared etiology by tumor mutational signature profiling abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C014.