Background: In the last 40 years, the incidence of colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing at an alarming rate in the US, and is expected to increase by >140% by 2030. Early-onset CRC represents a clinically distinct form of CRC often associated with a poor prognosis. During 2012-2017, more than 11% of the CRC cases in the US and more than 9% of the total CRC cases in Puerto Rico corresponded to patients <50 years old. This highlights the imperative need to describe the genetic drivers of early-onset CRC in Hispanics in order to increase early diagnosis, improve personalized clinical management, and improve survival outcomes. The objective of this study was to characterize the somatic mutation profile of early-onset tumors from Puerto Ricans, a Hispanic subpopulation with a high CRC burden, in order to better understand early-onset CRC biology.

Methods: Whole exome sequencing analyses were performed using the HiSeq4000 System (Illumina) on concordant colorectal adenocarcinoma and colonic mucosa tissue samples from 58 individuals diagnosed with colorectal cancer at <50 years old (early-onset CRC) and 25 individuals diagnosed with CRC >60 years old (late-onset CRC). Somatic variant calling and annotation/visualization were performed using Strelka and Ingenuity Variant Analysis software, respectively. All participants were recruited by Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR).

Results: Early-onset and late-onset CRC tumors showed distinct mutational profiles, only sharing TTN and MUC19 among their top 10 most mutated genes. The most frequently mutated genes in early-onset CRC tumors were: TTN (79%), MUC19 (75%), SYNE1 (68%), PCDHGA1 (68%), LPR1B (67%), PCDHGA2 (67%), PCDHGA3 (65%), PCDHGB1 (%), MUC16 (65%) and PCDHGA4 (65%). In late-onset CRC, the top ten most frequently mutated genes were: CSMD1 (68%), APC (68%), SYNE1 (64%), TTN (60%), MUC19 (60%), MUC16 (60%), PCDHA1 (60%), PCDHB1 (%), PCDHG1 (60%) and PCDHG2 (60%).

Conclusion: This study presents the somatic mutation profile of early-onset colorectal tumors from Puerto Ricans, a Hispanic subgroup with noted CRC health disparities. Somatic mutational profiles were found to be distinct when comparing early-onset and late-onset colorectal tumors. The majority of the somatic mutations detected in the early-onset CRC tumors were in non-coding regions, suggesting that epigenetic regulation may contribute to early-onset colorectal carcinogenesis.

Citation Format: Maria Gonzalez-Pons, Ingrid Montes-Rodriguez, Kelvin Carrasquillo-Carrion, Abiel Roche-Lima, Sandeep Singhal, Anna M. Napoles, Jung S. Byun, Eliseo Perez-Stable, Kevin Gardner, Marcia Cruz-Correa. Somatic mutation landscape in early-onset colorectal cancer tumors from hispanics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2180.