Background: Young-onset colorectal cancer, the majority of which are sporadic, may have distinct molecular characteristics and etiologies. However, thus far, the genomic landscape of young-onset CRCs has remained largely uncharacterized. This study aimed to compare somatic mutation differences between young-onset and late-onset CRCs using the AACR GENIE data, a consortium of patients treated at 8 global cancer centers. Methods: Clinical and DNA mutation data on 2,081 CRC samples were downloaded from Sage Bionetworks (Synapse ID: syn7222066). A total of 162 samples from CRC patients who had more than one samples or were likely to have Lynch syndrome were excluded. Young-onset CRCs were defined as cancers arising at age <50 years old while late-onset CRCs were defined as cancers arising at age ≥50 years old. Mutation rate per megabase (Mb) was calculated for each CRC and compared between groups by Wilcoxon rank sum test. The mutation frequency of each gene in young-onset and late-onset CRC was calculated separately for primary CRCs and metastatic CRCs. Mutation frequency differences between young- vs late-onset CRCs were tested by the Fisher's exact test with significance defined at the 5% alpha level. Results: Mutation data on 613 genes were analyzed on 955 primary and 676 metastatic CRCs. Overall, the most frequently mutated genes with a >10% mutation frequency include: TP53 (66.86%), APC (59.46%), KRAS (47.42%), PIK3CA (18.40%), SMAD4 (12.71%) and BRAF (10.06%). The metastatic CRCs were on average slightly older than primary CRCs (mean age=56.96 vs. 55.90, two sample t test P=0.09). Comparing gene mutation between 300 young-onset versus 655 late-onset primary CRCs, mutation rate per Mb was slightly but not significantly higher in the latter (median=3.74 vs. 4.14, P=0.2199). DOT1L (9.82% vs. 1.95%, P=0.0014), IGF1R (6.12% vs. 1.72%, P=0.0057), BRCA1 (5.61% vs. 1.47%, P=0.0069), JUN (6.25% vs. 1.17%, P=0.0104), PTCH1 (7.14% vs. 2.7%, P=0.0151), TSHR (5.36% vs. 1.17%, P=0.0253), EIF1AX (3.06% vs. 0%, P=0.02811), JAK2 (2.0% vs. 0.46%, P=0.0311), EP300 (8.67% vs. 4.41%, P=0.0414), PHOX2B (2.20% vs. 0.27%, P=0.0419), SMC1A (3.57% vs. 0%, P=0.0446) and CSF1R (3.02% vs. 1.03%, P=0.0439) had a significantly higher mutation rate in the young-onset primary CRCs. Meanwhile, KRAS was mutated more frequently in late-onset primary CRCs (44.0% vs. 51.3%, P=0.03679). For metastatic CRCs, NTRK1 was found mutated in 12 (3.80%) out of 316 later-onset metastatic CRCs but none out of 129 young-onset metastatic CRCs (P=0.0223). Meanwhile, CIC was mutated in only 1 out of 103 young-onset metastatic CRCs but 17 (6.44%) out of 264 late-onset metastatic CRCs (P=0.0302) and TP53 had a nearly 8% higher mutation rate in young-onset metastatic CRCs (79.01% vs. 71.19%, P=0.0488). Conclusions: Mutation rates were found significantly higher in many genes among young-onset primary CRCs compared to late-onset primary CRCs.

Citation Format: Jingqin Luo, Marios Giannakis, Graham Colditz, Jean Wang, William Chapman, Adetunji T. Toriola, Yoshiko Mito, Reiko Nishihara, Jonathan Nowak, Charles Fuchs, Edward Giovannucci, Andrew T. Chan, Adam Bass, Shuji Ogino, Ryan Fields, Yin Cao. Comparative genomic analysis of young-onset and late-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1228.