Evaluation of genomic alterations in early-onset versus late-onset colorectal cancer.
Authors: Lander Eric Michael , Rivero-Hinojosa Samuel , Aushev Vasily N. , Jurdi Adham A , Liu Minetta C. , Eng Cathy 
Published: June 2023

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Background: The etiology of the rising incidence of early-onset colorectal cancer (EOCRC), defined as CRC in patients aged < 50, remains unknown. In this study, we evaluated tumor genomic differences in patients with EOCRC versus average-onset CRC (AOCRC, age > 60). Methods: The cohort included 13,262 patients diagnosed with stages I-III colon or rectal cancer who had whole exome sequencing as part of their ctDNA testing (Signatera, bespoke mPCR NGS assay). Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from tumor whole exome sequencing analysis. The prevalence of somatic variants and mutations in known oncogenic pathways was compared between EOCRC and AOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between the groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 3,093 patients with EOCRC (70.8% colon, 27.4% rectal, 1.9% unknown) and 10,169 patients with AOCRC (79.9% colon, 18.3% rectal, 1.7% unknown) were included, where 9.0%/37.3%/53.7% were AJCC stages I, II, and III, respectively. Early-onset patients compared to average-onset patients had fewer cases of stage II CRC (30.7% vs. 39.3%, p < 0.01) and more cases of stage III CRC (60.9% vs 51.6%, p < 0.01). Patients with EOCRC were less commonly MSI-H compared to patients with AOCRC (10% vs. 17%, p < 0.01), or have high tumor mutational burden (15% vs. 19%, p < 0.01). The BRAF V600E mutation and truncated RNF43 mutations were less prevalent in EOCRC (3% vs. 15% and 2% vs. 9%, p < 0.01), regardless of TMB and MSI status. Molecular alterations of the RTK-RAS pathway were less prevalent in the EOCRC cohort (p < 0.01), while TP53 pathway alterations were more frequent in the EOCRC cohort (p < 0.01). In the TMB-low/MSS group, TP53 mutations were more common in EOCRC (8% vs. 5%, p < 0.01), but APC gene mutations were less common in EOCRC (56% vs. 66%, p < 0.01). In the TMB-H/MSI-H group, BRAF V600E (4% vs. 60%), RNF43G659V (16% vs. 45%), and WNT1 G619A (6% vs. 20%) mutations were less prevalent in EOCRC (p < 0.01 for all mutations); however, patients with EOCRC had more PIK3CA H1047R (22% vs. 9%) , APC R1468* (11% vs. 3%), and KRAS A146T (7% vs. 2%) variants (p < 0.01 for all mutations). In the TMB-H/MSS group, EOCRC patients were more likely to have driver mutations in the PI3K pathway (74% vs. 56%, p < 0.01). The POLE P286R mutation was more common in TMB-H/MSS patients with EOCRC (38% vs. 13%, p < 0.01), whereas ACVR2A K437R was less common (11% vs. 30%, p < 0.01). Prevalence of somatic variants and mutated oncogenic pathways did not vary significantly by tumor stage. Conclusions: Patients with AOCRC harbored more somatic variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases carried unique genomic alterations that varied across the TMB and microsatellite subpopulations. BRAF V600E and RNF43 truncating mutations were more frequent in AOCRC.