Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer

Abstract

Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.

Experimental design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.

Results: Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR < 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01).

Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.

Figure 1.

Age distribution of the entire cohort

Figure 2.

Across all colorectal cases, the most frequent alterations were in APC (76.8%), TP53 (75.9%), KRAS (50.5%), PIK3CA (17.8%), and SMAD4 (14.9%).

Figure 3.

Alteration rate in genes of interest between early-onset (< 40 years - blue) and later-onset (≥ 50 years - orange) in MSS and MSI-H CRC (patients between the ages of 40 and 49 are not included in these figures).

Figure 4.

A. Genes of interest with increasing alteration rates by age (all p values < 0.01). The dots show the alteration rates at each age (dots are sized according to how many samples there are at that age), and the red line shows the regression fit from the logistic regression model. B. Genes of interest with decreasing alteration rates by age (all p values < 0.01)

Figure 5:

Differing rates of specific BRAF and RNF43 mutations by age showing a clear distinction between BRAF V600E mutations versus other BRAF mutations as well as a difference in RNF43 659_660 mutations and RNF43 117 mutations.