High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer

Abstract

The global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher's exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

Fig. 1. Mutational landscape of early-onset colorectal cancer.

a Mutation burden of exome samples. Hypermutation was defined as samples with ≥10 mutations per mega base pair. A high indel ratio is notable in samples with mismatch repair gene mutations. b Mutation signature ratios of age-related Signature 1, POLE-related Signature 10, and mismatch repair-related Signatures 6, 15, 26 combined. c Commonly mutated genes in hypermutated samples. d Commonly mutated genes in non-hypermutated samples. mutation frequencies of non-hypermutated samples are shown on the right.

Fig. 2. Mutation frequencies between age groups for highly mutated genes.

Mutation frequencies of commonly mutated genes. The mutation frequency of the cohorts as a whole is shown on the left. Fisher’s exact *P < 0.05, **P < 0.01.

Fig. 3. Differences according to age using an integrated data set.

Summary of the integrated dataset in a early-onset colorectal cancer and b late-onset colorectal cancer. A copy number heatmap is presented.

Fig. 4. Mutation types in tumor-suppressor genes.

a Percentages of homozygous loss in TP53 and APC identified from sequencing data. Mutation types in b TP53 and c APC.