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

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-11
• Main Authors: Kim, Jeong Eun, Choi, Jaeyong, Sung, Chang-Ohk, Hong, Yong Sang, Kim, Sun Young, Lee, Hyunjung, Kim, Tae Won, Kim, Jong-Il
• Format: Article
• Language: English
• Subjects: 631/208/212/2301; 631/67/1504/1885/1393; Adenomatous polyposis coli; Adult; Age; Age of Onset; Biomedical and Life Sciences; Biomedicine; Carcinogenesis; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Copy number; DNA biosynthesis; DNA repair; Exome Sequencing - methods; Female; Genome, Human; Genomes; Genomic instability; Humans; Loss of Function Mutation; Male; Medical Biochemistry; Microsatellite Instability; Mismatch repair; Molecular Medicine; Mutation; p53 Protein; Stem Cells; Tumor Suppressor Protein p53 - genetics; Tumors; Young Adult; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00583-1

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. Colorectal cancer: tumor genetic classification could help guide treatment Researchers in South Korea have identified distinct types of genetic changes in colorectal cancer (CRC). Groups led by Tae Won Kim at the University of Ulsan, Seoul, and Jong-il Kim at Seoul National University looked for mutations in genes in tumors from 880 patients, including all active genes in 47 patients with early-onset colorectal cancer (EO-CRC). The cancers were classified into three subgroups. A “hypermutated” group had mutations in genes involved in DNA replication and repair. The entire genome was doubled in another group, which included the EO-CRC cases. In this group, TP53 gene function, which is known to be crucial in suppressing tumor formation, was lost. A third group had mutations in two other identified genes. Identifying which subgroups patients belong to may help determine the best treatment option.