DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset

Abstract

The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.

Figure 1. Mutation pattern within age groups.

Distribution of mutations in the gene set KRAS-BRAF-PIK3CA-PTEN-TP53, and MSI status, within each age group. Color coding: dark blue  =  MSI, light blue  =  MSS, red  =  mutation, green  =  wild type, white  =  not detected.

Figure 2. Graphic representation of patients with hypothesized response to EGFR-targeted therapy.

Percent-wise distribution of aberrations for KRAS, BRAF, PIK3CA and PTEN and their combinations, in the <50 age group and >70 age group. Patients negative for all mutations (quadruple negative) are potential responders to anti-EGFR-therapy. (Modified from Bardelli et al. [29])