# Early genetic events in the colorectal carcinogenic pathway of familial adenomatous polyposis and sporadic polyp: germline and somatic alterations in carcinogenesis

## TL;DR

This study compares genetic changes in colorectal cancer between inherited and sporadic cases, focusing on mutations in the APC and KRAS genes.

## Contribution

The study identifies a 'three-hit' alteration pattern in APC gene mutations among familial adenomatous polyposis patients.

## Key findings

- FAP and sporadic colorectal tumors show similar frequencies of APC and KRAS mutations.
- FAP tumors often have two or three APC mutations, while sporadic cases have fewer.
- Three-hit APC alterations suggest heterogeneity in colorectal cancer development.

## Abstract

Genetic mutations in the tumor suppressor gene APC and the oncogene KRAS are an initial event in the colorectal adenoma-carcinoma sequence. Multistep carcinogenesis has been discovered through the study of familial adenomatous polyposis (FAP), an inherited disease with a germline APC variant. We aimed to determine the premalignant mutational genotypes that progress to colorectal neoplasia using target sequencing to compare the characteristics of FAP patients with sporadic cases.

A total of 197 samples from 20 FAP and 13 sporadic cases were analyzed using next-generation sequencing (NGS) with a cancer panel. The analysis of APC germline variants identified FAP patients with a germline variant, those with whole APC deletion, and those with no alterations. The association between pathogenic germline variants and somatic mutations was assessed.

Colorectal tumors of FAP and non-polyposis patients showed a similar frequency of mutations (APC, 76% and 75%; KRAS, 32% and 25%). Somatic APC mutations in FAP patients was observed in the mutation cluster region (63.3%). In FAP, many colorectal tumors (57.5%) harbored two APC hits, whereas in sporadic cases, one or two hits were more common (44.4% and 22.2%, respectively). Of the 99 tumors in FAP patients with APC germline variants as the first hit, 74 tumors (74.7%) acquired somatic mutations as the second hit, and 9 tumors (9.9%) further gained a third hit, indicating a ‘three-hit’ alteration.

An identical cancer pathway may be associated with multistep carcinogenesis, accompanied by APC mutations in mutation hotspots. A combined analysis of germline and somatic alterations revealed ‘three-hit’ alterations in the APC gene among the FAP patients, suggesting that the heterogeneity of colorectal carcinogenesis contribute to these genetic changes.