ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
This article is part of the Research TopicGenetic and Genomic Alterations in CancerView all 6 articles
Early genetic events in the colorectal carcinogenic pathway of familial adenomatous polyposis and sporadic polyp: Germline and somatic alterations in carcinogenesis
Provisionally accepted
Hiroki Tanabe1*
Yusuke Mizukami1,2
Yusuke Ono2
HIDEHIRO TAKEI3
Nobue Tamamura1Yu Kobayashi1Keitaro Takahashi1
Katsuyoshi Ando1Nobuhiro Ueno1Shin Kashima1
Mishie Ann Tanino3
Kentaro Moriichi1
Mikihiro Fujiya1
Toshikatsu Okumura1- 1Asahikawa Medical University, Asahikawa, Japan
- 2Sapporo Higashi Tokushukai Byoin, Sapporo, Japan
- 3Asahikawa Ika Daigaku Byoin, Asahikawa, Japan
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: An identical cancer pathway may be associated with multistep carcinogenesis,
Keywords: FAP (familial adenomatous polyposis), NGS - next generation sequencing, Cancer, Adenoma, APC
Received: 17 Jul 2025; Accepted: 19 Nov 2025.
Copyright: © 2025 Tanabe, Mizukami, Ono, TAKEI, Tamamura, Kobayashi, Takahashi, Ando, Ueno, Kashima, Tanino, Moriichi, Fujiya and Okumura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hiroki Tanabe, tant@asahikawa-med.ac.jp
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.