{"doi":"10.3389/fgene.2025.1668133","title":"Early genetic events in the colorectal carcinogenic pathway of familial adenomatous polyposis and sporadic polyp: germline and somatic alterations in carcinogenesis","abstract":"<h4>Purpose</h4>Genetic mutations in the tumor suppressor gene <i>APC</i> and the oncogene <i>KRAS</i> 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 <i>APC</i> 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.<h4>Experimental design</h4>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 <i>APC</i> 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.<h4>Results</h4>Colorectal tumors of FAP and non-polyposis patients showed a similar frequency of mutations (<i>APC,</i> 76% and 75%; <i>KRAS</i>, 32% and 25%). Somatic <i>APC</i> mutations in FAP patients was observed in the mutation cluster region (63.3%). In FAP, many colorectal tumors (57.5%) harbored two <i>APC</i> 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 <i>APC</i> 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.<h4>Conclusion</h4>An identical cancer pathway may be associated with multistep carcinogenesis, accompanied by <i>APC</i> mutations in mutation hotspots. A combined analysis of germline and somatic alterations revealed 'three-hit' alterations in the <i>APC</i> gene among the FAP patients, suggesting that the heterogeneity of colorectal carcinogenesis contribute to these genetic changes.","journal":"Frontiers in Genetics","year":2025,"id":1965,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0403,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-12-19","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":22257,"name":"Yusuke Mizukami","orcid":"0000-0002-1068-7024","position":1,"is_corresponding":false},{"id":22258,"name":"Yusuke Ono","orcid":"0000-0001-8385-5386","position":2,"is_corresponding":false},{"id":22259,"name":"Hidehiro Takei","orcid":"0000-0002-2095-670X","position":3,"is_corresponding":false},{"id":22260,"name":"Nobue Tamamura","orcid":null,"position":4,"is_corresponding":false},{"id":22261,"name":"Yu Kobayashi","orcid":"0000-0002-6196-604X","position":5,"is_corresponding":false},{"id":22262,"name":"Keitaro Takahashi","orcid":"0000-0003-4188-0246","position":6,"is_corresponding":false},{"id":22263,"name":"Katsuyoshi Ando","orcid":"0000-0003-3500-5488","position":7,"is_corresponding":false},{"id":22264,"name":"Nobuhiro Ueno","orcid":null,"position":8,"is_corresponding":false},{"id":22265,"name":"Shin Kashima","orcid":"0000-0001-8309-4281","position":9,"is_corresponding":false},{"id":22266,"name":"Mishie Tanino","orcid":"0000-0003-3370-0452","position":10,"is_corresponding":false},{"id":22267,"name":"Kentaro Moriichi","orcid":"0000-0002-1298-3265","position":11,"is_corresponding":false},{"id":22268,"name":"Mikihiro Fujiya","orcid":null,"position":12,"is_corresponding":false},{"id":22269,"name":"Toshikatsu Okumura","orcid":"0000-0003-1810-007X","position":13,"is_corresponding":false},{"id":22256,"name":"Hiroki Tanabe","orcid":"0000-0001-9029-5081","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}