Yang Cuiping, Xiang Enfei, Chen Ping, Fang Xuqian
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Genet. 2024 Jul 3;15:1391851. doi: 10.3389/fgene.2024.1391851. eCollection 2024.
Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma.
Tissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma ( = 8), villous adenoma ( = 10), tubular adenoma ( = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC.
Inherited germline mutation sites in gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs19), FAP04 (p.E1538, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs3). Notably, p.V677Sfs3 mutation was recognized as a novel germline mutation in , supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (, and ) and DNA damage repair genes (, , , and ), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of "genomic scars") was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion.
We identified a novel pathogenic variant in namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.
家族性腺瘤性息肉病（FAP）是一种遗传综合征，其特征是在不同进化阶段出现多个息肉，若不治疗，不可避免地会发展为结直肠癌（CRC）。在本研究中，我们对FAP-CRC从癌前腺瘤到癌的进化史进行了全面分析。
通过胃肠内镜检查或手术切除收集组织。对8例腺癌、10例绒毛状腺瘤、9例管状腺瘤的多个区域进行外显子组测序，并从7个中国FAP家族的9例患者中获取血样。重建系统发育树，并进行进化分析以揭示导致CRC的事件的时间顺序。
在FAP01（p.S1281*，COSM19212）、FAP03（p.S384Tfs19）、FAP04（p.E1538，COSM6041693）、FAP05（p.Q1062*，COSM3696862）以及FAP07 - FAP09（p.V677Sfs3）中鉴定出APC基因的遗传性种系突变位点。值得注意的是，p.V677Sfs3突变被确认为APC基因中的一种新型种系突变，系谱分析中的基因型 - 表型相关性证据支持了这一点。腺瘤的突变率低于FAP - CRC，并在著名的染色体不稳定（CIN）基因（如KRAS、NRAS和BRAF）和DNA损伤修复基因（如MLH1、MSH2、MSH6和PMS2）中表现出反复改变，提示存在基因组不稳定。此外，从管状腺瘤到绒毛状腺瘤，最终到癌，观察到HRD评分（一种“基因组疤痕”的衡量指标）逐渐增加。APC成为腺瘤 - 癌转变的主要驱动基因，驱动突变始终同时出现，而非从腺瘤到癌依次获得。克隆进化表明肝转移可源自原发癌病灶中存在的同一个癌症起始细胞。
我们在APC基因中鉴定出一种新型致病变异，即p.V677Sfs*3。FAP - CRC的致癌过程支持经典的癌变模型，即最初的APC突变导致WNT信号通路激活和CIN。随后，其他假定的CIN基因（如DNA修复、染色质重塑）中发生额外突变，最终导致微卫星稳定（MSS）肿瘤的发展。我们的研究提供了对腺瘤向癌转变背后的基因组格局的全面理解。
