■家族性腺瘤性息肉病(FAP)是一种遗传综合征,其特征是在各个进化阶段的多个息肉,which,如果不及时治疗,不可避免地进展为结直肠癌(CRC)。在这项研究中,我们对FAP-CRC从癌前腺瘤到癌的进化历史进行了全面分析.
■从胃肠内窥镜检查或手术切除收集组织。对腺癌的多个区域(n=8)进行外显子组测序,绒毛状腺瘤(n=10),从属于7个中国FAP家族的9例患者中获得了管状腺瘤(n=9)和血液样本。重建了系统发育树,并进行进化分析以揭示导致CRC的事件的时间顺序。
■在FAP01中鉴定了APC基因中的遗传种系突变位点(p。S1281*,COSM19212),FAP03(p.S384Tfs*19),FAP04(p.E1538*,COSM6041693),FAP05(p.Q1062*,COSM3696862),和FAP07-FAP09(第V677Sfs*3)。值得注意的是,p.V677Sfs*3突变在APC中被认为是一种新的种系突变,家系分析中基因型-表型相关性的证据支持。腺瘤表现出比FAP-CRC更低的突变率,并且在众所周知的染色体不稳定性(CIN)基因(APC,RAS,SMAD4和TP53)和DNA损伤修复基因(SUZ12,KMT2C,BCLAF1、RUNX1和ARID1B),表明基因组不稳定的存在。此外,从管状腺瘤到绒毛状腺瘤,以及最终到癌,观察到HRD评分逐渐增加(“基因组疤痕”的量度).TP53成为腺瘤-癌转变的主要驱动基因,驱动突变始终同时出现,而不是从腺瘤到癌依次出现。克隆进化表明,肝转移可能源于原发癌性病变中存在的相同的癌引发细胞。
■我们在APC中发现了一种新的致病变异,即,p.V677Sfs*3。FAP-CRC的癌变过程支持经典的癌变模型,其中初始APC突变导致WNT信号通路和CIN的激活。随后,其他假定的CIN基因中会发生其他突变(例如,DNA修复,染色质重塑),最终导致微卫星稳定(MSS)肿瘤的发展。我们的研究提供了从腺瘤到癌过渡的基因组景观的全面理解。
UNASSIGNED: 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.
UNASSIGNED: Tissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 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.
UNASSIGNED: Inherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, 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 (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), 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. TP53 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.
UNASSIGNED: We identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC 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.