Rashid Mamunur, Fischer Andrej, Wilson Cathy H, Tiffen Jessamy, Rust Alistair G, Stevens Philip, Idziaszczyk Shelley, Maynard Julie, Williams Geraint T, Mustonen Ville, Sampson Julian R, Adams David J
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Population Genomics of Adaptation, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
J Pathol. 2016 Jan;238(1):98-108. doi: 10.1002/path.4643. Epub 2015 Nov 2.
Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss-of-function mutations in WTX (9%; p < 9.99e-06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes.
家族性腺瘤性息肉病（FAP）和MUTYH相关息肉病（MAP）是与多发性结直肠腺瘤相关的遗传性疾病，会导致患结直肠癌的风险非常高。在这些情况下驱动腺瘤发展的体细胞突变尚未得到全面研究。在本研究中，我们对患有FAP或MAP的个体的配对结直肠腺瘤和正常组织DNA进行了分析，对14个腺瘤全外显子组（8个MAP，6个FAP）、55个腺瘤靶向外显子组（33个MAP，22个FAP）以及每位患者的种系DNA进行了测序，并通过毛细管测序对另外63个腺瘤（41个FAP，22个MAP）进行了测序。利用这些数据，我们研究了突变基因的概况、突变特征和体细胞突变率，观察到不同腺瘤中驱动基因的突变组合存在显著差异，以及WTX基因存在功能丧失突变（9%；p < 9.99e - 06），该基因与WNT通路调控和p53乙酰化有关。这些数据扩展了我们对息肉病综合征中结直肠癌发生早期事件的理解。
