Temporal Dissection of Tumorigenesis in Primary cancers

The earliest genetic abnormalities in cancer represent a unique opportunity for timely clinical diagnosis. Classic deep sequencing of tumors identifies many aberrations acquired later in cancer progression. In this study, data regarding simple mutation and chromosomal aberration were integrated to trace the evolution of cutaneous squamous cell carcinomas and ovarian adenocarcinomas. Only after the second allele of TP53 was lost did the genome enter a window of extreme genomic vulnerability, in both cancer types, eventually acquiring more than 100,000 mutations in skin cancers. Inactivating Notch mutations were also identified as prevalent secondary changes. These results add context to the idea of TP53 mutation as dominant negative and occurring later in tumorigenesis.

癌症中最早出现的遗传异常，为及时开展临床诊断提供了独特契机。经典的肿瘤深度测序技术往往仅能检测到癌症进展后期才获得的多种异常突变。本研究整合了单纯突变与染色体异常相关的数据，以追溯皮肤鳞状细胞癌与卵巢腺癌的演化进程。在这两类癌症中，基因组仅在TP53（肿瘤蛋白p53）的第二个等位基因缺失后，才会进入极端基因组脆弱性窗口期；其中皮肤鳞状细胞癌最终会积累超过10万个突变。失活型Notch突变也被鉴定为常见的继发性分子改变。本研究结果为“TP53突变为显性负效突变且发生于肿瘤发生后期”这一学术观点补充了更多实验背景与依据。