Houlahan Kathleen E, Bihie Mahad, Contreras Julián Grandvallet, Fulop Daniel J, Lopez Gonzalo, Huang Hsin-Hsiung, Van Loo Peter, Curtis Christina, Boutros Paul C, Huang Kuan-Lin
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
bioRxiv. 2024 Oct 21:2024.10.17.618945. doi: 10.1101/2024.10.17.618945.
Optimizing prevention and early detection of cancer requires understanding the number, types and timing of driver mutations. To quantify this, we exploited the elevated cancer incidence and mutation rates in germline and carriers. Using novel statistical models, we identify genomic deletions as the likely rate-limiting mutational processes, with 1-3 deletions required to initiate breast and ovarian tumors. -driven hereditary and sporadic tumors undergo convergent evolution to develop a similar set of driver deletions, and deletions explain the elevated cancer risk of -carriers. Orthogonal mutation timing analysis identifies deletions of chromosome 17 and 13q as early, recurrent events. Single-cell analyses confirmed deletion rate differences in vs. non-carrier tumors as well as cells engineered to harbor . The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.
优化癌症的预防和早期检测需要了解驱动突变的数量、类型和发生时间。为了对此进行量化，我们利用了种系携带者中升高的癌症发病率和突变率。使用新颖的统计模型，我们确定基因组缺失是可能的限速突变过程，启动乳腺和卵巢肿瘤需要1至3次缺失。驱动的遗传性和散发性肿瘤经历趋同进化以产生一组相似的驱动缺失，并且缺失解释了携带者患癌风险的升高。正交突变时间分析将17号染色体和13q的缺失确定为早期复发性事件。单细胞分析证实了携带者与非携带者肿瘤以及经过工程改造以携带的细胞之间的缺失率差异。与缺失相关的染色体不稳定性在肿瘤发生中的核心地位塑造了对非恶性组织体细胞进化的解释，并指导了精准预防和早期检测策略。
