Mahdi Amar H, Huo Yanying, Chen Ying, Selenica Pier, Sharma Anchal, Merritt Elise, Barnard Nicola, Chan Chang, Ganesan Shridar, Reis-Filho Jorge S, Weigelt Britta, De Subhajyoti, Xia Bing
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
Genes Dis. 2020 Sep 5;9(3):807-813. doi: 10.1016/j.gendis.2020.08.012. eCollection 2022 May.
The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human breast cancers and mouse mammary tumors from , and conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in that disengages the PALB2-BRCA1 interaction in different backgrounds. Rather than mammary tumors, and compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of single mutant and compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.
BRCA1-PALB2-BRCA2轴，即BRCA通路，在维持基因组稳定性以及抑制乳腺癌和其他几种癌症中发挥关键作用。由于人类乳腺癌以及来自、和条件性敲除模型的小鼠乳腺肿瘤中经常出现p53突变，人们常常认为p53失活会加速BRCA1/2和PALB2相关的肿瘤发生。在此，我们研究了在不同背景下因突变而使PALB2-BRCA1相互作用解偶联的小鼠的肿瘤发展情况。与乳腺肿瘤不同，和复合突变小鼠发展出潜伏期大大缩短的淋巴瘤和肉瘤，这些肿瘤通常与种系失活有关。全外显子组测序未能在单突变和复合突变小鼠的相同肿瘤类型之间识别出基因组特征的任何显著差异。这些结果表明，BRCA通路的缺失加速了p53相关的肿瘤发展，可能并未改变基本的肿瘤发生过程。
