Zhu Qianqian, Wang Jie, Yu Han, Hu Qiang, Bateman Nicholas W, Long Mark, Rosario Spencer, Schultz Emily, Dalgard Clifton L, Wilkerson Matthew D, Sukumar Gauthaman, Huang Ruea-Yea, Kaur Jasmine, Lele Shashikant B, Zsiros Emese, Villella Jeannine, Lugade Amit, Moysich Kirsten, Conrads Thomas P, Maxwell George L, Odunsi Kunle
Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
Cancers (Basel). 2022 May 10;14(10):2350. doi: 10.3390/cancers14102350.
While and mutations are known to confer the largest risk of breast cancer and ovarian cancer, the incomplete penetrance of the mutations and the substantial variability in age at cancer onset among carriers suggest additional factors modifying the risk of cancer in mutation carriers. To identify genetic modifiers of , we carried out a whole-genome sequencing study of 66 ovarian cancer patients that were enriched with carriers, followed by validation using data from the Pan-Cancer Analysis of Whole Genomes Consortium. We found , a master regulator of mitochondrial biogenesis and function, to be highly mutated in carriers, and patients with both and mutations were diagnosed with breast or ovarian cancer at significantly younger ages, while the mutation status of each gene alone did not significantly associate with age of onset. Our study suggests as a possible modifier gene. Upon further validation, this finding can help improve cancer risk prediction and provide personalized preventive care for carriers.
虽然已知BRCA1和BRCA2突变会带来患乳腺癌和卵巢癌的最大风险，但这些突变的不完全外显率以及携带者中癌症发病年龄的显著差异表明，还有其他因素会改变BRCA1突变携带者患癌风险。为了确定BRCA1的遗传修饰因子，我们对66名富含BRCA1携带者的卵巢癌患者进行了全基因组测序研究，随后使用全基因组泛癌分析联盟的数据进行验证。我们发现，线粒体生物发生和功能的主要调节因子PGC-1α在BRCA1携带者中发生了高度突变，同时携带BRCA1和PGC-1α突变的患者被诊断出患有乳腺癌或卵巢癌的年龄要小得多，而单独每个基因的突变状态与发病年龄并无显著关联。我们的研究表明PGC-1α可能是一种BRCA1修饰基因。经过进一步验证，这一发现有助于改善癌症风险预测，并为BRCA1携带者提供个性化的预防护理。
