Whole-Genome Sequencing Identifies PPARGC1A as a Putative Modifier of Cancer Risk in BRCA1/2 Mutation Carriers

• Published in: Cancers Vol. 14; no. 10; p. 2350
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.05.2022; MDPI
• Subjects: BRCA modifier; BRCA1 protein; BRCA2 protein; Breast cancer; cancer susceptibility gene; Evolution; Family medical history; Genetic factors; Genomes; Mitochondria; Mutation; Ovarian cancer; Whole genome sequencing; breast cancer; BRCA modifier; cancer susceptibility gene; ovarian cancer; whole-genome sequencing
• ISSN: 2072-6694; 2072-6694
• 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.