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

Qianqian Zhu*, Jie Wang, Han Yu, Qiang Hu, Nicholas W. Bateman, Mark Long, Spencer Rosario, Emily Schultz, Clifton L. Dalgard, Matthew D. Wilkerson, Gauthaman Sukumar, Ruea Yea Huang, Jasmine Kaur, Shashikant B. Lele, Emese Zsiros, Jeannine Villella, Amit Lugade, Kirsten Moysich, Thomas P. Conrads, George L. MaxwellKunle Odunsi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


While BRCA1 and BRCA2 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 BRCA1/2 mutation carriers. To identify genetic modifiers of BRCA1/2, we carried out a whole-genome sequencing study of 66 ovarian cancer patients that were enriched with BRCA carriers, followed by validation using data from the Pan-Cancer Analysis of Whole Genomes Consortium. We found PPARGC1A, a master regulator of mitochondrial biogenesis and function, to be highly mutated in BRCA carriers, and patients with both PPARGC1A and BRCA1/2 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 PPARGC1A as a possible BRCA modifier gene. Upon further validation, this finding can help improve cancer risk prediction and provide personalized preventive care for BRCA carriers.

Original languageEnglish
Article number2350
Issue number10
StatePublished - 1 May 2022
Externally publishedYes


  • BRCA modifier
  • breast cancer
  • cancer susceptibility gene
  • ovarian cancer
  • whole-genome sequencing


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