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. 2022 May 10;14(10):2350.
doi: 10.3390/cancers14102350.

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

Qianqian Zhu  1 , Jie Wang  1 , Han Yu  1 , Qiang Hu  1 , Nicholas W Bateman  2   3 , Mark Long  1 , Spencer Rosario  1 , Emily Schultz  1 , Clifton L Dalgard  4   5 , Matthew D Wilkerson  4   5 , Gauthaman Sukumar  3   5 , Ruea-Yea Huang  6 , Jasmine Kaur  7 , Shashikant B Lele  7 , Emese Zsiros  7 , Jeannine Villella  8 , Amit Lugade  6 , Kirsten Moysich  9 , Thomas P Conrads  2   10 , George L Maxwell  2   10 , Kunle Odunsi  6   7   11   12
Affiliations

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

Qianqian Zhu et al. Cancers (Basel). .

Abstract

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.

Keywords: BRCA modifier; breast cancer; cancer susceptibility gene; ovarian cancer; whole-genome sequencing.

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Conflict of interest statement

K.O. is a co-founder of Tactiva Therapeutics and receives research support from AstraZeneca and Tesaro. T.P.C. is a scientific advisory board member for ThermoFisher Scientific, Inc. G.L.M. is a consultant for Kiyatec, GSK, and Merck. The other authors have declared no conflict of interest exists. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DoD), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., or the U.S. Government.

Figures

Figure 1
Figure 1
Schema of the analyses to identify genetic modifiers of ovarian and breast cancer risks in BRCA carriers.
Figure 2
Figure 2
The largest gene sub-network significantly altered in BRCA carriers. Genes that were significantly highly mutated in BRCA carriers (Table 1) were highlighted by red underscores.
Figure 3
Figure 3
Fraction of BRCA carriers and non-carriers that contained PPARGC1A mutations: (a) analysis within the PCAWG validation cohorts; (b) analysis within our discovery cohort, the PCAWG validation cohorts, and all cohorts combined. The numbers inside the bars are the numbers of BRCA carriers and non-carriers.
Figure 4
Figure 4
The distribution of cancer age onset by BRCA and PPARGC1A mutation status in PCAWG breast and ovarian cancer patients. The number in parenthesis is the sample size of each group.
Figure 5
Figure 5
The PPARGC1A variants identified in the discovery stage (a); and validation stage (b); respectively.
See this image and copyright information in PMC

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