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Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer

2015; Impact Journals LLC; Volume: 6; Issue: 37 Linguagem: Inglês

10.18632/oncotarget.5554

1949-2553

Émmanuelle Nicolas, Sanjeevani Arora, Yan Zhou, Ilya G. Serebriiskii, Mark Andrake, Elizabeth Handorf, Dale L. Bodian, Joseph G. Vockley, Roland L. Dunbrack, Eric A. Ross, Brian L. Egleston, Michael J. Hall, Erica A. Golemis, Veda N. Giri, Mary B. Daly,

Cancer-related gene regulation

// Emmanuelle Nicolas 1 , Sanjeevani Arora 2 , Yan Zhou 3 , Ilya G. Serebriiskii 2, 4 , Mark D. Andrake 2 , Elizabeth D. Handorf 3 , Dale L. Bodian 5 , Joseph G. Vockley 5 , Roland L. Dunbrack 2 , Eric A. Ross 3 , Brian L. Egleston 3 , Michael J. Hall 6 , Erica A. Golemis 2 , Veda N. Giri 7 , Mary B. Daly 6 1 Programs in Genomics, Fox Chase Cancer Center, Philadelphia, PA, USA 2 Programs in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA, USA 3 Programs in Biostatistics, Fox Chase Cancer Center, Philadelphia, PA, USA 4 Kazan Federal University, Kazan, Russia 5 Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA 6 Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA 7 Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA Correspondence to: Mary B. Daly, e-mail: Mary.Daly@fccc.edu Veda N. Giri, e-mail: Veda.Giri@jefferson.edu Keywords: familial prostate cancer, whole exome sequencing, DNA damage response, genetic susceptibility to prostate cancer, case-only study Received: July 30, 2015 Accepted: October 02, 2015 Published: October 14, 2015 ABSTRACT Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX ( p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation.