PROJECT 4

Clinical implication of the acquisition of BRCA1/2 function in BRCA1/2 deficient ovarian carcinoma (Abbrev.: Restoration of BRCA 1/2)

Toshiyasu Taniguchi, MD, PhD - Fred Hutchinson Cancer Research Center
Elizabeth Swisher, MD - University of Washington

Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal, we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA1/2-deficient hereditary and sporadic ovarian carcinomas.

First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcomes of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in the presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression.

With these studies, we will determine the clinical significance of the restoration of BRCA1/2 function in the treatment of BRCA1/2-deficient cancer as shown in the figure. Our study will provide critical information about the mechanisms of platinum-resistance of BRCA1/2-deficient tumors, which will enable us to predict platinum resistance of recurrent carcinomas, and may eventually lead to new therapeutic strategies to overcome platinum resistance.

Other Research

Project 1
Project 2
Project 3
Project 4
Project 5
Clinical Core
Informatics Core
Specimen Core
Leadership Core

Project 4 Publications

1. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King M, Swisher EM. Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas. Clin Cancer Res. 2014 Feb 1;20(3):764-75. doi: 10.1158/1078-0432.CCR-13-2287. Epub 2013 Nov 15. PMCID:PMC3944197. PubMed Link ↗

2. Pennington KP, Wickramanayake A, Norquist BM, Pennil CC, Garcia RL, Agnew KJ, Taniguchi T, Welcsh P, Swisher EM. 53BP1 expression in sporadic and inherited ovarian carcinoma: Relationship to genetic status and clinical outcomes. Gynecol Oncol. 2013 128(3):493-9. PMCID: PMC3889639. PubMed Link ↗

3. Johnson N, Johnson SF, Yao W, Li YC, Choi YE, Bernhardy AJ, Wang Y, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell MI, Liu JF, D'Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6. doi: 10.1073/pnas.1305170110. Epub 2013 Oct 1. PMCID:PMC3801063. PubMed Link ↗

4. Norquist BM, Pennington KP, Agnew KJ, Harrell MI, Pennil CC, Lee MK, Casadei S, Thornton AM, Garcia RL, Walsh T, Swisher EM. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol. 2013 128(3):483-7. PMCID:PMC3913382. PubMed Link ↗

5. Swisher E, Walsh T: BRCA1 and BRCA2 mutations in ovarian cancer. JAMA 307:359-360; author reply 360-351, 2012. PMID: 22274679. PubMed Link ↗

6. Swisher EM, Taniguchi T, Karlan BY. Molecular scores to predict ovarian cancer outcomes: a worthy goal, but not ready for prime time. J Natl Cancer Inst. 2012 May 2;104(9):642-5. PMCID: PMC3341312. PubMed Link ↗

7. Wickramanyake A, Bernier G, Pennil C, Casadei S, Agnew KJ, Stray SM, Mandell J, Garcia RL, Walsh T, King MC, Swisher EM. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 Dec;127(3):552-5. PMCID: PMC3905744. PubMed Link ↗

8. Dhillon KK, Swisher EM, Taniguchi T. Secondary mutations of BRCA1/2 and drug resistance. Cancer Sci. 2011 Apr;102(4):663-9. doi: 10.1111/j.1349-7006.2010.01840.x. PMCID: PMC3095365. PubMed Link ↗

9. Norquist B, Wurz K, Pennil CC, Garcia R, Gross J, Sakai W, Karlan B, Taniguchi T, Swisher EM. Secondary Somatic Mutations Restoring BRCA1/2 Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas. J Clin Oncol. 2011 Aug 1:29(22):3008-15. PMCID: PMC3157963. PubMed Link ↗

10. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King MC, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMCID: PMC3207658. PubMed Link ↗