BRCA2 gene mutation and prostate cancer risk. Comprehensive review and update

Noor N. Junejo, Sultan S. AlKhateeb


The second most common type of tumor worldwide is prostate cancer (PCa). Certain genetic factors contribute to a risk of developing PCa of as much as 40%. BRCA1 and BRCA2 mutations have linked with an increased risk for breast, ovarian, and PCa. However, BRCA2 is the most common gene found altered in early-onset of PCa in males younger than 65. BRCA2 mutation has a higher chance of developing an advanced stage of the disease, resulting in short survival time. This review aimed to describe the genetic changes in BRCA2 that contribute to the risk of PCa, to define its role in the early diagnosis in a man with a strong family history, and to outline the purpose of genetic testing and counseling. Also, the review summarizes the impact of BRCA2 gene mutation in localized PCa, and the treatment strategies have used for PCa patients with a BRCA2 modification. 

Saudi Med J 2020; Vol. 41 (1): 9-17

How to cite this article:

Junejo NN, AlKhateeb SS. BRCA2 gene mutation and prostate cancer risk. Comprehensive review and update. Saudi Med J. 2020 Jan;41(1):9-17.
doi: 10.15537/smj.2020.1.24759


BRCA2; hereditary; prostate cancer; mutation

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424.

Kvale R, Myklebust TA, Engholm G, Heinävaara S, Wist E, Moller B. Prostate and breast cancer in four Nordic countries: a comparison of incidence and mortality trends across countries and age groups 1975-2013. Int J Cancer 2017; 141: 2228-2242.

Saudi Cancer Registry. Annual Report; 2010. Available from:

Mosli HA. Prostate cancer in Saudi Arabia in 2002. Saudi Med J 2003; 24: 573-581.

Kehinde EO. Age-specific reference levels of serum prostate-specific antigen and prostate volume in healthy Arab men 2005. BJU Int 2005; 96: 308-312.

Alyaiya AA. Proteomics-based signature for human benign prostate hyperplasia and prostate adenocarcinoma. Int J Oncol 2011; 38: 1047-1057.

Hemminki K, Li X, Czene K. Cancer risks in first-generation immigrants to Sweden. Int J Cancer 2002; 99: 218-228.

Visser O, van Leeuwen FE. Cancer risk in first generation migrants in North-Holland/Flevoland, The Netherlands 1995-2004. Eur J Cancer 2007; 43: 901-908.

Nasseri K, Mills P, Allan A. Cancer incidence in the Middle Eastern population of California 1988-2004. Asian Pac J Cancer Prev 2007; 8: 405-411.

Hanash K, Al-Othaimeen A, Kattan S, Lindstedt E, Al-Zahrani H. Prostatic carcinoma: a nutritional disease? Conflicting data from the Kingdom of Saudi Arabia. J Urol 2000; 164: 1570-1572.

American Cancer Society. Cancer Facts and Figures 2019. Atlanta (GA): American Cancer Society; 2019.

Salinas CA, Tsodikov A, Ishak-Howard M, Cooney KA. Prostate cancer in young men: an important clinical entity. Nat Rev Urol 2014; 11: 317-323.

Hjelmborg JB, Scheike T, Holst K, Skytthe A, Penney KL, Graff RE, et al. The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomarkers Prev 2014; 23: 2303-2310.

Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990; 17: 337-347.

Stanford JL, Ostrander EA. Familial prostate cancer. Epidemiol Rev 2001; 23: 19-23.

Matikaine MP, Pukkala E, Schleutker J, Tammela TL, Koivisto P, Sankila R, et al. Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 2000; 12: 223-230.

Bratt O, Garmo H, Adolfsson J, Bill-Axelson A, Holmberg L, Lambe M, et al. Effects of prostate-specific antigen testing on familial prostate cancer risk estimates. J Natl Cancer Inst 2010; 102: 1336-1343.

Jacqueline Mersch, Michelle A. Jackson, Minjeong Park, Denise Nebgen, Susan K. Peterson, Claire Singletary, et al. Cancer. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 2015; 121: 269-275.

Giri VN, Beebe-Dimmer JL. Familial prostate cancer. Seminoncol 2016; 43: 560-565.

Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375: 443-453.

Castro E, Romero-Laorden N, Del Pozo A, Lozano R, Medina A, Puente J, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019; 37: 490-503.

Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localized prostate cancer. Eur Urol 2015; 68: 186-193.

Robinson D, Eliezer M. van Allen, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161: 1215-1228.

Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373: 1697-1708.

Kasmintan A. Schrader, Donavan T. Cheng, Vijai Joseph, Meera Prasad, Michael Walsh, Ahmet Zehir, et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol 2016; 2: 104-111.

King M-C, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302: 643-646.

Schoenborn JR, Nelson P, Fang M. Genomic profiling defines subtypes of prostate cancer with the potential for therapeutic stratification. Clin Cancer Res 2013; 19: 4058-4066.

Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nat Gen 2013; 45: 1134-1139.

Grasso CS, Wu YM, Robinson DR, Dhanasekaran SM, Khan AP, Quist MJ, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239-243.

Kumar A, White TA, MacKenzie AP, Clegg N, Lee C, Dumpit RF, et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc Natl Acad Sci USA 2011; 108: 17087-17092.

Bisbal C, Silverman RH. Diverse functions of RNase L and implications in pathology. Biochimie 2007; 89: 789-798.

Takaku H, Minagawa A, Takagi M, Nashimotoet M. A candidate prostate cancer susceptibility gene encodes tRNA 3 processing endoribonuclease. Nucleic Acids Res 2003; 31: 2272- 2278.

Beuten J, Gelfond JAL, Franke JL, Shook S, Teresa L. Johnson-Pais, Thompson Ian M, et al. Single and multivariate associations of MSR1, ELAC2, and RNase L with prostate cancer in an ethnic diverse cohort of men. Cancer Epidemiol Biomarkers Prev 2010; 19: 588 -599.

Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, et al. Germ line mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 141-149.

Risbridger G. P, Taylor RA, Clouston D, Sliwinski A, Thorne H, Hunter S, et al. Patient- derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis. Eur Urol 2015; 67: 496-503.

Porter LH, Lawrence MG, Ilic D, Clouston D, Bolton DM, Frydenberg M, et al. Systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories. Eur Urol 2017; 72: 492-495.

Taylor RA, Fraser M, Rebello RJ, Boutros PC, Murphy DG, Bristow RG, et al. The influence of BRCA2 mutation on localized prostate cancer. Nat Rev Urol 2019; 16: 281-229.

Castro E, Mateo J, Olmos D, de Bono JS. Targeting DNA repair: The role of PARP inhibition in the treatment of castration resistant prostate cancer. Cancer J 2016; 22: 353-356.

Armenia J, Wankowicz S.A.M, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet 2018; 50: 645-651.

Narod SA, Neuhausen S, Vichodez G, Armel S, Lynch HT, Ghadirian P, et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 2008; 99: 371-374.

Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 2010; 16: 2115-2121.

Thorne H, Willems A.J, Niedermayr E, Hoh I.M, Li J, Clouston D, et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res 2011; 4: 1002-1010.

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with a higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer. J Clin Oncol 2013; 31: 1748-1757.

Cheng H.H, Pritchard C.C, Boyd T, Nelson P.S, Montgomery B. Biallelic Inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol 2016; 69: 992-995.

Zafeiriou Z, Bianchini D, Chandler R, Rescigno P, Yuan W, Carreira S, et al. Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency. Eur Urol 2019; 75: 184-192.

Pomerantz MM, Spisak S, Jia L, Cronin AM, Csabai I, Ledet E, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 2017; 123: 3532-3539.

Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373:1697-1708.

Nombela P, Lozano R, Aytes A, Mateo J, Olmos D, Castro E. BRCA2 and Other DDR Genes in Prostate Cancer. Cancers 2019; 11: 352.

Bancroft E.K, Page E.C, Castro E, Lilja H, Vickers A, Sjoberg D, et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study. Eur Urol 2014; 66: 489-499.

Kasivisvanathan V, Rannikko A.S, Borghi M, Panebianco V, Mynderse L.A, Vaarala M.H, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med 2018; 378: 1767-1777.

Nielsen F.C, van Overeem Hansen, T, Sorensen C.S. Hereditary breast and ovarian cancer: New genes in confined pathways. Nat Rev Cancer 2016; 16: 599-612.

Zhen JT, Syed J, Nguyen KA, Leapman MS, Agarwal N, Brierley K, et al. Genetic testing for hereditary prostate cancer: Current status and limitations. Cancer 2018; 124: 3105-3117.

Hart SN, Ellingson MS, Schaal K, Vedell PT, Carlson RE, Sinnwell JP, et al. Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer. BMJ Open 2016; 6: e010332.

Na R, Zheng SL, Han M, Yu H, Jiang D, Shah S, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol 2017; 71: 740-747.

Beltran H, Eng K, Mosquera JM, Sigaras A, Romanel A, Rennert H, et al. Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol 2015; 1: 466-474.

Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery Bet al: Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol 2016; 69: 992-995.

Giri VN, Obeid E, Gross L, Bealin L, Hyatt C, Hegarty SE, et al. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation. J Precis Oncol JCO Precision Oncology 2017; 1: 1-17.

Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N, et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer 2011; 105: 1230-1234.

Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015; 33: 3660-3667.

Bancroft EK, Saya S, Page EC, Myhill K, Thomas S, Pope J, et al. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations. BJU Int 2019; 123: 284-292.

Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010; 28: 375-379.

Von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomized phase 2 trial. Lancet Oncol 2014; 15: 747-756.

Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood A.K, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011; 306: 1557-1565.

Hager S, Ackermann C.J, Joerger M, Gillessen S, Omlin A. Anti-tumor activity of platinum compounds in advanced prostate cancer-a systematic literature review. Ann Oncol 2016; 27: 975-984.

Pomerantz MM, Spisak S, Jia L, Cronin AM, Csabai I, Ledet E, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 2017; 123: 3532-3539.

Morales J, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr 2014; 24: 15-28.

Lord CJ, Tutt AN, Ashworth A. Synthetic lethality and cancer therapy: Lessons learned from the development of PARP inhibitors. Annu Rev Med 2015; 66: 455-470.

Sonpavde G, Di Lorenzo G, Higano CS, Kantoff PW, Madan R, Shore ND. The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature. Eur Urol 2012; 61: 639-634.

Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of phase II randomized controlled trial of Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28: 1099-1105.

Thorne H, Willems AJ, Niedermayr E, Hoh IM, Li J, Clouston D, et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res 2011; 4: 1002-1010.

Caffo O, Veccia A, Kinspergher S, Rizzo M, Maines F. Aberrations of DNA Repair Pathways in Prostate Cancer: Future Implications for Clinical Practice? Front Cell Dev Biol 2018; 5: 61.

Akbari MR, Wallis CJ, Toi A, Trachtenberg J, Sun P, Narod SA, et al. The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer. Br J Cancer 2014; 111: 1238-1240.

Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 2003; 72: 1-12.

Kirchhoff T, Kauff ND, Mitra N, Nafa K, Huang H, Palmer C, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 2004; 10: 2918-2921.

Sinclair CS, Berry R, Schaid D, Thibodeau SN, Couch FJ. BRCA1 and BRCA2 have a limited role in familial prostate cancer. Cancer Res 2000; 60: 1371-1375.

Maier C, Herkommer K, Luedeke M, Rinckleb A, Schrader M, Vogel W. Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations. Prostate 2014; 74: 1444-1451.

Ikonen T, Matikainen MP, Syrjäkoski K, Mononen N, Koivisto PA, Rökman A, et al. BRCA1 and BRCA2 mutations have no major role in predisposition to prostate cancer in Finland. J Med Genet 2003; 40: e98.

Manguoğlu E, Güran S, Yamaç D, Colak T, Simşek M, Baykara M, et al. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. Cancer Genet Cytogenet 2010; 203: 230-237.

Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, Jonasson JG, Olafsdóttir EJ, Olafsdóttir GH, Prostate cancer progression, and survival in BRCA2 mutation carriers. J Natl Cancer Inst 2007; 99: 929-935.

Agalliu I, Gern R, Leanza S, Burk RD. Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 2009; 15: 1112-1120.

Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet 2016; 387: 70-82.

Artibani W, Porcaro AB, De Marco V, Cerruto MA, Siracusano, S. Management of biochemical recurrence after primary curative treatment for prostate cancer: a review. Urol Int 2018; 100: 251-262.

Castro E, Jugurnauth-Little S, Karlsson Q, Al-Shahrour F, Piñeiro-Yañez E, Van de Poll F, et al. High burden of copy number alterations and c- MYC amplification in prostate cancer from BRCA2 germline mutation carriers. Ann Oncol 2015; 26: 2293-2300.

Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V et al. Genomic hallmarks of localized, non- indolent prostate cancer. Nature 2017; 541: 359-364.


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