Genetic risk factors for prostate cancer
- Heather H Cheng, MD, PhD
Heather H Cheng, MD, PhD
- Assistant Professor, Division of Medical Oncology, University of Washington
- Assistant Member, Division of Clinical Research, Fred Hutchinson Cancer Research Center
- Peter S Nelson, MD
Peter S Nelson, MD
- Member, Divisions of Human Biology and Clinical Research
- Fred Hutchinson Cancer Research Center
- Professor, Division of Medical Oncology, University of Washington
- Section Editors
- Jerome P Richie, MD, FACS
Jerome P Richie, MD, FACS
- Section Editor — Cancer of the Urethra, Penis, and Ureter; Urologic Surgery; Prostate Cancer
- Elliott Carr Cutler Professor of Surgery
- Harvard Medical School
- Nicholas Vogelzang, MD
Nicholas Vogelzang, MD
- Section Editor — Prostate Cancer
- Professor of Medicine
- University of Nevada School of Medicine
- US Oncology Research
- W Robert Lee, MD, MS, MEd
W Robert Lee, MD, MS, MEd
- Section Editor — Prostate Cancer
- Professor of Radiation Oncology
- Duke University Medical Center
Prostate cancer is the most common cancer in men worldwide, with an estimated 1,600,000 cases and 366,000 deaths in 2015. Prostate cancer was the leading cause of cancer deaths for men in 29 countries .
The most important known risk factors for prostate cancer are age, ethnicity, and inherited genetic variants. The genetic risk factors for adenocarcinoma of the prostate are reviewed here. Other risk factors for prostate cancer are discussed separately. (See "Risk factors for prostate cancer".)
Prostate cancer has a strong genetic component. However, identifying specific genes that underlie the disease is challenging.
Evidence supporting the role of genetic factors comes from studies of relatives of patients with prostate cancer (linkage studies), genome-wide association studies (GWAS), patients from families with inherited mutations in known cancer predisposition genes (such as BRCA2 and BRCA1), and next-generation sequencing studies in men with metastatic prostate cancer. This observation, coupled with an association with more aggressive features, may contribute to strategies for the early detection, diagnosis, and management of prostate cancer in the context of certain deleterious variants (for example, in BRCA2) .
Contemporary studies have found a much higher prevalence of known inherited cancer predisposition genes (eg, BRCA2) than previously appreciated in men with aggressive prostate cancer. This observation may contribute to strategies for the early detection, diagnosis, and management.
- Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2017; 3:524.
- Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year Outcomes Following Conservative Management Among Men Aged 65 Years or Older with Localized Prostate Cancer. Eur Urol 2015; 68:805.
- Genitourinary cancer syndromes. In: ASCO Curriculum: Cancer Genetics and Cancer Predisposition Testing, 2nd, Offitt K, Garber J, Grady M (Eds), ASCO Publishing, Alexandria 2004. p.10.
- National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
- Bancroft EK, Page EC, Castro E, 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.
- Bratt O, Drevin L, Akre O, et al. Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study. J Natl Cancer Inst 2016; 108.
- Mucci LA, Hjelmborg JB, Harris JR, et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 2016; 315:68.
- Hemminki K, Ji J, Försti A, et al. Concordance of survival in family members with prostate cancer. J Clin Oncol 2008; 26:1705.
- Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366:141.
- Cai Q, Wang X, Li X, et al. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget 2015; 6:42312.
- Kote-Jarai Z, Mikropoulos C, Leongamornlert DA, et al. Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann Oncol 2015; 26:756.
- Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38:652.
- Freedman ML, Haiman CA, Patterson N, et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A 2006; 103:14068.
- Gudmundsson J, Sulem P, Manolescu A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 2007; 39:631.
- Haiman CA, Patterson N, Freedman ML, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 2007; 39:638.
- Yeager M, Orr N, Hayes RB, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007; 39:645.
- Zheng SL, Sun J, Cheng Y, et al. Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst 2007; 99:1525.
- Eeles RA, Kote-Jarai Z, Giles GG, et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 2008; 40:316.
- Thomas G, Jacobs KB, Yeager M, et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 2008; 40:310.
- Gudmundsson J, Sulem P, Steinthorsdottir V, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 2007; 39:977.
- Zheng SL, Sun J, Wiklund F, et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med 2008; 358:910.
- Szulkin R, Karlsson R, Whitington T, et al. Genome-wide association study of prostate cancer-specific survival. Cancer Epidemiol Biomarkers Prev 2015; 24:1796.
- Al Olama AA, Kote-Jarai Z, Berndt SI, et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 2014; 46:1103.
- Sun J, Zheng SL, Wiklund F, et al. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat Genet 2008; 40:1153.
- Marzec J, Mao X, Li M, et al. A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population. Oncotarget 2016; 7:21393.
- Rand KA, Rohland N, Tandon A, et al. Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. Hum Mol Genet 2016; 25:371.
- Dong JT. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev 2001; 20:173.
- Chang BL, Liu W, Sun J, et al. Integration of somatic deletion analysis of prostate cancers and germline linkage analysis of prostate cancer families reveals two small consensus regions for prostate cancer genes at 8p. Cancer Res 2007; 67:4098.
- Xu J, Dimitrov L, Chang BL, et al. A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 2005; 77:219.
- Grönberg H, Adolfsson J, Aly M, et al. Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol 2015; 16:1667.
- SEER Cancer Statistics Review, 1973-1999 http://seer.cancer.gov/csr/1973_1999/ (Accessed on February 25, 2012).
- Hankey BF, Feuer EJ, Clegg LX, et al. Cancer surveillance series: interpreting trends in prostate cancer--part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst 1999; 91:1017.
- Delongchamps NB, Singh A, Haas GP. The role of prevalence in the diagnosis of prostate cancer. Cancer Control 2006; 13:158.
- Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91:1310.
- 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.
- Mitra A, Fisher C, Foster CS, et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 2008; 98:502.
- Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 2007; 99:929.
- Narod SA, Neuhausen S, Vichodez G, et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 2008; 99:371.
- Edwards SM, Evans DG, Hope Q, et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 2010; 103:918.
- Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013; 31:1748.
- Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur Urol 2015; 68:186.
- Leongamornlert D, Mahmud N, Tymrakiewicz M, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 2012; 106:1697.
- Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 2010; 16:2115.
- Helgason H, Rafnar T, Olafsdottir HS, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 2015; 47:906.
- Hale V, Weischer M, Park JY. CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. Prostate Cancer 2014; 2014:294575.
- Näslund-Koch C, Nordestgaard BG, Bojesen SE. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol 2016; 34:1208.
- Southey MC, Goldgar DE, Winqvist R, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 2016; 53:800.
- Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375:443.
- Erkko H, Xia B, Nikkilä J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 2007; 446:316.
- Raymond VM, Mukherjee B, Wang F, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013; 31:1713.
- Haraldsdottir S, Hampel H, Wei L, et al. Prostate cancer incidence in males with Lynch syndrome. Genet Med 2014; 16:553.
- Na R, Zheng SL, Han M, 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.
- HERITABLE FACTORS
- REFERRAL FOR GENETIC EVALUATION
- SCREENING IMPLICATIONS OF INCREASED RISK
- FAMILY STUDIES
- Impact of family history
- Impact of specific genes identified in family studies
- - HOXB13
- POPULATION STUDIES
- DNA REPAIR GENES
- BRCA2 and BRCA1
- - BRCA2
- - BRCA1
- Lynch syndrome
- Assessments of germline DNA repair gene mutations in aggressive prostate cancer
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS