Most Common Cause of Prostate Cancer
Prostate cancer is fundamentally a multifactorial disease where genetic factors account for more than 50% of risk, making inherited genetic susceptibility the single most important causative factor, followed by advancing age and race. 1
Primary Causative Factors
Genetic Predisposition (Strongest Factor)
- Inherited genetic factors are responsible for 40-50% of all prostate cancer cases, representing the largest attributable risk for the disease 2, 1
- Approximately 9-15% of prostate malignancies are due to clearly identifiable inherited predisposition with specific gene mutations 3, 4
- Among men with metastatic prostate cancer, 11.8% harbor germline mutations in DNA repair genes, with BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), and BRCA1 (0.9%) being most common 3, 5
Key hereditary syndromes include:
- BRCA2 mutations confer 2-6 fold increased risk and account for up to 2% of early-onset cases, representing the strongest single-gene hereditary risk factor 3, 6, 7
- HOXB13 G84E mutation increases risk 3.3-8.6 fold, particularly in men with positive family history and early-onset disease 3
- Lynch syndrome (MLH1, MSH2, MSH6, PMS2 mutations) confers 2-5 fold increased risk 5, 7
Family History (Reflects Genetic Susceptibility)
- Men with one first-degree relative affected have 2.5-fold increased risk; two relatives confer 5-fold risk; three relatives result in 11-fold increased risk 3, 6, 7
- Genetic analyses demonstrate autosomal dominant inheritance patterns with 88% penetrance in hereditary cases 3, 7
- Approximately 42% of early-onset prostate cancers (diagnosed before age 55) have a hereditary component 3, 6
Age (Universal Risk Factor)
- More than 70% of prostate cancer patients are older than 65 years at diagnosis, with median age of 71 years 3, 6
- More than 90% of prostate cancer deaths occur in men older than 65 years 3, 6
- A 50-year-old man has a 42% lifetime risk of developing histological prostate cancer, though only 9.5% risk of clinically important disease 3
Race and Ethnicity
- African American men have 64% higher incidence and 2.3-fold increase in mortality compared to white men (annual incidence: 173.0 vs 97.1 per 100,000) 6, 1
- African American men present with higher-grade prostatic intraepithelial neoplasia and higher Gleason scores, though stage- and grade-adjusted mortality rates are similar to white men 3
- Asian males have the lowest incidence globally 8
Important Clinical Caveats
Common pitfall: Clinicians often underestimate the genetic contribution to prostate cancer. Unlike environmental cancers where modifiable risk factors dominate, prostate cancer is primarily driven by inherited susceptibility that cannot be modified through lifestyle changes alone.
Critical distinction: While diet and environmental factors are frequently cited, no dietary or environmental cause has been definitively established as causative for prostate cancer 8. These factors may modify risk in genetically susceptible individuals but are not primary causes.
Actionable implication: The strong genetic basis means that family history assessment and consideration of germline genetic testing should be standard practice, particularly for men with metastatic disease, early-onset disease (age <55), or multiple affected relatives 3, 5.