DNA repair and DNA damage response genes associated with increased risk of prostate cancer (PrCa)
| Gene | Function of gene | RR/OR/disease evolution | Research notes |
| BRCA2 | Tumour suppressor, involved in homologous recombination, G2 checkpoint control and resistance to DNA damage81 | Risk by age 65 years 2.5-fold to 8.6-fold (constitutional variant)21
Earlier age of diagnosis82 83 More aggressive disease82 84 Lifetime risk of PrCa with this variant is 40%9 | Most common DNA-repair variant seen in PrCa.21
The results from the first round of the IMPACT Study (https://clinicaltrials.gov/ct2/show/NCT00261456) (prospective study looking at PSA testing in PwPs aged 40–69 years with BRCA1/2 variants vs non-variant carrier controls) found that the positive predictive value of biopsy in BRCA2 variant carriers with PSA >3 ng/mL was 48%—twice that reported in population screening studies.73 85 86 Of the tumours detected, 66% were intermediate or high-risk with a significant difference in tumour detection rates in the BRCA2 cohort compared with controls.85 This supports targeted screening for BRCA2 variant carriers which is now a European Association of Urology (EAU) guideline. |
| BRCA1 | Tumour-suppressor gene essential to chromosome stability with similar function to that of the BRCA2 gene87 | RR 1.8-fold to 3.5-fold that of the general population22 84 88
Lifetime risk of PrCa is 20%9 Standardised incidence ratio (SIR) at age <65 years is 3.57 in the paper by Nyberg et al 16 | Interim results from the IMPACT Study found no significant difference in disease stage or age of diagnosis in BRCA1 carriers versus controls and further follow-up is ongoing.73
Nyberg et al 16 conducted a prospective analysis of PrCa risk in BRCA1 carriers which along with BRCA2 data will be included in the CanRisk Score for PrCa (Antoniou personal communication). |
| ATM | Tumour-suppressor gene involved in DNA repair and inducing apoptosis89 | OR for PrCa 2.18 has been seen in an Icelandic study90
PRACTICAL consortium found an OR of 4.4 86 | The age of onset has been reported to be younger at below 65 years.86 Variants in this gene have also been linked to more aggressive disease.91
ATM is the second most commonly mutated DNA damage response gene seen in PrCa.21 |
| CHEK2 | Tumour-suppressor gene that encodes CHK2 serine-threonine kinase protein, inducing cell cycle arrest in the case of DNA damage92 | OR 1.8–8.291. Cybulski et al,93 Leongamornlert et al,83 Wu et al 94 and Shi et al 95 detail variants in this gene and their PrCa associations | Most of these risk data relate to the 1100delC96 variant and originate from Poland,21 though other variants in CHEK2 have also been implicated in aggressive disease and found in higher frequency than 1100delC.83 Brandão et al reported a significantly higher prevalence of constitutional variants in the CHEK2 gene in metastatic than in localised PrCa, interestingly with no association with age at diagnosis or family history.91 |
| PALB2 | Codes for a binding protein involved in the BRCA complex essential for DNA homologous recombination repair97 | OR 3.591 98
Associated with more aggressive disease33 | Deleterious PALB2 variants have been linked to PrCa and seen frequently in Polish cohorts.99 Biallelic loss of function leads to Fanconi anaemia, though heterozygosity is linked to increased risk of pancreatic and breast cancer.100 Studies looking at breast cancer identified this gene as being linked to their relatives developing prostate cancer, but the evidence was poor.101 Only recently have PALB2 variants been associated with aggressive disease, and PARP inhibitor sensitivity has been noted in PALB2 mutated cancers.102 103 |
| MSH2, MSH6 | MMR genes repair errors in DNA replication. Failure of MMR results in point deletions or microsatellite instability104 | 2-fold to 10-fold PrCa RR and aggressive disease linked to younger age of diagnosis associated with tumours containing a variant in MSH2 105–109 | The IMPACT Study provided the first prospective screening study for PwPs with pathogenic variants in the MMR genes, which published initial findings in 2021.85 The IMPACT Study results demonstrated a larger positive predictive value for prostate cancer detection on biopsy in those with PSA >3 ng/mL in the high-risk cohort than the control cohort; 51.4% vs 32.1%, respectively.85 The IMPACT Study found incidence of PrCa is higher among carriers of MSH2 and MSH6, but not MLH1 85. There were no data on PMS2. |
| NBS1/NBN | The Nijmegen Breakage Syndrome 1 (NBS1) gene is involved in the double-strand DNA break repair complex110 111 | A founder variant in this gene (c.657del5) has been associated with a threefold increased risk of prostate cancer below the age of 60 years, and a fourfold increased risk for PwP carriers with a positive family history91 | The gene is associated with more aggressive and lethal disease and is commonly found in Slavic populations.93 Cybulski et al found significantly increased mortality with 5-year survival reducing to 49%, compared with 72% in controls. They also found that heterozygous carriers were associated with increased PrCa risk.93 |
| Other genes associated with prostate cancer: | |||
| HOXB13 G84E | This gene encodes for the transcription factor homeobox B13, important in prostate development.112 Expression of HOXB13 is restricted to the prostate, where it functions as an androgen receptor repressor and potent transcriptional regulator to modulate androgen receptor signals113 | Kote-Jarai et al in UK data114 — 2.93-fold increase in PrCa risk, up to 4.53-fold with family history. Nyberg et al — Carriers of the G84E variant have an RR of 5.96 (born after 1930) lifetime risk of PrCa by age 85%–60% (no positive family history) and 98% (two relatives diagnosed at a young age), compared with 15% in the general population. Darst et al 31 X285K deletion — OR 2.4-fold and observed more aggressive and advanced disease. OR 5.1 in those with metastatic PrCa | The G84E variant in HOXB13 has been observed to be 20 times more prevalent in people with PrCa than controls and significantly more common in those with a family history of early onset PrCa.115
G84E is a missense and founder mutation found more commonly in Nordic populations and has almost exclusively been found in European people. Kote-Jarai et al calculated PRS for PrCa using the 71 SNPs associated with the disease and the HOXB13 G84E variant, which act multiplicatively on risk. According to these estimations, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. Recently, a rare African ancestry–specific constitutional deletion variant in HOXB13 (rs77179853) which removes the stop codon (X285K) and elongates the HOXB13 protein, was observed.116 Allele frequencies ranged from 0% to 0.26% in Black African ancestry controls from North America, the UK and France, likely due to the high degree of European admixture in these populations. The HOXB13X285K variant was found to be significantly associated with a 2.4-fold increased PrCa risk. |
IMPACT, Identification of Men With a Genetic Predisposition to Prostate Cancer Study; MMR, mismatch repair; PARP, poly ADP ribose polymerase; PRACTICAL consortium, The Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome; PSA, prostate-specific antigen; PwP, people with prostates; RR, relative risk.