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Distinct gene alterations are associated with different clinical considerations and prognostic value in the management of patients with prostate cancer.[1,2,3,4] Germline mutations in BRCA1 and BRCA2 are implicated in heritable prostate cancer, increased risk of diagnosis with aggressive cancer and are associated with other cancer-predisposition syndromes.[5] Germline mutations in some genes impact on the prognosis and response to therapy in patients with prostate cancer.[1–3] Response to therapy has been evaluated in patients with mono- and biallelic DNA DDR alterations; the impact of zygosity on the response to PARP inhibitors is unclear, at least for metastatic CRPC.[4]

 

There is a spectrum of risk depending on the genes affected and the nature of the alteration. BRCA2 and other HRR mutations have a negative effect on outcome of prostate cancer, including:

 

  • Advanced disease at diagnosis[6]
  • Shorter metastasis-free survival[7,8]
  • Shorter time to castration resistance[9,10]
  • Radiographic progression[10]
  • Poorer survival outcomes[6,9,10]

HRR pathway gene mutations

BRCA2 is a key constituent of the HRR pathway. BRCA2 disruption via mutation or deletion can result in a compromised ability to repair double-strand DNA breaks. The distinct genome-wide instability signature includes frequent large insertions and deletions.[11]. ATM is a kinase upstream of the HRR pathway, but ATM-mutant tumours do not appear to exhibit the same characteristic mutational signatures as those with BRCA2 biallelic loss.[12] Mutations in several other HRR-related genes such as PALB2, RAD51B/C, and BRCA1 are recurrent in metastatic CRPC,[13] but are rare and less well-characterised in terms of effect on HRR proficiency in prostate cancers.

CDK12 mutations

Inactivating somatic mutations in CDK12 are present in approximately 5% of metastatic CRPC. CDK12 has been linked to the HRR pathway but CDK12 mutations are associated with a different phenotype to alterations in BRCA2: focal tandem duplications dispersed across the whole genome.[12] This suggests that CDK12 plays an important role outside of HRR. CDK12 mutations are hypothesised to increase sensitivity to immune checkpoint blockade.[14]

MMR pathway gene mutations

Defects to the DNA mismatch repair (MMR) pathway are present in ~3%–4% of metastatic CRPC.[15,16] The most-commonly disrupted genes are MSH2, MSH6, and MLH1.[16,17] Mismatch repair defects may result in high tumour mutational burden (TMB) with distinctive mutational signatures and high microsatellite instability (MSI-H). This can be inferred in patients with metastatic CRPC via targeted sequencing of tumour tissue or Circulating tumour DNA (ctDNA).[15,16] Some tumours with MMR gene defects can acquire secondary alterations to other DNA damage repair genes but these are typically monoallelic events.

Distribution and prevalence of mutations in metastatic prostate cancer

The reported prevalence of deleterious germline mutations in metastatic prostate cancer varies across populations, ranging from approximately 5% to approximately 30%.[9,18,19,20,21,22] Mutations in BRCA2, ATM and CDK12 account for more than half of all DNA damage repair defects. Individual genes can have different effects on DNA damage repair fidelity.[22]

Data from key studies are shown. Mutations in these genes are generally mutually exclusive.

Distribution of Germline Mutations in Metastatic Prostate Cancer: Individual Gene Frequencies Among Patients with a DNA Repair Defect Identified (Adapted from Pritchard et al. [19])
Distribution of Germline Mutations

Other: MSH2/6, RAD51C, MRE11A, BRIP1, FAM175A (all 1%)

 

Distribution of Common DDR Mutations in Metastatic Prostate Cancer: Individual Gene Frequencies Among Patients with a DNA Repair Defect Identified (Adapted from Mateo et al. [21])

 

Reported Prevalence of Deleterious Germline Mutations in Metastatic Prostate Cancer (Adapted from Warner et al [22])

Study

Proportion of cohort with deleterious germline mutations (BRCA1/2, ATM)

Quigley 2018 [11]

4.0%

Warner 2021 [22]

4.9%

Antonarakis 2018 [14]

5.2%

Annala 2018 [9]

5.6%

Castro 2019 [10]

6.5%

Pritchard 2016 [19]

7.8%

Yadav 2019 [23]

8.3%

References

[1] Meyer A, Wilhelm B, Dörk T, et al. ATM missense variant P1054R predisposes to prostate cancer. Radiother Oncol. 2007 Jun;83(3):283-288.

[2] Wang Y, Dai B, Ye D. CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med. 2015 Sep 15;8(9):15708-15715.

[3] Oh M, Alkhushaym N, Fallatah S, et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate. 2019 Jun;79(8):880-895.

[4] Lozano R, Castro E, Aragón IM, et al. Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer. Br J Cancer. 2021 Feb;124(3):552-563.

[5] Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med. 2002 Dec;8(12):571-6.

[6] 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 May 10;31(14):1748-1757.

[7] 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 Aug;68(2):186-93.

[8] Petrovics G, Price DK, Lou H, et al. Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population. Prostate Cancer Prostatic Dis. 2019 Sep;22(3):406-410.

[9] Annala M, Vandekerkhove G, Khalaf D, et al. Circulating tumor dna genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018 Apr;8(4):444-457.

[10] Castro E, Romero-Laorden N, Del Pozo A, 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 Feb 20;37(6):490-503.

[11] Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018 Jul 26;174(3):758-769.

[12] Wu YM, Cieślik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018 Jun 14;173(7):1770-1782.e14.

[13] Doan DK, Schmidt KT, Chau CH, Figg WD. Germline genetics of prostate cancer: prevalence of risk variants and clinical implications for disease management. Cancers (Basel). 2021 Apr 29;13(9):2154.

[14] Antonarakis ES, Isaacsson Velho P, Fu W, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis Oncol. 2020;4:370-381.

[15] Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019 Apr 1;5(4):471-478.

[16] Ritch E, Fu SYF, Herberts C, et al. Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer. Clin Cancer Res. 2020 Mar 1;26(5):1114-1125.

[17] Pritchard CC, Morrissey C, Kumar A, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun. 2014 Sep 25;5:4988.

[18] Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-1228.

[19] Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016 Aug 4;375(5):443-53.

[20] de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020 May 28;382(22):2091-2102.

[21] Mateo J, Seed G, Bertan C, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020 Apr 1;130(4):1743-1751.

[22] Warner E, Herberts C, Fu S, et al. BRCA2, ATM, and CDK12 defects differentially shape prostate tumor driver genomics and clinical aggression. Clin Cancer Res. 2021 Mar 15;27(6):1650-1662.

[23] Yadav S, Hart SN, Hu C, et al. JCO Precision Oncology - published online September 17, 2019.

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