How to Cite
Abstract
Introduction. Alterations in DNA homologous recombination repair (HRR) genes play an important role in the pathogenesis of metastatic prostate cancer (PC). Detection of HRR alterations is of practical importance because tumor cells with HRR deficiency are more sensitive to DNA — damaging agents and to PARP inhibitors.
Aim. To analyze the frequency and spectrum of hereditary and somatic mutations in the main HRR genes in Russian prostate cancer patients.
Materials and methods. The coding regions of 34 HRR genes were analyzed by targeted next — generation sequencing in a group of 541 predominantly aggressive PC cases. Paired DNA samples isolated from blood leukocytes and archived tumor tissue (n = 430), tumor only (n = 61) or normal (n = 50) samples were used for analysis.
Results. Hereditary or somatic pathogenic/likely pathogenic variants in any of the 34 HRR genes were detected in 102/541 (18.9 %) PC cases. A total of 121 mutations were detected in 102 patients, of which the majority (72/121, 59.5 %) were germline variants. Most frequently, mutations were detected in BRCA2 (25/121, 20.7 %), CDK12 (15.7 %), ATM (13.2 %), CHEK2 (11.6 %), NBN (7.4 %), BRCA1 (5.0 %), FANCM (4.1 %), RAD54L (3.3 %). The pattern of BRCA2, CHEK2, and NBN lesions was dominated by inherited defects (68.0, 92.9 and 66.7 %, respectively), whereas 56.3 % of ATM variants and all CDK12 mutations were of somatic origin. ATM and CDK12 mutations were represented by unique variants. In BRCA2, a nonsense substitution p.Gln2157Ter was detected twice.
Loss of heterozygosity in tumor tissue or a second somatic mutation was observed in 9/13 (69.2 %) patients with germline BRCA2 variants. Similar rates for ATM, CHEK2, NBN and BRCA1 genes were 57.1, 50.0, 40.0 and 50.0 % respectively.
Conclusions. The frequency of mutations in 34 HRR genes in aggressive PC is about 20 %. Germline disease — causing variants in BRCA2, CHEK2, NBN, ATM, BRCA1, PALB2 are found in about 10 % of metastatic PC. In addition, about 10 % of advanced PC carry germline or somatic alterations that predict the efficacy of PARP inhibitors.
References
Sung H., Ferlay J., Siegel R.L., et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209249. DOI: 10.3322/caac.21660.
Abida W., Campbell D., Patnaik A., et al. Non — BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration — resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020; 26(11): 24872496. DOI: 10.1158/1078-0432.CCR-20-0394.
de Bono J., Mateo J., Fizazi K., et al. Olaparib for metastatic castration — resistant prostate cancer. N Engl J Med. 2020; 382(22): 20912102. DOI: 10.1056/NEJMoa1911440.
Smith M.R., Scher H.I., Sandhu S., et al. Niraparib in patients with metastatic castration — resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022; 23(3): 362-373.-DOI: 10.1016/S1470-2045(21)00757-9.
de Bono J.S., Mehra N., Scagliotti G.V., et al. Talazoparib monotherapy in metastatic castration — resistant prostate cancer with DNA repair alterations (TALAPRO — 1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22(9): 12501264. DOI: 10.1016/S1470-2045(21)00376-4.
Stopsack K.H. Efficacy of PARP inhibition in metastatic castration — resistant prostate cancer is very different with non — BRCA DNA repair alterations: reconstructing prespecified endpoints for cohort B from the phase 3 PROfound trial of olaparib. Eur Urol. 2021; 79(4): 442 445. DOI: 10.1016/j.eururo.2020.09.024.
Mateo J., Porta N., Bianchini D., et al. Olaparib in patients with metastatic castration — resistant prostate cancer with DNA repair gene aberrations (TOPARPB): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21(1): 162174. DOI: 10.1016/S1470-2045(19)30684-9.
Fallah J., Xu J., Weinstock C., et al. Efficacy of poly (ADP — ribose) polymerase inhibitors by individual genes in homologous recombination repair gene — mutated metastatic castration — resistant prostate cancer: a US Food and Drug Administration pooled analysis. J Clin Oncol. 2024; 42(14): 16871698. DOI: 10.1200/JCO.23.02105.
Pritchard C.C., Mateo J., Walsh M.F., et al. Inherited DNA — repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016; 375(5): 44353.-DOI: 10.1056/NEJMoa1603144.
Robinson D., Van Allen E.M., Wu Y.M., et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 162(2): 454. DOI: 10.1016/j.cell.2015.06.053.
de Sarkar N., Dasgupta S., Chatterjee P., et al. Genomic attributes of homology — directed DNA repair deficiency in metastatic prostate cancer. JCI Insight. 2021; 6(23): e152789. DOI: 10.1172/jci.insight.152789.
Sokol E.S., Pavlick D., Khiabanian H., et al. Pan — cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome — wide loss of heterozygosity. JCO Precis Oncol. 2020; 4: 442465. DOI: 10.1200/po.19.00345.
Lang S.H., Swift S.L., White H., et al. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol. 2019; 55(3): 597616. DOI: 10.3892/ijo.2019.4842.
Darst B.F., Dadaev T., Saunders E., et al. Germline sequencing DNA repair genes in 5545 men with aggressive and nonaggressive prostate cancer. J Natl Cancer Inst. 2021; 113(5): 616625. DOI: 10.1093/jnci/djaa132.
Plym A., Dióssy M., Szallasi Z., et al. DNA repair pathways and their association with lethal prostate cancer in african american and european american men. JNCI Cancer Spectr. 2021; 6(1): pkab097. DOI: 10.1093/jncics/pkab097.
Lukashchuk N., Barnicle A., Adelman C.A., et al. Impact of DNA damage repair alterations on prostate cancer progression and metastasis. Front Oncol. 2023; 13: 1162644. DOI: 10.3389/fonc.2023.1162644.
Матвеев В.Б., Киричек А.А., Филиппова М.Г., et al. Влияние герминальных мутаций в генах BRCA2 и CHEK2 на время до развития кастрационной резистентности у больных метастатическим гормоночувствительным раком предстательной железы. Урология. 2019; 5: 7985. DOI: 10.18565/urology.2019.5.79-85.
[Matveev V.B., Kirichek A.A., Filippova M.G., et al. Impact of germline BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone — naïve prostate cancer. Urology. 2019; 5: 7985.-DOI: 10.18565/urology.2019.5.79-85 (In Rus)].
Маилян О.А., Калпинский А.С., Решетов И.В., et al. Определение распространенности мутаций в генах репарации ДНК в российской популяции у больных метастатическим кастрационно-резистентным раком предстательной железы. Онкоурология. 2022; 18(3): 6066. DOI: 10.17650/1726-9776-2022-18-3-60-66.
[Mailyan O.A., Kalpinsky A.S., Reshetov I.V., et al. Prevalence of mutations in DNA repair genes in Russian patients with metastatic castration — resistant prostate cancer. Oncourology. 2022; 18(3): 6066. DOI: 10.17650/1726-9776-2022-18-3-60-66 (In Rus)].
Ni Raghallaigh H., Eeles R. Genetic predisposition to prostate cancer: an update. Familial Cancer. 2022; 21: 101114. DOI: 10.1007/s10689-021-00227-3.
Kote — Jarai Z., Jugurnauth S., Mulholland S., et al. A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer. Br J Cancer. 2009; 100(2): 42630. DOI: 10.1038/sj.bjc.6604847.
Ledet E.M., Antonarakis E.S., Isaacs W.B., et al. Germline BLM mutations and metastatic prostate cancer. Prostate. 2020; 80(2): 235237. DOI: 10.1002/pros.23924.
Stempa K., Wokołorczyk D., Kluźniak W., et al. Do BARD1 mutations confer an elevated risk of prostate cancer? Cancers (Basel). 2021; 13(21): 5464. DOI: 10.3390/cancers13215464.
Otahalova B., Volkova Z., Soukupova J., et al. Importance of germline and somatic alterations in human MRE11, RAD50, and NBN genes coding for MRN complex. Int J Mol Sci. 2023; 24(6): 5612. DOI: 10.3390/ijms24065612.
Imyanitov E.N. Cytotoxic and targeted therapy for BRCA1/2 — driven cancers. Hered Cancer Clin Pract. 2021; 19(1): 36.-DOI: 10.1186/s13053-021-00193-y.
Póti Á., Gyergyák H., Németh E., et al. Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. Genome Biol. 2019; 20(1): 240. DOI: 10.1186/s13059-019-1867-0.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2025