Complex Relationships Between Homologous Recombination Deficiency (HRD) Score and Mutational Status of Homologous Recombination Repair (HRR) Genes in Prostate Carcinomas
Homologous recombination deficiency (HRD) resulting from inactivation of <i>BRCA1/2</i> genes promotes chromosomal instability and renders tumor cells susceptible to platinum derivatives and PARP inhibitors (PARPi). The contribution of alterations in other homologous recombination repair (HRR) genes to HRD remains understudied. This investigation aimed to analyze the spectrum of mutations in 34 HRR genes in prostate carcinomas (PCs) and study the relationship between HRR status and HRD. HRR mutations and HRD scores were examined by NGS in 1131 and 680 PCs, respectively. Pathogenic or likely pathogenic variants in HRR genes were detected in 216/1131 cases (19.1%). HRD, defined by an HRD score cut-off of ≥42, was observed more frequently in HRR-mutated than in wild-type tumors (23/120 (19.2%) vs. 29/560 (5.2%), <i>p</i> < 0.0001). The highest HRD scores were detected in PCs with biallelic inactivation of the <i>BRCA2</i> or <i>PALB2</i> genes, as well as in tumors with <i>BRIP1</i> mutations. HRD was also occasionally seen in PCs with <i>ATM</i>, <i>NBN, FANCM</i>, <i>BRCA1</i> and <i>CDK12</i> alterations, but never in cases with <i>CHEK2</i> mutations. HRD was significantly more associated with aggressive PC features than HRR mutations. The majority of <i>CDK12</i>-mutated tumors exhibited a distinct type of copy number variations (CNV)-a tandem duplication phenotype. Our study suggests that the selection of PC patients for PARPi treatment requires a significant revision of existing attitudes towards tumor genetic profiling.
Authors
- A.S. Peremyshlenko (ORCID: https://orcid.org/0000-0003-0333-5562)
- Ekatherina Sh. Kuligina (ORCID: https://orcid.org/0000-0002-2396-6540)
- A. V. Agaeva (ORCID: https://orcid.org/0000-0002-6121-274X)
- Anna D. Shestakova (ORCID: https://orcid.org/0000-0003-0649-9693)
- Анна Петровна Соколенко (ORCID: https://orcid.org/0000-0001-6304-1609)
- Ekaterina A. Otradnova (ORCID: https://orcid.org/0009-0003-0158-1820)
- Р. В. Орлова (ORCID: https://orcid.org/0000-0003-4447-9458)
- Nadezhda S. Morozova (ORCID: https://orcid.org/0009-0003-3335-872X)
- Mhitar M. Grigoryan (ORCID: https://orcid.org/0000-0001-5555-7437)
- Vladimir Krivtsov (ORCID: https://orcid.org/0000-0003-0844-5007)
- A. Dzyuba (ORCID: https://orcid.org/0000-0003-3612-3195)
- Евгений Наумович Имянитов (ORCID: https://orcid.org/0000-0003-4529-7891)
- А. А. Белоусов
- Aglaya G. Iyevleva (ORCID: https://orcid.org/0000-0001-5454-5186)
- Irina K. Amirkhanova
- M. Nechaeva (ORCID: https://orcid.org/0009-0005-4128-2643)
- С. В. Попов (ORCID: https://orcid.org/0000-0002-9050-4493)
- А. В. Орлов (ORCID: https://orcid.org/0000-0002-2069-7111)
- Светлана Николаевна Алексахина (ORCID: https://orcid.org/0000-0002-2149-7728)
- А. М. Belyaev (ORCID: https://orcid.org/0000-0001-5580-4821)
- Vladislav F. Kutyan
- Maria V. Syomina (ORCID: https://orcid.org/0009-0003-3206-2871)
- Natalya V. Prokudina (ORCID: https://orcid.org/0009-0005-8178-1199)
- Alisa S. Nikitina
- Kira A. Kashko (ORCID: https://orcid.org/0009-0002-9410-9009)
- Elena N. Vorobyeva
- Lyubov I. Zatulivetrova
- Pavel V. Vyazovcev
- Tatyana Yu. Luchkova
- Irina Yu. Povorina
- Aryuna B. Gomboeva
- Natalya A. Butunina
- Nadezhda V. Kryukova
- Olga M. Gudkova
- Oksana N. Shkodenko
- Andrey V. Levushkin
- Daniil O. Moiseev
- Demyan V. Gubarev
- Spartak I. Lefterov
- Olga I. Shchiglik
- Timur M. Topuzov
Institutions
- Penza State University (RU)
- Vologda State University (RU)
- Buryat State University (RU)
- Severance Hospital (KR)
- Stavropol Regional Clinical Oncology Center (RU)
- Leningrad Regional Cancer Center (RU)
- Saratov Research Institute of Traumatology and Orthopedics (RU)
- Institute of Oncology NN Petrov (RU)
- City Clinical Oncology Center (RU)
- Pyatigorsk Oncology Center (RU)
- Penza State University of Architecture and Construction (RU)
- Oncological Dispensary No. 2 (RU)
- Guz "Tul'skiy Oblastnoy Onkologicheskiy Dispanser (RU)
- Saint Luke's Hospital (US)
- Pskov State University (RU)
- Saratov Research Center (RU)
- Arkhangel'skiy Klinicheskiy Onkologicheskiy Dispanser (RU)
- Chelyabinsk Regional Clinical Oncology Center (RU)
- Karelian Research Centre (RU)
- Pskov State Pedagogical Institute (RU)
- Krasnodar Higher Military School named after General of the Army S. Shtemenko (RU)
- International Institute of Management Arkhangelsk (RU)
- Saint Petersburg State Pediatric Medical University (RU)
- Kaliningrad State Technical University (RU)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-12-08
- DOI
- https://doi.org/10.3390/ijms262411851
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Russian Science Foundation
- National Medical Research Council