Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jan-Dec:29:10732748221129451.
doi: 10.1177/10732748221129451.

Prognostic Role of DNA Damage Response Genes Mutations and their Association With the Sensitivity of Olaparib in Prostate Cancer Patients

Dong Zhang  1 , Xinchi Xu  1 , Yuang Wei  1 , Xinglin Chen  1 , Guangyao Li  1 , Zhongwen Lu  1 , Xu Zhang  1 , Xiaohan Ren  1 , Shangqian Wang  1 , Chao Qin  1
Affiliations

Prognostic Role of DNA Damage Response Genes Mutations and their Association With the Sensitivity of Olaparib in Prostate Cancer Patients

Dong Zhang et al. Cancer Control. 2022 Jan-Dec.

Abstract

Objective: Evidence shows that gene mutation is a significant proportion of genetic factors associated with prostate cancer. The DNA damage response (DDR) is a signal cascade network that aims to maintain genomic integrity in cells. This comprehensive study was performed to determine the link between different DNA damage response gene mutations and prostate cancer.

Materials and methods: A systematic literature search was performed using PubMed, Web of Science, and Embase. Papers published up to February 1, 2022 were retrieved. The DDR gene mutations associated with prostate cancer were identified by referring to relevant research and review articles. Data of prostate cancer patients from multiple PCa cohorts were obtained from cBioPortal. The OR or HR and 95% CIs were calculated using both fixed-effects models (FEMs) and random-effects models (REMs).

Results: Seventy-four studies were included in this research, and the frequency of 13 DDR genes was examined. Through the analysis of 33 articles that focused on the risk estimates of DDR genes between normal people and PCa patients, DDR genes were found to be more common in prostate cancer patients (OR = 3.6293 95% CI [2.4992; 5.2705]). Also, patients in the mutated group had a worse OS and DFS outcome than those in the unmutated group (P < .05). Of the 13 DDR genes, the frequency of 9 DDR genes in prostate cancer was less than 1%, and despite differences in race, BRCA2 was the potential gene with the highest frequency (REM Frequency = .0400, 95% CI .0324 - .0541). The findings suggest that mutations in genes such as ATR, BLM, and MLH1 in PCa patients may increase the sensitivity of Olaparib, a PARP inhibitor.

Conclusion: These results demonstrate that mutation in any DDR pathway results in a poor prognosis for PCa patients. Furthermore, mutations in ATR, BLM, and MLH1 or the expression of POLR2L, PMS1, FANCE, and other genes significantly influence Olaparib sensitivity, which may be underlying therapeutic targets in the future.

Keywords: DNA damage response; frequency; gene mutations; prognosis; prostate cancer.

PubMed Disclaimer

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Flow diagram of literature search strategy for the meta-analysis.
Figure 2.
Figure 2.
Forest plots of the DDR genes mutation rate in patients with prostate cancer (A) BRCA2 (B) CHEK2 (C) ATM (D) MUTYH (E) BRCA1 (F) TP53 (G) PMS2 (H) MSH2 (I) PALB2 (J) NBN (K) MSH6 (L) BRIP1 (M) RAD51D.
Figure 3.
Figure 3.
Forest plots of the 6 DNA damage response genes mutation rate in patients with prostate cancer regarding each country (A) ATM (B) BRCA1 (C) BRCA2 (D) CHEK2 (E) MSH2 (F) NBN.
Figure 4.
Figure 4.
Funnel plots of effect estimates on DNA damage response genes mutation rate in patients with prostate cancer (A) ATM (B) BRCA1 (C) BRCA2 (D) CHEK2 (E) MSH2 (F) NBN.
Figure 5.
Figure 5.
Forest plots of the key factors in each analysis rate (A) ATM (B) BRCA1 (C) BRCA2 (D) CHEK2 (E) MSH2 (F) NBN.
Figure 6.
Figure 6.
(A) Forest plots of the DNA damage response genes mutation rate between patients with prostate cancer and normal population (B) Forest plots performed the Key factors (C) Funnel plots performed effect estimates of each study.
Figure 7.
Figure 7.
Kaplan-Meier curves showing that the patients with DNA damage response mutations may have a worse prognosis (A) BER pathway (B) Checkpoint factors (C) FA pathway (D) HR pathway (E) HRR pathway (F) MMR pathway (G) NER pathway (H) NHEJ pathway (I) TLS pathway.
Figure 8.
Figure 8.
(A) The IC50 of Olaparib in multiple cancers (B) The mutations of ATR, BLM, and MLH1 could improve the sensitivity of patients to Olaparib (C) The volcano plot of the association between gene expression with Olaparib sensibility. The blue dot could decrease the sensibility of Olaparib and the red dot could increase the sensibility of Olaparib.
Figure 9.
Figure 9.
(A) The IC50 of rucaparib in multiple cancers (B) The mutations of MLL2 could improve the sensitivity of patients to Olaparib.
See this image and copyright information in PMC

References

    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA A Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708. - DOI - PubMed
    1. Lichtenstein P, Holm NV, Verkasalo K, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland [J]. N Engl J Med. 2000;343(2):78-85. - PubMed
    1. Leongamornlert D, Saunders E, Dadaev T, et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease [J]. British journal of cancer. 2014;110(6):1663-1672. - PMC - PubMed
    1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer [J]. N Engl J Med. 2016;375(5):443-453. - PMC - PubMed
    1. Verhage BA, Baffoe-Bonnie AB, Baglietto L, et al. Autosomal dominant inheritance of prostate cancer: a confirmatory study [J]. Urology. 2001;57(1):97-101. - PubMed

Publication types

Substances