Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer

DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63–0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.

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Germline analysis of DNA-damage repair genes in men with advanced prostate cancer in comparison to women with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13147 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13147-e13147

Author(s):

Amy Kunz ◽

Natalie Tri ◽

Arash Samiei ◽

Shifeng Mao

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Dna Damage ◽

Genetic Counseling ◽

Genetic Testing ◽

Advanced Prostate Cancer ◽

Dna Damage Repair ◽

Local Therapy ◽

Genetic Alterations ◽

Damage Repair

e13147 Background: Women with breast cancer have traditionally been the population for genetic counseling. The association of hereditary cancer syndromes and the development of advanced prostate cancer have been established only since recent years. There has been increased utilization of germline analysis in men with prostate cancer since NCCN updated its guideline on genetic testing for DNA damage repair (DDR) genes in the homologous recombination (HR) pathway in this population. In this study, we analyzed the prevalence of genetic alterations in DDR genes in men with advanced prostate cancer in relevance to women with breast cancer in our institution. Methods: Patients who were referred to genetic counseling in 2018 and met NCCN criteria underwent genetic testing following pretest genetic counseling. Samples obtained from buccal mucosa or peripheral blood were analyzed for germline variants using commercially available multi-gene panels which included DDR genes in the HR pathway. Results: In 2018, 54 men with prostate cancer with relapsed disease following local therapy, or de novo metastasis, and 305 women with breast cancer were included. At least one pathogenic or likely pathogenic variant was identified in 9 men (16.7%), most frequently in BRCA2, ATM, and CHEK2, as compared to those in 30 women (9.8%), p = 0.137. 17 men (31.5%) had at least one variant of uncertain clinical significance (VUS) detected in a DDR gene as compared to those in 74 (24.3%) women with breast cancer, p = 0.261. Conclusions: Men with advanced prostate cancer have a statistically comparable but numerically trending higher frequency of pathogenic variants and VUS in DDR genes detected on germline testing in comparison to women with breast cancer. The high prevalence of VUS in prostate cancer is an intriguing finding. VUS represent a genetic alteration with undefined clinical outcome. With increasing genetic testing in prostate cancer, further correlation between VUS of DDR genes and clinical risk features from a larger population is warranted.

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Comparing the characteristics of advanced Prostate Cancer (PC) patients with and without DNA Damage Repair mutations (DDRm): A systematic review

European Urology Open Science ◽

10.1016/s2666-1683(20)36211-x ◽

2020 ◽

Vol 21 ◽

pp. S154

Author(s):

E. Castro ◽

S.H. Lang ◽

S.L. Swift ◽

R.M. Leadley ◽

A. Chalker ◽

...

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

Dna Damage ◽

Advanced Prostate Cancer ◽

Dna Damage Repair ◽

Damage Repair

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Anaplastic Features in Advanced Prostate Cancer with and without DNA Damage Repair Mutations

Clinical Genitourinary Cancer ◽

10.1016/j.clgc.2021.05.005 ◽

2021 ◽

Author(s):

Vincent Chau ◽

Ravi A. Madan ◽

Marijo Bilusic ◽

Helen Owens ◽

Lisa M. Cordes ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Advanced Prostate Cancer ◽

Dna Damage Repair ◽

Damage Repair

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Breast Cancer Susceptibility and DNA Damage/Repair

10.21236/ada424044 ◽

2003 ◽

Author(s):

Roy E. Shore

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cancer Susceptibility ◽

Dna Damage Repair ◽

Breast Cancer Susceptibility ◽

Damage Repair

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DNA damage repair gene mutation testing and genetic counseling in men with/without prostate cancer: a systematic review

Future Oncology ◽

10.2217/fon-2020-0569 ◽

2020 ◽

Author(s):

Nigel Armstrong ◽

Ruben GW Quek ◽

Steve Ryder ◽

Janine Ross ◽

Titas Buksnys ◽

...

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

At Risk ◽

Dna Damage ◽

Clinical Trials ◽

Genetic Counseling ◽

Mutation Screening ◽

Dna Damage Repair ◽

Mutation Testing ◽

Damage Repair

Background: Ongoing clinical trials are investigating poly(ADP-ribose) polymerase (PARP) inhibitors to target the DNA damage repair (DDR) pathway in prostate cancer. DDR mutation screening will guide treatment strategy and assess eligibility for clinical trials. Materials & methods: This systematic review estimated the rate of DDR mutation testing or genetic counseling among men with or at risk of prostate cancer. Results: From 6856 records, one study fulfilled the inclusion criteria and described men undiagnosed with prostate cancer with a family history of BRCA1/2 mutation who received DDR mutation testing. Conclusion: With only one study included in this first systematic review of DDR mutation testing or genetic counseling in men with or at risk of prostate cancer, more research is warranted.

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