| Title: | KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression |
| Journal: | Prostate Cancer and Prostatic Diseases |
| Published: | 11 Feb 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35149774/ |
| DOI: | https://doi.org/10.1038/s41391-021-00466-6 |
| Citations: | 3 (3 in last 2 years) as of 8 Aug 2024 |
Publication 12535
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Abstract
BackgroundGermline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations.MethodsGermline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using a logistic regression model adjusting for genetic background (top ten principal components).ResultsIn the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs−/KLK3−), RPMs−/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression.ConclusionsTwo different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.</p>
8 Keywords
- DNA Repair
- Genetic Predisposition to Disease
- Genotype
- Germ-Line Mutation
- Humans
- Male
- Prostate
- Prostatic Neoplasms
12 Authors
- Jianfeng Xu
- Zhuqing Shi
- Jun Wei
- Rong Na
- W. Kyle Resurreccion
- Chi-Hsiung Wang
- Chris Sample
- Misop Han
- S. Lilly Zheng
- Kathleen A. Cooney
- Brian T. Helfand
- William B. Isaacs
1 Application
| Application ID | Title |
|---|---|
| 50295 | Validity and performance of inherited risk assessment for common diseases using polygenic risk score, family history, and high-penetrance genes |
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