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Cited by 24Ovarian cancer diagnosis and treatmentBRCA gene mutations in cancerPARP inhibition in cancer therapy

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Correlation between gene expression and mutator phenotype predicts homologous recombination deficiency and outcome in ovarian cancer

Lu, Jianping, Wu, Di, Li, Chuanxing, Zhou, Meng, Hao, Dapeng·2014·Journal of Molecular Medicine
DOI 10.1007/s00109-014-1191-9
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Abstract

Unlabelled New strategies are needed to predict response to platinum-based chemotherapy and outcome of ovarian cancers. We hypothesized that the mutator phenotype in the cancer genome represents the overuse of alternative DNA repair mechanisms, which might be a sign of homologous recombination (HR) deficiency and can be captured by gene expression. Multidimensional data of ovarian cancer patients and breast cancer patients from The Cancer Genome Atlas (TCGA) database were used for the development and validation of a potential clinical information-independent score that correlates with HR deficiency and predicts outcome. Correlation of the score with platinum response, outcome, and BRCA mutations was assessed. The score correlated with increased genomic mutation rate in both ovarian cancer and breast cancer cases that harbored a substantial subset of HR-deficient samples. Significantly improved outcomes were observed in the high-scoring group versus the low-scoring group in the TCGA dataset and in three large gene expression microarray datasets. A strong correlation was found between the score and the likelihood of achieving complete response to chemotherapy. The score was also found to be highly robust to noises in genomic mutations. Sixty-four patients harboring BRCA mutations were successfully divided into two groups based on scores, with the high-scoring group showing significantly improved outcomes compared with wild-type cases and the low-scoring group showing no significance in all the same analyses. The score was significantly correlated with the response to platinum therapy and outcome. Evaluation of the score as a prognostic tool in ovarian cancer patients is warranted. Key message We develop a diagnostic signature for the HR-deficiency based on a novel hypothesis. HR-deficiency score is significantly correlated to platinum therapy and outcomes. HRDS was validated by its association with OS, PFS, DFS and CR in validation datasets. Evaluation of the score as a prognostic tool in ovarian cancer patients is warranted.

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Metadata

Authors
Lu, J., Wu, D., Li, C., Zhou, M., & Hao, D.
Affiliations
Harbin Medical University (CN)
Corresponding author
  • Zhou, Meng
  • Hao, Dapeng
ORCID
Venue
Journal of Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-07-27
Volume
92
Issue
11
Pages
1159-1168
ISSN
  • 0946-2716 (ISSN-L)
  • 1432-1440
DOI
10.1007/s00109-014-1191-9
OpenAlex
W1990146159
Cited by
24
References
3
Citations by year
2026: 1 · 2025: 1 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2017: 2 · 2016: 3
FWCI
2.02
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Journal of Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
ovarian cancer, homologous recombination deficiency, mutator phenotype, gene expression signatures, platinum response, BRCA mutations, prognostic score, breast cancer, overall survival, progression-free survival, complete response
MeSH terms
Adult, Aged, Aged, 80 and over, Female, Humans, Middle Aged, Ovarian Neoplasms, Phenotype, Prognosis, Recombination, Genetic, Gene Expression Regulation, Neoplastic, Proportional Hazards Models, Drug Resistance, Neoplasm, Genes, BRCA1, Kaplan-Meier Estimate, Mutation Rate, Homologous Recombination

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