Assessment of PARP4 as a candidate breast cancer susceptibility gene

Autor: Peter Ang, Jimin Yuan, Min-Han Tan, Aldo Prawira, Yoon Sim Yap, Prabhakaran Munusamy, Timothy Wai Ho Shuen, Claire Hian Tzer Chan, Ann Siew Gek Lee, Geok Ling Koh, Jiancheng Hu
Rok vydání: 2018
Předmět:
0301 basic medicine
Oncology
Male
Cancer Research
0302 clinical medicine
Risk Factors
skin and connective tissue diseases
Exome
Tumor Stem Cell Assay
Singapore
medicine.diagnostic_test
High-Throughput Nucleotide Sequencing
Nuclear Proteins
Middle Aged
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Cohort
Neoplastic Stem Cells
Female
Adult
medicine.medical_specialty
Heterozygote
Susceptibility gene
Breast Neoplasms
Risk Assessment
03 medical and health sciences
Young Adult
Breast cancer
Internal medicine
Cell Line
Tumor
medicine
Biomarkers
Tumor
Humans
Genetic Predisposition to Disease
Genetic Testing
Gene
Genetic Association Studies
Genetic association
Genetic testing
Aged
Cell Proliferation
Neoplasm Staging
Cell growth
business.industry
Computational Biology
medicine.disease
030104 developmental biology
Case-Control Studies
Neoplasm Grading
business
Zdroj: Breast cancer research and treatment. 177(1)
ISSN: 1573-7217
Popis: PARP4 has been proposed as a candidate breast cancer susceptibility gene. However, its function and involvement in breast carcinogenesis is unclear. We sought to determine the variant frequency of PARP4 in BRCA-negative women referred for genetic testing from Singapore and to perform functional analyses of PARP4. Next-generation sequencing of PARP4 was conducted for 198 BRCA-negative cases from Singapore. Three independent case–control association analyses of PARP4 were performed for (1) our Singaporean cohort, (2) three dbGaP datasets, and (3) cases from TCGA, with controls from the Exome Aggregation Consortium (ExAC). PARP4 knockout cells were generated utilizing the CRISPR-Cas9 approach in MDA-MB-231 (breast cancer) and MCF10A (normal breast) cell lines, and colony formation, cell proliferation, and migration assays carried out. Candidate variants in PARP4 were identified in 5.5% (11/198) of our Singapore cohort. Case–control association studies for our cases and the dbGaP datasets showed no significant association. However, a significant association was observed for PARP4 variants when comparing 988 breast cancer cases from the TCGA provisional data and 53,105 controls from ExAC (ALL) (OR 0.249, 95% CI 0.139–0.414, P = 2.86 × 10−11). PARP4 knockout did not affect the clonogenicity, proliferation rate, and migration of normal breast cells, but appeared to decrease the proliferation rate and clonogenicity of breast cancer cells. Taken together, our results do not support that PARP4 functions as a cancer susceptibility gene. This study highlights the importance of performing functional analyses for candidate cancer predisposition genes.
Databáze: OpenAIRE
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