Germline breast cancer susceptibility gene mutations and breast cancer outcomes View Full Text


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Article Info

DATE

2018-03-22

AUTHORS

Yong Alison Wang, Jhih-Wei Jian, Chen-Fang Hung, Hung-Pin Peng, Chi-Fan Yang, Hung-Chun Skye Cheng, An-Suei Yang

ABSTRACT

BACKGROUND: It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis. METHODS: The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic. RESULTS: We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P = 0.007). CONCLUSIONS: Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation. More... »

PAGES

315

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s12885-018-4229-5

    DOI

    http://dx.doi.org/10.1186/s12885-018-4229-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1101701441

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29566657


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        "description": "BACKGROUND: It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.\nMETHODS: The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.\nRESULTS: We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P\u2009=\u20090.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P\u2009=\u20090.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P\u2009=\u20090.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P\u2009=\u20090.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P\u2009=\u20090.007).\nCONCLUSIONS: Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.", 
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