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Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab

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Abstract

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA.

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Acknowledgements

Authors thank the Central University of Punjab for providing necessary facilities and infrastructure.

Funding

This study was funded by Central University of Punjab, Bathinda.

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Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India

    Heena Singla, Raman Preet Kaur & Anjana Munshi

  2. Department of Clinical Genomics and Bioinformatics, Positive Bioscience, Mumbai, India

    Gowhar Shafi

  3. Max Super-Speciality Hospital, Bathinda, India

    Rajesh Vashistha

  4. Guru Gobind Singh Medical College and Hospital, Faridkot, India

    Raja Paramjeet Singh Banipal

  5. Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, India

    Vinod Kumar

  6. Centre for Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India

    Anjana Munshi

  7. Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India

    Vinod Kumar

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  1. Heena Singla
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Contributions

HS and RPK are researchers working in the field of BC and have conducted all the study. GS has undertaken the analysis of GSA results and carried out the statistical analysis. AM along with VK, RV and RPSB designed the work and helped in the interpretation of results. All the authors contributed to manuscript writing and approved it.

Corresponding authors

Correspondence to Vinod Kumar or Anjana Munshi.

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Authors declare that they do not hold any conflict of interest.

Ethical approval

The authors declare that the Institutional Ethics Committee of the Central University of Punjab, Bathinda approved this study which was conducted in agreement with the recommendations of the Helsinki Declaration.

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Informed consent was obtained from all individual participants included in the study.

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Singla, H., Kaur, R.P., Shafi, G. et al. Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab. Mol Biol Rep 46, 823–831 (2019). https://doi.org/10.1007/s11033-018-4537-5

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  • DOI: https://doi.org/10.1007/s11033-018-4537-5

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