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Distinct genetic landscape and a low response to doxorubicin in a luminal-A breast cancer cell line of Pakistani origin

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Abstract

Background

Breast cancers exhibit genetic heterogeneity which causes differential responses to various chemotherapy agents. Given the unique demographic and genomic background in South Asia, genetic architecture in breast cancers is not fully explored.

Methods and results

In this study, we determined the genetic landscape of our previously established luminal-A subtype breast cancer cell line (BC-PAK1), and compared it with a Caucasian origin MCF7 breast cancer cell line of the same molecular subtype. Deep whole-exome sequencing (100X) was performed from early passages of the primary cancer cells using the Illumina NextSeq500. Data analysis with in silico tools showed novel non-silent somatic mutations previously not described in breast cancers, including a frameshift insertion (p.Ala1591AlafsTer28) in CIC, and a frameshift deletion (p.Lys333LysfsTer21) in PABPC1. Five genes CDC27, PIK3CG, ARAP3, RAPGEF1, and EFNA3, related with cell cycle pathway (hsa04110), ErbB signaling pathway (hsa04012), Ras signaling pathway (hsa04014), and Rap1 signaling pathway (hsa04015) were found to have recurrent non-silent somatic mutations. Further, the major contribution of COSMIC signatures 3 (failure of DNA double-strand break repair by homologous recombination), and 12 (transcriptional strand-bias for T>C substitutions) was observed. Also, the somatic mutations landscape in BC-PAK1 was found to be different as compared to the MCF7 cell line. The unique genetic landscape of BC-PAK1 might be responsible for significantly reduced response to doxorubicin than the MCF7 cell line.

Conclusion

This study presents a distinct genetic architecture in luminal-A breast cancer potentially responsible for differential response to chemotherapy. Further studies on large cohorts of breast cancer patients are suggested for implementation in personalized medicine.

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Data availability

All the data presented herein has been included in the main manuscript and supplementary material.

Code availability

The bioinformatics tools/codes used in the analysis are freely available in the GitHub repository or at the tools’ websites.

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Funding

The study was performed with funds granted to the institute, Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karachi-75270, Pakistan, by the Searle Pharmaceuticals Pakistan Ltd. The funding agency had no role in the study design and presentation of the results.

Author information

Author notes

  1. Muhammad Shakeel and Salman Ahmed Khan have contributed equally to this work.

Authors and Affiliations

  1. Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, ICCBS, University of Karachi, Karachi, 75270, Pakistan

    Muhammad Shakeel, Salman Ahmed Khan, Muhammad Irfan, Muhammad Aurongzeb & Ishtiaq Ahmad Khan

  2. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Muhammad Shakeel, Salman Ahmed Khan, Anum Jabeen Mughal, Muhammad Irfan, Daniel C. Hoessli, M. Iqbal Choudhary, Muhammad Aurongzeb & Ishtiaq Ahmad Khan

  3. Department of Molecular Medicine, Dow College of Biotechnology, Dow University of Health Sciences, Karachi, Pakistan

    Salman Ahmed Khan

  4. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    M. Iqbal Choudhary

Authors
  1. Muhammad Shakeel
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  2. Salman Ahmed Khan
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  3. Anum Jabeen Mughal
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  4. Muhammad Irfan
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Contributions

MS: performed NGS experimental work, bioinformatics analysis, data visualization, and manuscript preparation; SAK: conceived the study, performed experimental work, and manuscript preparation; AJM: performed experimental work to establish the BC-PAK1 cell line; MI: Performed data analysis, DCH: supervised in the establishment of the cell line, intellectual insights, and manuscript review; MIC: overall supervised the study, intellectual insights, and manuscript review; MA: performed DNA extraction from the cultured BC-PAK1 cells; IAK: intellectual insights, and manuscript review.

Corresponding authors

Correspondence to Salman Ahmed Khan or Ishtiaq Ahmad Khan.

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Shakeel, M., Khan, S.A., Mughal, A.J. et al. Distinct genetic landscape and a low response to doxorubicin in a luminal-A breast cancer cell line of Pakistani origin. Mol Biol Rep 48, 6821–6829 (2021). https://doi.org/10.1007/s11033-021-06681-7

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  • DOI: https://doi.org/10.1007/s11033-021-06681-7

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