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Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy

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Abstract

Therapy-related acute leukemias (t-ALs) represent approximately 10–20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3′-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.

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Acknowledgement

The authors are grateful to Professor Richard Larson (University of Chicago) for critical reading of the manuscript. SKH was supported by a grant from ICMR, New Delhi (Ref # 56/7/2019_HAE-BMS).

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Author notes

  1. Bhausaheb Bagal and Rohit Kumar have contributed equally to this work.

Authors and Affiliations

  1. Adult Hemato-Lymphoid Disease Management Group, Tata Memorial Hospital, Mumbai, 400012, India

    Bhausaheb Bagal, Vikas Talreja, Avinash Bonda, Nikhil Patkar, Dhanlaxmi Shetty, P. G. Subramanian & Syed K. Hasan

  2. Cell and Tumor Biology Group, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Sector 22, Raintree street, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Rohit Kumar, Tarang Gaur & Syed K. Hasan

  3. Genome Biology Group, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, 410210, India

    Pradnya Kowtal & Rajiv Sarin

  4. Department of Medical Oncology, Tata Memorial Centre, Mumbai, 400012, India

    Sudeep Gupta

  5. Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, 400094, India

    Bhausaheb Bagal, Avinash Bonda, Nikhil Patkar, P. G. Subramanian, Sudeep Gupta, Rajiv Sarin & Syed K. Hasan

Authors
  1. Bhausaheb Bagal
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  2. Rohit Kumar
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Contributions

BB, RK, and SKH conducted experiments, data acquisition, and data analyses. TG, VT, AB, and NP contributed to patients’ samples, processing and real-time PCR. DS is responsible for cytogenetics; PK and RS contributed to genetic screening of BRCA1. SG and PGS provided clinical data. SKH designed the study and wrote this paper.

Corresponding author

Correspondence to Syed K. Hasan.

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Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Both the patients provided written informed consent in accordance with the Declaration of Helsinki, and the Ethics Committee of Tata Memorial Centre, Mumbai (TMC-IEC III) DCGI registration number: IECIII: ECR/149/Inst/MH/2013 approved this study (IEC reference number 219/2019 dated 24/05/2019).

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Bagal, B., Kumar, R., Gaur, T. et al. Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy. Med Oncol 37, 48 (2020). https://doi.org/10.1007/s12032-020-01371-z

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  • DOI: https://doi.org/10.1007/s12032-020-01371-z

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