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Contribution of constitutional BRCA1 promoter methylation to early-onset and familial breast cancer patients from Pakistan

  • Original Laboratory Investigation
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Abstract

Purpose

Constitutional BRCA1 promoter methylation has been identified as a potential risk factor for breast cancer (BC) in the Caucasian population. However, this data is lacking for BC patients of Asian origin. Therefore, we assessed the contribution of constitutional BRCA1 promoter methylation in Pakistani BC patients.

Methods

A total of 385 BRCA1/2-negative index BC patients (197 early-onset BC (≤ 30 years), 152 familial BC, 17 familial BC and ovarian cancer, 19 male BC) and 107 healthy controls were screened for the constitutional BRCA1 promoter methylation by methylation-sensitive high-resolution melting assay. Overall, 131 patients displayed triple-negative BC (TNBC) and 254 non-TNBC phenotypes. The prevalence of BRCA1 promoter methylation was calculated based on clinicopathological characteristics using univariable and multivariable logistic regression models.

Results

Constitutional BRCA1 promoter methylation was identified in 19.5% (75/385) of BC patients and 13.1% (14/107) of controls. The frequency of methylation was higher in early-onset BC (23.4% vs. 13.1%, P = 0.035) and TNBC patients (29.0% vs. 13.1%, P = 0.004) compared to controls. Methylation was also more prevalent in patients with high-grade than low-grade tumors (21.7% vs. 12.2%, P = 0.034) and progesterone receptor (PR)-negative than PR-positive tumors (26.0% vs. 13.9%, P = 0.004). Constitutional BRCA1 promoter methylation remained independently associated with TNBC phenotype (odds ratio 1.99; 95% CI 1.12–3.54; P = 0.02) after adjusting for BC diagnosis age, tumor grade, ER, and PR status.

Conclusion

Constitutional BRCA1 promoter methylation is associated with TNBC and can serve as a non-invasive blood-based biomarker for Pakistani TNBC patients.

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Data availability

The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to all study subjects for their participation. We thank Asim Amin for the critical reading of the manuscript. We thank the clinicians (Neelam Siddiqui, Mazhar Ali Shah, Narjis Muzaffar, Usman Ahmad, Umm E Kalsoom, Amir Ali Syed, Huma Majeed, Zulqarnain Chaudhry, Muhammad Asad Parvaiz, and Amina Khan) and Clinical Research Officers (Saima Faisal, Mariam Hassan) for their help in recruitment of study participants.

Funding

The study was supported by the institutional support from Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan (Grant # ONC-BRCA-002). Muhammad Usman Rashid has received research support from Shaukat Khanum Memorial Cancer Hospital and Research Centre.

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Authors and Affiliations

  1. Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, 54770, Pakistan

    Noor Muhammad, Ayesha Azeem & Muhammad Usman Rashid

  2. Department of Cancer Registry and Clinical Data Management, SKMCH&RC, Lahore, Pakistan

    Muhammad Abu Bakar

  3. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Karolina Prajzendanc & Anna Jakubowska

  4. Department of Pathology, SKMCH&RC, Lahore, Pakistan

    Asif Loya

  5. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland

    Anna Jakubowska

  6. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Ute Hamann

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Contributions

MUR, NM, AA, and KP contributed to data acquisition, molecular analyses, and manuscript drafting. AL contributed to expert histopathologist and reviewed pathological data. MAB contributed to statistical analysis of the data. AJ, UH, and MUR contributed to study concept and design and data interpretation. MUR contributed to funding acquisition, enrollment of study participants, study supervision, and manuscript revision. All authors have read and approved the final manuscript.

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Correspondence to Muhammad Usman Rashid.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board (IRB) of Shaukat Khanum Memorial Cancer Hospital and Research Centre (IRB approval numbers Date: June 01, 2001/No. ONC-BRCA-001 and Date: May 05, 2006/No. ONC-BRCA-002).

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Muhammad, N., Azeem, A., Bakar, M.A. et al. Contribution of constitutional BRCA1 promoter methylation to early-onset and familial breast cancer patients from Pakistan. Breast Cancer Res Treat 202, 377–387 (2023). https://doi.org/10.1007/s10549-023-07068-x

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