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Germline pathogenic variants in metaplastic breast cancer patients and the emerging role of the BRCA1 gene

European Journal of Human Genetics volume 31, pages 1275–1282 (2023)Cite this article

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A Comment to this article was published on 17 August 2023

Abstract

Metaplastic breast cancer (MpBC) is a rare, aggressive breast cancer (BC) histotype. Scarce information is available about MpBC genetic predisposition. Previous studies, mainly consisting of case reports, retrospective reviews and others on target therapies, pointed to a possible involvement of the BRCA1 gene in increasing MpBC risk, without ever confirming it. In this study, we retrospectively reviewed all BC patients counseled at our Institute for genetic testing of at least BRCA1 or BRCA2 (BRCA) genes and we found that 23 (23/5226 = 0.4%) were affected by MpBC. About 65% (15/23) of MpBC patients harbored a germline pathogenic variant (PV): 13 in BRCA1 (86.7%), including two patients who received genetic testing for known familial PV, one in TP53 (6.7%), and one in MLH1 (6.7%). We observed a statistically different frequency of MpBC in patients who carried a PV in the BRCA genes (13/1114 = 1.2%) vs. all other BC patients (10/4112 = 0.2%) (p = 0.0002). BRCA carriers proved to have an increased risk of developing MpBC compared to all other BC patients who were tested for BRCA genes (OR = 4.47; 95% CI: 1.95–10.23). Notably, MpBCs were diagnosed in 2.1% (13/610) of BRCA1 carriers. No MpBCs were observed in BRCA2 carriers (0/498 = 0%), revealing a statistically significant difference between the prevalence of MpBCs in BRCA1 and BRCA2 carriers (p = 0.0015). Our results confirmed that BRCA1 is involved in MpBC predisposition. Further studies on unselected patients are needed to elucidate the authentic role of BRCA1 and to explore the possible implication of other genes in MpBC predisposition.

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Fig. 1
Fig. 2: Distribution of unique germline BRCA1 PVs identified in MpBC patients (modified from BRCA Exchange https://brcaexchange.org/).

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

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Funding

This manuscript was partially supported by the Italian Ministry of Health with Ricerca Corrente 5 × 1000 funds.

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Authors and Affiliations

  1. Division of Breast Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Giovanni Corso, Antonia Girardi, Alessandra Margherita De Scalzi, Francesca Magnoni & Paolo Veronesi

  2. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Giovanni Corso, Paolo Veronesi & Elena Guerini-Rocco

  3. European Cancer Prevention Organization (ECP), Milan, Italy

    Giovanni Corso

  4. Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Monica Marabelli, Mariarosaria Calvello, Matilde Risti, Irene Feroce, Sara Mannucci, Aliana Guerrieri-Gonzaga & Bernardo Bonanni

  5. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Sara Gandini

  6. Clinic Unit of Oncogenomics, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Elena Marino, Loris Bernard & Massimo Barberis

  7. Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Elena Guerini-Rocco

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Contributions

Concept and design: GC, MC, MM, AGG, and BB; Supervisor board: AGG, BB, and PV; Iconography and graphic design: MM, MR, IF, and SM; Acquisition of data, analysis, and interpretation of data: EM, LB, EGR, AG, AMDS, FM; Statistical analyses: SG; Drafting of the manuscript: MM, MC, and GC with input of all authors; Critical revision of the manuscript for important intellectual content: AGG, BB, MB, and PV; Final approval of the manuscript: all authors.

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Correspondence to Monica Marabelli.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the European Institute of Oncology (UID 0833, date of approval 23/05/2018). Informed consent was obtained from all patients involved in the study.

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Corso, G., Marabelli, M., Calvello, M. et al. Germline pathogenic variants in metaplastic breast cancer patients and the emerging role of the BRCA1 gene. Eur J Hum Genet 31, 1275–1282 (2023). https://doi.org/10.1038/s41431-023-01429-2

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