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. 2023 Nov;31(11):1275-1282.
doi: 10.1038/s41431-023-01429-2. Epub 2023 Jul 18.

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

Giovanni Corso  1   2   3 , Monica Marabelli  4 , Mariarosaria Calvello  5 , Sara Gandini  6 , Matilde Risti  5 , Irene Feroce  5 , Sara Mannucci  5 , Antonia Girardi  1 , Alessandra Margherita De Scalzi  1 , Francesca Magnoni  1 , Elena Marino  7 , Loris Bernard  7 , Paolo Veronesi  1   2 , Elena Guerini-Rocco  2   8 , Massimo Barberis  7 , Aliana Guerrieri-Gonzaga  5 , Bernardo Bonanni  5
Affiliations

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

Giovanni Corso et al. Eur J Hum Genet. 2023 Nov.

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the study showing the number of patients and genetic testing results.
Fig. 2
Fig. 2. Distribution of unique germline BRCA1 PVs identified in MpBC patients (modified from BRCA Exchange https://brcaexchange.org/).
Alternate exons are shown as rectangles, with the corresponding number underneath. After exon 3, subsequent exon numbers are increased by one, due to historical mis-annotation of an additional “exon 4”. Exon 11 is not to scale, since it covers >65% of BRCA1 sequence. PVs described in our series are indicated in bold; PVs reported in previous case reports are in normal type. areported twice in our series. breported both in our series and in ref. [23]. The three regions of BRCA1 protein that are mutated in cancer patients with a higher frequency are indicated above the graph.
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