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Article

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance

1
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
2
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 08518 Florence, Italy
3
Division of Pathological Anatomy, Department of Health Sciences, University of Florence, 08518 Florence, Italy
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Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
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Department of Oncology and Haematology, University of Modena and Reggio Emilia, 41124 Modena, Italy
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IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
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Department of Pathology, ASST Settelaghi and Centro di Ricerca per lo Studio dei Tumori Eredo-Familiari, Università dell’Insubria, 21100 Varese, Italy
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Department of Pathology, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, VIC 3000, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia
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Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Research Department, PeterMacCallum Cancer Centre, Melbourne, VIC 3000, Australia
*
Author to whom correspondence should be addressed.
Current affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy.
Current affiliation: Unit of Medical Genetics, San Giovanni Calibita-Fatebenefratelli Hospital, 00161 Rome, Italy.
Academic Editor: Anupama Munshi
Cancers 2021, 13(18), 4515; https://doi.org/10.3390/cancers13184515
Received: 30 July 2021 / Revised: 30 August 2021 / Accepted: 1 September 2021 / Published: 8 September 2021
Breast cancer in men is a rare disease; however, morbidity and mortality in male breast cancer (MBC) patients is a serious concern. The identification of specific molecular features in MBC is essential for developing more appropriate and targeted therapeutic strategies for MBC patients. In this study, by transcriptome analysis of 63 MBCs characterized for germline mutations in the most relevant BC susceptibility genes, mainly BRCA1/2, we highlighted possible differences in the molecular pathways underlying MBC pathogenesis in relation to germline mutation status. Furthermore, we identified two distinct subgroups of MBCs of clinical relevance, which are characterized by different biological features and prognosis. Overall, our results showed that transcriptome profiling by RNA sequencing is a valuable approach to dissect the molecular heterogeneity of MBC and suggest that the transcriptome matched with germline profiling may lead to the identification of MBC subtypes with possible relevance in the clinical setting, which is a primary step to improve the clinical management of MBC patients.
Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly BRCA1/2 and PALB2. Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 BRCA2, 6 BRCA1, 2 PALB2, 1 RAD50, and 1 RAD51D germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting. View Full-Text
Keywords: male breast cancer; transcriptome profiling; germline mutations; BRCA1/2; molecular subtypes male breast cancer; transcriptome profiling; germline mutations; BRCA1/2; molecular subtypes
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MDPI and ACS Style

Zelli, V.; Silvestri, V.; Valentini, V.; Bucalo, A.; Rizzolo, P.; Zanna, I.; Bianchi, S.; Coppa, A.; Giannini, G.; Cortesi, L.; Calistri, D.; Tibiletti, M.G.; Fox, S.B.; Fab, k.; Palli, D.; Ottini, L. Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance. Cancers 2021, 13, 4515. https://doi.org/10.3390/cancers13184515

AMA Style

Zelli V, Silvestri V, Valentini V, Bucalo A, Rizzolo P, Zanna I, Bianchi S, Coppa A, Giannini G, Cortesi L, Calistri D, Tibiletti MG, Fox SB, Fab k, Palli D, Ottini L. Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance. Cancers. 2021; 13(18):4515. https://doi.org/10.3390/cancers13184515

Chicago/Turabian Style

Zelli, Veronica, Valentina Silvestri, Virginia Valentini, Agostino Bucalo, Piera Rizzolo, Ines Zanna, Simonetta Bianchi, Anna Coppa, Giuseppe Giannini, Laura Cortesi, Daniele Calistri, Maria G. Tibiletti, Stephen B. Fox, kCon Fab, Domenico Palli, and Laura Ottini. 2021. "Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance" Cancers 13, no. 18: 4515. https://doi.org/10.3390/cancers13184515

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