Dottore di ricerca

ciclo: XXXIV

supervisore: Prof.ssa Laura Ottini
relatore: Prof.ssa Laura Ottini

Titolo della tesi: Investigating genetic susceptibility to male breast cancer by multigene panel testing: an Italian population-based case-control study

Male breast cancer (MBC) is a rare and understudied disease compared with female breast cancer. A positive family history (FH) of breast cancer (BC) is considered the main risk factor for MBC. About 20% of MBCs have positive BC FH and about 20% of MBCs develop a second tumor other than BC. These data suggest the importance of the genetic component in MBC susceptibility. BRCA1 and BRCA2 are responsible of about 15% of all MBCs. Moreover, recent evidence indicates that PALB2, and possibly other genes, may play a role in MBC susceptibility. Studies are needed to better define the role of these genes and to further explore the missing genetic component in MBC susceptibility. In this context, Next generation sequencing (NGS) technologies offer an unprecedented opportunity for investigating genetic susceptibility as they allow for the evaluation of a large number of genes simultaneously using a multigene panel approach. The aim of this study was to investigate the genetic susceptibility to MBC and estimate MBC risk associated with pathogenic variants in cancer genes other than BRCA1/2. To this end, we performed a population-based case-control study analyzing a large series of Italian MBCs and healthy male controls using a custom multigene panel that included 50 cancer genes; moreover, we compared the main clinical-pathologic characteristics of MBCs with and without pathogenic variants, in order to identify possible distinctive features. A series of 725 MBC negative for BRCA1/2 mutations and 917 male controls, all enrolled in the frame of the Italian multicenter study, were included in the present study. Mutational analysis was performed using NGS technologies by multigene panel approach. All pathogenic variants identified were confirmed by Sanger sequencing. The case-control associations were performed using chi-square test and logistic regression models. Of the 725 MBCs, 36 (5%) were carriers of pathogenic variants in 15 genes and 21 of the 917 healthy male controls (2.3%) were carriers of pathogenic variants in 13 genes. The percentage of pathogenic variants was significantly higher in MBCs compared to male controls (p=0.003). PALB2 was the most common mutated gene. The logistic regression analysis showed that PALB2 pathogenic variant carriers had an approximately 5-fold increased MBC risk (OR: 4.6, 95% CI: 1.00-22.3; p=0.04). Statistically significance difference in the genotype frequency, between cases and control emerged for BLM and FANCM genes (p=0.02, each). The comparison of clinical pathologic characteristics between MBC with and without pathogenic variants showed that MBCs with pathogenic variants had more frequently a positive FH of cancer (p=0.007) and a positive PH of a second tumor other than BC (p=0.02). In conclusion, our data highlight the importance of NGS-based approaches, as multigene panel testing, toward a better comprehension of MBC susceptibility. Our results show that PALB2 may be considered the third MBC susceptibility gene, after BRCA1/2, in the Italian population. Overall, our findings may guide the management of MBC patients, particularly those with family and personal history of multiple cancer, and eventually their relatives, in terms of cancer surveillance and screening.

Produzione scientifica

11573/1701389 - 2024 - HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy
Silvestri, Valentina; Valentini, Virginia; Bucalo, Agostino; Conti, Giulia; Manzella, Livia; Turchetti, Daniela; Russo, Antonio; Capalbo, Carlo; Ottini, Laura - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:001160040000001 (0) - scopus: 2-s2.0-85184927191 (0)

11573/1701390 - 2024 - Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond
Valentini, Virginia; Bucalo, Agostino; Conti, Giulia; Celli, Ludovica; Porzio, Virginia; Capalbo, Carlo; Silvestri, Valentina; Ottini, Laura - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:001160993900001 (2) - scopus: 2-s2.0-85184713757 (0)

11573/1681363 - 2023 - Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study
Bucalo, Agostino; Conti, Giulia; Valentini, Virginia; Capalbo, Carlo; Bruselles, Alessandro; Tartaglia, Marco; Bonanni, Bernardo; Calistri, Daniele; Coppa, Anna; Cortesi, Laura; Giannini, Giuseppe; Gismondi, Viviana; Manoukian, Siranoush; Manzella, Livia; Montagna, Marco; Peterlongo, Paolo; Radice, Paolo; Russo, Antonio; Tibiletti, Maria Grazia; Turchetti, Daniela; Viel, Alessandra; Zanna, Ines; Palli, Domenico; Silvestri, Valentina; Ottini, Laura - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF CANCER (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL:,, INTERNET:,, Fax: 011 44 1865 843010) pp. 183-191 - issn: 0959-8049 - wos: WOS:001017609100001 (4) - scopus: 2-s2.0-85160532771 (4)

11573/1664405 - 2023 - Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology
Valentini, Virginia; Silvestri, Valentina; Bucalo, Agostino; Conti, Giulia; Karimi, Mina; Di Francesco, Linda; Pomati, Giulia; Mezi, Silvia; Cerbelli, Bruna; Pignataro, Maria Gemma; Nicolussi, Arianna; Coppa, Anna; D’Amati, Giulia; Giannini, Giuseppe; Ottini, Laura - 01a Articolo in rivista
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. - - issn: 2234-943X - wos: WOS:000916823700001 (4) - scopus: 2-s2.0-85146553102 (4)

11573/1574218 - 2022 - Breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers using polygenic risk scores
Barnes, Daniel R; Silvestri, Valentina; Leslie, Goska; Mcguffog, Lesley; Dennis, Joe; Yang, Xin; Adlard, Julian; Agnarsson, Bjarni A; Ahmed, Munaza; Aittomäki, Kristiina; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Auber, Bernd; Azzollini, Jacopo; Balmaña, Judith; Barkardottir, Rosa B; Barrowdale, Daniel; Barwell, Julian; Belotti, Muriel; Benitez, Javier; Berthet, Pascaline; Boonen, Susanne E; Borg, Åke; Bozsik, Aniko; Brady, Angela; Brennan, Paul; Brewer, Carole; Brunet, Joan; Bucalo, Agostino; Buys, Saundra S; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Cassingham, Hayley; Lotte Christensen, Lise; Cini, Giulia; Claes, Kathleen B M; Cook, Jackie; Coppa, Anna; Cortesi, Laura; Damante, Giuseppe; Darder, Esther; Davidson, Rosemarie; De La Hoya, Miguel; De Leeneer, Kim; De Putter, Robin; Del Valle, Jesús; Diez, Orland; Chun Ding, Yuan; Domchek, Susan M; Donaldson, Alan; Eason, Jacqueline; Eeles, Ros; Engel, Christoph; Gareth Evans, D; Feliubadaló, Lidia; Fostira, Florentia; Frone, Megan; Frost, Debra; Gallagher, David; Gehrig, Andrea; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Greene, Mark H; Gregory, Helen; Gross, Eva; Hahnen, Eric; Hamann, Ute; Hansen, Thomas V O; Hanson, Helen; Hentschel, Julia; Horvath, Judit; Izatt, Louise; Izquierdo, Angel; James, Paul A; Janavicius, Ramunas; Birk Jensen, Uffe; Johannsson, Oskar Th; John, Esther M; Kramer, Gero; Kroeldrup, Lone; Kruse, Torben A; Lautrup, Charlotte; Lazaro, Conxi; Lesueur, Fabienne; Lopez-Fernández, Adria; Mai, Phuong L; Manoukian, Siranoush; Matrai, Zoltan; Matricardi, Laura; Maxwell, Kara N; Mebirouk, Noura; Meindl, Alfons; Montagna, Marco; Monteiro, Alvaro N; Morrison, Patrick J; Muranen, Taru A; Murray, Alex; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nguyen-Dumont, Tu; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Palli, Domenico; Parsons, Michael T; Sokilde Pedersen, Inge; Peissel, Bernard; Perez-Segura, Pedro; Peterlongo, Paolo; Petersen, Annabeth H; Pinto, Pedro; Porteous, Mary E; Pottinger, Caroline; Angel Pujana, Miquel; Radice, Paolo; Ramser, Juliane; Rantala, Johanna; Robson, Mark; Rogers, Mark T; Rønlund, Karina; Rump, Andreas; María Sánchez De Abajo, Ana; Shah, Payal D; Sharif, Saba; Side, Lucy E; Singer, Christian F; Stadler, Zsofia; Steele, Linda; Stoppa-Lyonnet, Dominique; Sutter, Christian; Yen Tan, Yen; Teixeira, Manuel R; Teulé, Alex; Thull, Darcy L; Tischkowitz, Marc; Toland, Amanda E; Tommasi, Stefania; Toss, Angela; Trainer, Alison H; Tripathi, Vishakha; Valentini, Virginia; Van Asperen, Christi J; Venturelli, Marta; Viel, Alessandra; Vijai, Joseph; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Whaite, Anna; Zanna, Ines; Offit, Kenneth; Thomassen, Mads; Couch, Fergus J; Schmutzler, Rita K; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Ottini, Laura - 01a Articolo in rivista
rivista: JOURNAL OF THE NATIONAL CANCER INSTITUTE (Cary NC: Oxford University Press [Bethesda Md.?]: U.S. Dept. of Health Education and Welfare Public Health Service National Institutes of Health; [Washington D.C.) pp. 109-122 - issn: 0027-8874 - wos: WOS:000748167200017 (19) - scopus: 2-s2.0-85122613384 (19)

11573/1657631 - 2022 - A possible link between gut microbiome composition and cardiovascular comorbidities in psoriatic patients
Valentini, Virginia; Silvestri, Valentina; Bucalo, Agostino; Marraffa, Federica; Risicato, Maria; Grassi, Sara; Pellacani, Giovanni; Ottini, Laura; Richetta, Antonio Giovanni - 01a Articolo in rivista
rivista: JOURNAL OF PERSONALIZED MEDICINE (Basel: MDPI AG, 2011-) pp. - - issn: 2075-4426 - wos: WOS:000833804400001 (6) - scopus: 2-s2.0-85137220471 (5)

11573/1500906 - 2021 - Gut microbiome profile in psoriatic patients treated and untreated with biologic therapy
Valentini, V.; Silvestri, V.; Marraffa, F.; Greco, G.; Bucalo, A.; Grassi, S.; Gagliardi, A.; Mazzotta, A.; Ottini, L.; Richetta, A. G. - 01a Articolo in rivista
rivista: JOURNAL OF DERMATOLOGY (Nihon Hifuka Gakkai:(Japanese Dermatological Association), Taisei Building, 3-14-10 Hongo, Bunkyoku Tokyo 113 Japan) pp. - - issn: 0385-2407 - wos: WOS:000612550800001 (12) - scopus: 2-s2.0-85099821795 (13)

11573/1574212 - 2021 - Transcriptome of male breast cancer matched with germline profiling reveals novel molecular subtypes with possible clinical relevance
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.; Kconfab, ; Palli, D.; Ottini, L. - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:000699104100001 (7) - scopus: 2-s2.0-85114514701 (7)

11573/1450800 - 2020 - Paradoxical psoriasis induced by Anti-TNFα treatment: Evaluation of disease-specific clinical and genetic markers
Bucalo, A.; Rega, F.; Zangrilli, A.; Silvestri, V.; Valentini, V.; Scafetta, G.; Marraffa, F.; Grassi, S.; Rogante, E.; Piccolo, A.; Cucchiara, S.; Viola, F.; Bianchi, L.; Ottini, L.; Richetta, A. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000588902800001 (18) - scopus: 2-s2.0-85093960459 (21)

11573/1422512 - 2020 - Matched germline and tumor profiling in male breast cancer for the discovery of molecular subtypes with clinical relevance
Zelli, V; Silvestri, V; Valentini, V; Bucalo, A; Rizzolo, P; Zanna, I; Cortesi, L; Calistri, D; Tibiletti, Mg; Giannini, G; Fox, Sb; Palli, D; Ottini, L - 04d Abstract in atti di convegno
rivista: CANCER RESEARCH (American Association of Cancer Research:150 South Independence Mall West, #826:Philadelphia, PA 19106:(215)440-9300, EMAIL:, INTERNET:, Fax: (215)440-7228) pp. - - issn: 0008-5472 - wos: WOS:000527012502117 (1) - scopus: (0)
congresso: 2019 San Antonio Breast Cancer Symposium (San Antonio, Texas)
libro: Cancer Research - ()

11573/1337485 - 2019 - Evaluation of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk
Rizzolo, Piera; Silvestri, Valentina; Valentini, Virginia; Zelli, Veronica; Bucalo, Agostino; Zanna, Ines; Bianchi, Simonetta; Tibiletti, Maria Grazia; Russo, Antonio; Varesco, Liliana; Tedaldi, Gianluca; Bonanni, Bernardo; Azzollini, Jacopo; Manoukian, Siranoush; Coppa, Anna; Giannini, Giuseppe; Cortesi, Laura; Viel, Alessandra; Montagna, Marco; Peterlongo, Paolo; Radice, Paolo; Palli, Domenico; Ottini, Laura; Giannini, Giuseppe - 01a Articolo in rivista
rivista: ENDOCRINE CONNECTIONS (Bristol : BioScientifica) pp. 1224-1229 - issn: 2049-3614 - wos: WOS:000483142900017 (7) - scopus: 2-s2.0-85076029019 (7)

11573/1305702 - 2019 - MiRNAs as potential prognostic biomarkers for metastasis in thin and thick primary cutaneous melanomas
Valentini, Virginia; Zelli, Veronica; Gaggiano, Emanuela; Silvestri, Valentina; Rizzolo, Piera; Bucalo, Agostino; Calvieri, Stefano; Grassi, Sara; Frascione, Pasquale; Pietro, Donati; Soda, Giuseppe; Ottini, Laura; Richetta, Antonio Giovanni - 01a Articolo in rivista
rivista: ANTICANCER RESEARCH (Kapandriti: International Institute of Anticancer Research, 1995 Earliest publisher: Καπανδρίτι: Ιωάννης Γ. Δεληνάσιος, 1981-1995 Kapandriti: Iōannīs G. Delīnasios, 1981-1995) pp. 4085-4093 - issn: 0250-7005 - wos: WOS:000482701400014 (12) - scopus: 2-s2.0-85070682011 (11)

11573/1221814 - 2018 - Contribution of MUTYH variants to male breast cancer risk: results from a multicenter study in Italy
Rizzolo, Piera; Silvestri, Valentina; Bucalo, Agostino; Zelli, Veronica; Valentini, Virginia; Catucci, Irene; Zanna, Ines; Masala, Giovanna; Bianchi, Simonetta; Spinelli, Alessandro Mauro; Tommasi, Stefania; Tibiletti, Maria Grazia; Russo, Antonio; Varesco, Liliana; Coppa, Anna; Calistri, Daniele; Cortesi, Laura; Viel, Alessandra; Bonanni, Bernardo; Azzollini, Jacopo; Manoukian, Siranoush; Montagna, Marco; Radice, Paolo; Palli, Domenico; Peterlongo, Paolo; Ottini, Laura - 01a Articolo in rivista
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. - - issn: 2234-943X - wos: WOS:000452014300001 (21) - scopus: 2-s2.0-85060588892 (25)

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma