Valentina Silvestri1, Piera Rizzolo1, Veronica Zelli1, Virginia Valentini1, Ines Zanna2, Simonetta Bianchi3, Maria Grazia Tibiletti4, Liliana Varesco5, Antonio Russo6, Stefania Tommasi7, Anna Coppa8, Carlo Capalbo1, Daniele Calistri9, Alessandra Viel10, Laura Cortesi11, Siranoush Manoukian12, Bernardo Bonanni13, Marco Montagna14, Domenico Palli2, Paolo Radice15, Paolo Peterlongo16, Laura Ottini17. 1. Department of Molecular Medicine, Sapienza University of Rome, Italy. 2. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy. 3. Division of Pathological Anatomy, Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy. 4. Unit of Pathology, Ospedale di Circolo, Varese, Italy. 5. Unit of Hereditary Cancers, IRCCS AOU San Martino - IST, Genoa, Italy. 6. Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Italy. 7. Molecular Genetics Laboratory, Istituto Tumori "Giovanni Paolo II", Bari, Italy. 8. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 9. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy. 10. Unit of Experimental Oncology 1, CRO Aviano, National Cancer Institute, Aviano, PN, Italy. 11. Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy. 12. Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy. 13. Division of Cancer Prevention and Genetics, European Institute of Oncology IEO, Milan, Italy. 14. Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 15. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 16. IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy. 17. Department of Molecular Medicine, Sapienza University of Rome, Italy. Electronic address: laura.ottini@uniroma1.it.
Abstract
INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.
INTRODUCTION:Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.
Authors: Cathy B Moelans; Joep de Ligt; Petra van der Groep; Pjotr Prins; Nicolle J M Besselink; Marlous Hoogstraat; Natalie D Ter Hoeve; Miangela M Lacle; Robert Kornegoor; Carmen C van der Pol; Wendy W J de Leng; Ellis Barbé; Bert van der Vegt; John Martens; Peter Bult; Vincent T H B M Smit; Marco J Koudijs; Isaac J Nijman; Emile E Voest; Pier Selenica; Britta Weigelt; Jorge S Reis-Filho; Elsken van der Wall; Edwin Cuppen; Paul J van Diest Journal: Endocr Relat Cancer Date: 2019-10 Impact factor: 5.678