The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases
Predisposició al càncer de mama; Factors de risc de càncer de mama; Espectre de mutació ; Predisposición al cáncer de mama; Factores de riesgo de cáncer de mama; Espectro de mutación ; Breast cancer predisposition; Breast cancer risk factors; Mutation spectrum ; Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases. ; This research was partially funded by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo, a fellowship from Fondazione Umberto Veronesi to G. Figlioli and by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds. E. Tham is supported by Region Stockholm (ALF). The Czech study was supported by a grant of the Ministry of Health of the Czech Republic NV16-29959A. CNIO study was partially supported by projects PI16/00440 and PI19/00640, supported by the Instituto de Salud Carlos III, cofunded by European Regional Development Fund (ERDF), the Spanish Network on Rare Diseases (CIBERER) and BRIDGES project H2020. Financial support for GENESIS resource and genotyping was provided by the Ligue Nationale contre le Cancer (grants PRE05/DSL, PRE07/DSL, PRE11/NA), the French National Institute of Cancer (INCa grant No b2008-029/LL-LC) and the comprehensive cancer center SiRIC, (Site de Recherche Intégrée sur le Cancer: Grant INCa-DGOS-4654). HEBCS was funded by Helsinki University Hospital Research Fund, Sigrid Juselius Foundation, The cancer Society of Finland. A.Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII) through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). This work was supported by the Australian National Health and Medical Research Council (APP1029974 and APP1074383) and by a Victorian Life Sciences Computation Initiative grant (number VR0182) on its Peak Computing Facility, an initiative of the Victorian Government. T.N-D is a Career Development Fellow of the National Breast Cancer Foundation (Australia, ECF-17-001). M.C.S. is a National Health and Medical Research Council (Australia) Senior Research Fellow. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI OTKA K-112228 to E. Olah. Lithuanian study was supported by The Research Council of Lithuania grant SEN18/2015 and P-MIP-20-25 to R. Janavicius. The ICO was supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI16/00563, PI19/00553 and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS) Project MedPerCan, 2017SGR1282 and 2017SGR496]; and CERCA program.
