The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases.

Gisella Figlioli ,Johanna I Kiiski ,Zdeněk Kleibl ,Dominique Stoppa‐Lyonnet ,Therese Törngren ,Jana Soukupová ,Petra Kleiblová ,Florentia Fostira ,Bernardo Bonanni ,Orland Dı́ez ,Daniele Calistri ,Laura Papi ,Marta Santamariña ,Edith Oláh ,Drakoulis Yannoukakos ,Manuel R Teixeira ,Tímea Pócza ,Dijana Plaseska‐Karanfilska ,Jacopo Azzollini ,Paolo Radice ,Nadine Andrieu ,Ana Osorio ,Conxi Lázaro ,Ana Vega ,Fabienne Lesueur ,Angela Toss ,Valentina Zampiga ,Birgitte Bertelsen ,Virginie Moncoutier ,Aleksander Myszka ,Claude Houdayer ,Ramūnas Janavičius ,Séverine Eon-Marchais ,Bernard Peissel ,Zdeňka Vlčková ,Vilius Rudaitis ,Judith Balmañà ,Ugnius Mickys ,Ana Blanco ,Javier Benı́tez ,Heli Nevanlinna ,Esther Darder ,Jesús Del Valle ,Tú Nguyen-Dumont ,Ana Peixoto ,Irene Konstantopoulou ,Maria Rossing ,Mariarosaria Calvello ,Snezhana Smichkoska ,Alicia Barroso ,Stepan Chvojka ,Taru Muranen ,Emma Tham ,Catarina Santos ,Ruta Marcinkute ,Katerina Kubelka-Sabit ,Anders Kvist ,Markéta Janatová ,Laura Cortesi ,Siranoush Manoukian ,Francesca Gensini ,Hans Ehrencrona ,Finn Cilius Nielsen ,Miguel Urioste ,Melissa C Southey ,Joan Brunet ,Rimvydas Norvilas ,Åke Borg ,Paolo Peterlongo

doi:10.3390/cancers12020292

Abstract

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.

Highlights

FANCM, the Fanconi anemia (FA) complementation group M gene (OMIM609644), was originally described as one of the members of the FA molecular pathway [1] that is primarily responsible for the repair of the DNA inter-strand crosslinks through homologous recombination
Additional data on common and rare FANCM protein truncating variants (PTVs) were derived from previously published studies based on FANCM sequencing of German breast cancer
2020, 12, 292 four common PTVs and the rare PTVs combined in a cohort of breast cancer probands (Figure 1)

Summary

Introduction

FANCM, the Fanconi anemia (FA) complementation group M gene (OMIM609644), was originally described as one of the members of the FA molecular pathway [1] that is primarily responsible for the repair of the DNA inter-strand crosslinks through homologous recombination. FANCM is part of the core complex in the FA pathway, accumulating evidence indicates that protein truncating variants (PTVs) in this gene are not causative of FA. Five carriers of homozygous FANCM PTVs were identified among females diagnosed with breast cancer, two of which were diagnosed with early onset disease [3].

Methods

Results

Conclusion