Marcel F Glaas1, Constanze Wiek1, Linda-Maria Wolter1, Katharina Roellecke1, Vera Balz2, Vera Okpanyi1, Martin Wagenmann1, Thomas Karl Hoffmann3, Rene Grässlin3, Christian Plettenberg1, Jörg Schipper1, Helmut Hanenberg4,5, Kathrin Scheckenbach4. 1. Department of Otorhinolaryngology & Head/Neck Surgery, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany. 2. ITZ, Heinrich Heine University School of Medicine, Duesseldorf, Germany. 3. Department of Otorhinolaryngology & Surgery (ENT), University School of Medicine, Ulm, Germany. 4. Department of Otorhinolaryngology & Head/Neck Surgery, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany Helmut.Hanenberg@uni-due.de scheckenbach@med.uni-duesseldorf.de. 5. Department of Pediatrics III, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany.
Abstract
BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. MATERIALS AND METHODS: Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. RESULTS AND CONCLUSION: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function. Copyright
BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. MATERIALS AND METHODS: Germline DNA of 85 consecutive HNSCCpatients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. RESULTS AND CONCLUSION: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary humanFANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function. Copyright
Authors: Margaretha A Skowron; Katharina Eul; Alexa Stephan; Gillian F Ludwig; Gamal A Wakileh; Arthur Bister; Christian Söhngen; Katharina Raba; Patrick Petzsch; Gereon Poschmann; Edmund Osei Kuffour; Daniel Degrandi; Shafaqat Ali; Constanze Wiek; Helmut Hanenberg; Carsten Münk; Kai Stühler; Karl Köhrer; Elvira Mass; Daniel Nettersheim Journal: Mol Oncol Date: 2022-07-26 Impact factor: 7.449
Authors: Margaretha A Skowron; Teresa K Becker; Lukas Kurz; Sina Jostes; Felix Bremmer; Florian Fronhoffs; Kai Funke; Gamal A Wakileh; Melanie R Müller; Aaron Burmeister; Thomas Lenz; Anja Stefanski; Kai Stühler; Patrick Petzsch; Karl Köhrer; Peter Altevogt; Peter Albers; Glen Kristiansen; Hubert Schorle; Daniel Nettersheim Journal: Mol Oncol Date: 2021-08-02 Impact factor: 6.603