title: Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer.
abstract: Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Stoepker
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Lelij
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Irsan E
authors.initials: IE
authors.lastname: Kooi
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Anneke B
authors.initials: AB
authors.lastname: Oostra
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Brink
authors.affiliation: German Fanconi Anemia Support Group and Research Fund, Unna-Siddinghausen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dietrich
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jesper A
authors.initials: JA
authors.lastname: Balk
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.affiliation: Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, United Kingdom.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands. rh.brakenhoff@vumc.nl.
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002842:Chromatids / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D012854:Sister Chromatid Exchange; D000077195:Squamous Cell Carcinoma of Head and Neck