Defects in the fanconi anemia pathway and chromatid cohesion in head-and-neck cancer

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 (FA) is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since FA patients have a high risk to develop HNSCC, we investigated whether and to which extent FA pathway inactivation underlies CIN in HNSCC of non-FA individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without FA. 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, while 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 FA 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.