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. Cancer Res; 75(17); 3543-53. Ó2015 AACR.

Establishment and Genetic Landscape of Precancer Cell Model Systems from the Head and Neck Mucosal Lining

“…VU-SCC-040 (formerly 92VU040), VU-SCC-096 (formerly 93VU096), VU-SCC-120 (formerly 93VU120), VU-SCC-147 (formerly 93VU147) and VU-SCC-OE, were reported by Hermsen and colleagues (24). VU-SCC-1131 (formerly VU1131) and VU-SCC-1365 (formerly VU1365) were described in van Zeeburg and colleagues (25), and VU-SCC-1604 in Stoepker and colleagues (26). UM-SCC-22A, UM-SCC-22B, UM-SCC-11B, UM-SCC-06, UM-SCC-11B, UM-SCC-38 and UM-SCC-47 were obtained from Prof. T. Carey (University of Michigan, Ann Arbor, MI; ref.…”

Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection

“…The cohesin complex is known to organize chromatin loops at DNA replication factories, to mediate replication stress tolerance, and to enhance the restart of stalled forks (Wu and Yu, 2012). Somatic mutation of STAG2 in some cancers accounts for crosslinker-dependent chromosome breakage and cisplatin sensitivity, a phenotype similar to cancers with FA/ BRCA pathway deficiency (Stoepker et al, 2015). Interestingly, STAG2 also plays a role in replication fork progression and has a synthetic lethal relationship with PARP and ATR loss in DSB repair (Mondal et al, 2019).…”

Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2–/– (C57BL/6) Mice

“…Previous studies showing normalization of the radiosensitive phenotype of Fancd2 −/− cells in bone marrow stromal cell lines by JP4-039 are consistent with either model (19). FA cells may have more mitochondria but a defective mitochondrial pathway unrelated to cellular or tissue radiosensitivity (34, 35). Experiments are underway to quantitate the uptake of JP4-039 per cell relative to the number and viability of mitochondria in Fancd2 −/− cells, as well as in cells from Fancg −/− and Fanca −/− mice.…”