Alterations in chromosomal number and structure are found in most solid malignancies including head and neck squamous cell carcinoma (HNSC), however, the presence of ongoing, chromosomal instability in HNSC and its relation to spindle assembly checkpoint defects has not been formally demonstrated. We investigated the status of chromosomal instability (
Key words: head and neck squamous cell carcinoma; chromosomal instability; spindle assembly checkpointHead and neck squamous cell carcinoma (HNSC) accounts for more than 40,000 new cancer diagnosis annually in the United States. 1 HNSC exhibits a significant degree of structural and numerical chromosomal alterations compared to other solid tumors of epithelial origin. 2 These chromosomal alterations include aneuploidy, translocations, as well as intrachromosomal amplification and deletion. These terms that describe chromosomal alterations merely refer to a state, whereas chromosomal instability refers to an increased rate of change in chromosomal structure. 3,4 A state of aneuploidy may not necessarily imply underlying chromosomal instability, as many hematologic malignancies demonstrate stably inheritable chromosomal alterations in the absence of ongoing CIN.Molecular genetic progression models and data on premalignant lesions have demonstrated that chromosomal loss occurs early in HNSC progression, accompanied by a high incidence of structural and numerical chromosomal aberrations. Recent investigation of genetic alterations in other malignancies has implicated chromosomal instability (CIN) as a major pathway for the genetic progression of malignancy, and was reported in lung, 5 prostate, 6 cervical, 7 endometrial, 8 breast, 9 multiple myeloma 10 and colorectal cancer. 11 HNSC and other solid tumors have a much lower frequency of microsatellite instability (MIN, sometimes referred to as sequence instability) when compared to MIN tumors such as hereditary non-polyposis colon cancer. 12 Aneuploidy present in premalignant oral lesions can predict risk of subsequent development of HNSC 13 and a similar phenomenon has been observed in laryngeal lesions as well. 14 Other studies have shown increased sensitivity to bleomycin-induced chromosomal breakage in lymphocytes from HNSC patients, 15,16 and cell line studies have implicated breakage-fusion-bridge cycles and altered spindle function as a feature of these chromosomal alterations. 17 Although mitotic abnormalities consistent with chromosomal instability due to defects in chromosomal segregation were described in this examination of cultured oral cancer cells, 17 formal analysis of the rate of formation of these alterations or chromosomal instability has not yet been described for HNSC.Multiple mechanisms of CIN have been proposed for solid tumors, including defects in chromosome cohesion and condensation, deregulated mitotic progression, as well as alterations in the spindle assembly checkpoint. 18 HNSC demonstrates alterations in multiple genes that control mitotic checkpoints, including p53, p16, p14 ARF and oth...