Shin D M, Charuruks N, Lippman S M, Lee J J, Ro J Y, Hong W K, Hittelman W N
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2001 Jun;10(6):603-9.
Head and neck cancer develops in a multistep process and is associated with increasing frequencies of p53 alterations and with increasing genomic instability. To study the relationship of p53 alterations and genomic instability during head and neck tumorigenesis, we analyzed p53 protein expression and chromosome 9 and 17 polysomy in 48 squamous cell carcinomas of the head and neck and their adjacent normal epithelium (31 sites), hyperplastic (24 sites), and dysplastic lesions (26 sites). Normal oral epithelium obtained from seven nonsmoking, cancer-free individuals served as negative controls. Six (19%) of 31 lesions in adjacent normal epithelium, 7 (29%) of 24 hyperplastic lesions, 12 (46%) of 26 dysplastic lesions, and 28 (58%) of 48 squamous cell carcinomas expressed p53. In contrast, no normal control epithelium had detectable p53 expression. To determine the relationship between dysregulated p53 expression and genomic instability during tumorigenesis, we compared p53 immunohistochemistry distributions and chromosome polysomy levels (by chromosome in situ hybridization) in different histological groups associated with tissue progression. Although the degree of chromosome polysomy increased for all of the groups during histological progression, lesions with dysregulated p53 expression showed nearly 2-4-fold increased levels of chromosome polysomy. This trend was significant for dysplastic lesions (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively) and for squamous cell carcinoma (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively). Image analysis studies for 28 p53-expressing tumors and their adjacent premalignant lesions demonstrated a strong spatial correlation between stepwise transitions from low to high p53 expression and increased chromosome polysomy frequencies in 13 (46%) of 28 cases. These findings suggest that altered p53 expression is associated with increased genetic instability in preneoplastic epithelium and may play a driving force for increasing the rate of accumulation of genetic events during head and neck tumorigenesis.
头颈部癌的发生是一个多步骤过程，与p53改变频率的增加以及基因组不稳定性的增加相关。为了研究头颈部肿瘤发生过程中p53改变与基因组不稳定性的关系，我们分析了48例头颈部鳞状细胞癌及其相邻正常上皮组织（31个部位）、增生性病变（24个部位）和发育异常病变（26个部位）中的p53蛋白表达以及9号和17号染色体多体性。从7名不吸烟、无癌症的个体获取的正常口腔上皮组织作为阴性对照。相邻正常上皮组织的31个病变中有6个（19%）、24个增生性病变中有7个（29%）、26个发育异常病变中有12个（46%）以及48例鳞状细胞癌中有28个（58%）表达p53。相比之下，正常对照上皮组织中未检测到p53表达。为了确定肿瘤发生过程中p53表达失调与基因组不稳定性之间的关系，我们比较了与组织进展相关的不同组织学组中的p53免疫组化分布和染色体多体性水平（通过染色体原位杂交）。尽管在组织学进展过程中所有组的染色体多体性程度均增加，但p53表达失调的病变显示染色体多体性水平增加了近2至4倍。这种趋势在发育异常病变（9号和17号染色体分别为P = 0.005和P = 0.002）和鳞状细胞癌（9号和17号染色体分别为P = 0.005和P = 0.002）中具有显著性。对28例表达p53的肿瘤及其相邻癌前病变的图像分析研究表明，在28例病例中的13例（46%）中，从低到高p53表达的逐步转变与染色体多体性频率增加之间存在很强的空间相关性。这些发现表明，p53表达改变与癌前上皮组织中遗传不稳定性增加相关，并且可能在头颈部肿瘤发生过程中作为增加遗传事件积累速率的驱动力。
