A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5-8
A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5-8
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DOI：
10.1002/ijc.11389
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发表时间：
2003-11-10
影响因子：
6.4
通讯作者：
Manni, JJ
中科院分区：
文献类型：
--
作者：
Hafkamp, HC;Speel, EJM;Manni, JJ
除了众所周知的危险因素，如吸烟和饮酒，致癌性人类乳头瘤病毒(HPV)感染最近也被认为促进头颈部肿瘤的发生。众所周知，HPV通过表达病毒癌蛋白E6和E7，使细胞周期调节因子P53和pRb失活，从而导致癌症。这表明P53突变不是HPV诱导肿瘤发生的先决条件。然而，在头颈部鳞状细胞癌(HNSCC)中携带致癌HPV DNA的频率和这些肿瘤中显示P53突变的部分存在差异。在我们的研究中，我们通过荧光原位杂交(FISH)检测HNSCC中HPV16/18整合的频率，并通过免疫组织化学和外显子5-8的单链构象多态性(SSCP)分析来研究它们的P53(突变)状态。对27例癌前病变和47例HNSCC的石蜡包埋活检资料进行了分析。47例HNSCC中有10例(21%)明确显示HPV16型整合，包括12例扁桃体癌中的8例(67%)。免疫组织化学检测p16(Ink4a)在所有10个HPV阳性肿瘤中的过度表达支持了这一点。虽然FISH被认为对HPV的检测不如基于PCR的方法敏感，但我们的数据清楚地表明了HPV与这些肿瘤的克隆性关联，如在2名患者的原发肿瘤及其转移瘤中存在整合的HPV16。而癌前病变中未检出HPV16118。在47例HNSCC中，30例(%)有P53蛋白积聚，其中8例HPV阳性。然而，在后一例中，除1例患者外显子6的第213密码子存在多态外，其余病例均未发现外显子5-8的突变。对临床数据的评估显示，吸烟与饮酒或不饮酒与肿瘤的HPV阳性之间存在显著的负相关。(C)2003年Wiley-Liss，Inc.
Besides well-known risk factors such as tobacco use and alcohol consumption, oncogenic human papillomavirus (HPV) infection also has recently been suggested to promote head and neck tumorigenesis. HPV is known to cause cancer by inactivation of cell cycle regulators p53 and pRb via expression of viral oncoproteins E6 and E7. This indicates that p53 mutations are not a prerequisite in HPV-induced tumor development. However, discrepancy exists with respect to the frequency of head and neck squamous cell carcinomas (HNSCC) harboring DNA of oncogenic HPV and the fraction of these tumors showing p53 mutations. In our study, we examined the frequency of HNSCC demonstrating HPV 16/18 integration as identified by fluorescence in situ hybridization (FISH) and investigated their p53 (mutation) status by immunohistochemistry and single-strand conformation polymorphism (SSCP) analysis of exons 5-8. Paraffin-embedded, archival biopsy material from 27 premalignant mucosal lesions and 47 cases of HNSCC were analyzed. Ten of the 47 (21%) HNSCC unequivocally exhibited HPV 16 integration, including 8 of 12 (67%) tonsillar carcinomas. This is supported by the immunohistochemical detection of p16(INK4A) overexpression in all 10 HPV-positive tumors. Although FISH is considered to be less sensitive than PCR-based methods for HPV detection, our data clearly demonstrate clonal association of HPV with these tumors, as illustrated by the presence of integrated HPV 16 in both the primary tumor and their metastases in 2 patients. In contrast, HPV 16118 DNA could not be detected in the premalignant lesions. In 30 of 47 (64%), HNSCC accumulation of p53 was observed, including 8 of the 10 HPV-positive carcinomas. However, in none of the latter cases could mutations in exons 5-8 be identified, except for a polymorphism in codon 213 of exon 6 in one patient. Evaluation of clinical data revealed a significant inverse relation between tobacco use with or without alcohol consumption, and HPV positivity of the tumors. (C) 2003 Wiley-Liss, Inc.