Frequent mutations of p53 gene in oesophageal squamous cell carcinomas with and without human papillomavirus (HPV) involvement suggest the dominant role of environmental carcinogens in oesophageal carcinogenesis.
Frequent mutations of p53 gene in oesophageal squamous cell carcinomas with and without human papillomavirus (HPV) involvement suggest the dominant role of environmental carcinogens in oesophageal carcinogenesis.
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DOI：
10.1038/bjc.1994.305
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发表时间：
1994-08
影响因子：
8.8
通讯作者：
Syrjanen, K
中科院分区：
文献类型：
--
作者：
Chang, F;Syrjanen, S;Tervahauta, A;Kurvinen, K;Wang, L;Syrjanen, K
流行病学证据表明，饮酒、吸烟、摄入真菌毒素和亚硝胺以及营养缺乏是食管癌发生的高危因素。同样，病毒感染也被认为在某些肿瘤中起作用。然而，食管癌发生发展的分子机制至今仍知之甚少。p53抑癌基因功能的丧失已在不同的人类恶性肿瘤中被发现，并且它可以以多种方式发生，包括基因突变和与致癌人乳头瘤病毒（HPV）的E6蛋白的相互作用。由于食管粘膜可能暴露于诱变剂和HPV，我们研究了来自9个HPV阳性鳞状细胞癌和12个HPV阴性肿瘤的DNA样本。应用聚合酶链反应-单链构象多态性（PCR-SSCP）技术检测p53基因第5-9外显子的遗传保守区。用生物素标记的HPV DNA探针进行DNA原位杂交检测HPV。在21例病例中的8例（38%）中检测到突变。在外显子5/6中发现3个突变，在外显子7中发现3个突变，在外显子8/9中发现2个突变。12例HPV阴性癌中有6例（50%）显示p53突变。9例HPV阳性癌中有2例（22.2%）也发现含有p53突变; 1例含有HPV 16 DNA序列，并在外显子8/9显示p53突变，另1例为HPV 6/11阳性，外显子5/6突变。虽然突变在HPV阴性肿瘤中更常见（50.0% vs 22.2%），但HPV阳性和阴性肿瘤中p53突变的差异未达到统计学显著性（P = 0.1946）。这些数据表明，p53基因的失活是一个常见的事件在食管鳞状细胞癌，这种失活可能是一个重要的分子途径，食管癌的发展。HPV阳性食管癌中p53基因突变的发现提示HPV和p53基因突变并非相互排斥的事件。p53基因在HPV阳性和阴性食管癌中均存在频繁突变，提示环境致癌物在食管癌发生中起主导作用。
Epidemiological evidence suggests that alcohol intake, use of tobacco, ingestion of mycotoxins and nitrosamines and nutritional deficiencies are high-risk factors for the development of oesophageal cancer. Similarly, viral infections have been postulated to play a role in some tumours. However, the molecular events underlying the development of oesophageal carcinoma are poorly understood as yet. Loss of p53 tumour-suppressor gene function has been found in different human malignancies, and it can occur in a variety of ways, including gene mutation and interaction with the E6 protein of oncogenic human papillomaviruses (HPVs). Because the oesophageal mucosa is potentially exposed to mutagens and HPVs, we studied DNA samples derived from nine HPV-positive squamous cell carcinomas and 12 HPV-negative tumours. Exons 5-9 of the p53 gene containing phylogenetically conserved domains were examined using the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) technique. HPV detection was done using DNA in situ hybridisation with biotin-labelled HPV DNA probes. Mutations were detected in eight (38%) out of the 21 cases. Three mutations were found in exons 5/6, three in exon 7 and two in exon 8/9. Six (50%) of the 12 HPV-negative carcinomas showed p53 mutations. Two (22.2%) of the nine HPV-positive carcinomas were found to contain p53 mutations as well; one contained HPV 16 DNA sequences and showed p53 mutation in exon 8/9, and the other was HPV 6/11 positive with the mutation in exon 5/6. Although mutations were more common in HPV-negative tumours (50.0% vs 22.2%), the difference in p53 mutations in HPV-positive and -negative tumours did not reach statistical significance (P = 0.1946). These data indicate that inactivation of the p53 gene is a frequent event in oesophageal squamous cell carcinomas and such an inactivation might be an important molecular pathway for the development of oesophageal cancer. The findings of p53 mutations in HPV-positive oesophageal carcinomas suggest that HPV and p53 mutation were not mutually exclusive events. The presence of frequent mutations of p53 gene in both HPV-positive and -negative oesophageal carcinomas suggests a dominant role of environmental carcinogens in oesophageal carcinogenesis.