High frequency of deletion mutations in p53 gene from squamous cell lung cancer patients in Taiwan.

Lung cancer is the leading and second-leading cause of cancer deaths among women and men in Taiwan, respectively. However, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. A study that analyzed the mutation spectrum of the p53 tumor suppressor gene in 35 female lung cancer patients in Hong Kong showed that a high proportion of the mutations observed were deletions, suggesting the possible involvement of a distinct mutagenic factor(s) in Chinese female lung cancer patients (Y. Takagi et al., Cancer Res., 55: 5354-5357, 1995). Therefore, to gain insight into the role of the p53 tumor suppressor gene and possible etiological factors in lung tumorigenesis in Taiwan, we investigated the mutation spectra of exons 4-11 in the p53 tumor suppressor gene of 60 lung cancer patients in Taiwan. These data were also correlated with clinical pathological characteristics of patients. Lung tumors were surgically resected, genomic DNA was isolated, and their mutation spectra were examined using PCR/single-strand conformational polymorphism analysis and direct sequencing. The frequency of p53 gene mutation was 18% (11 of 60). However, distinct patterns of p53 gene mutation were observed. Seven of 11 mutations detected (64%) were deletions of 1-12 bp at G:C bp or at bp in the immediate vicinity of repetitive sequences and/or tandem repeat sequences. In addition, two patients (2 of 11, 18%) exhibited nonsense mutations. In contrast to the frequent occurrence of missense mutations in the p53 gene reported in the literature, the majority (82%) of the mutations in lung cancer patients in Taiwan were nonmissense mutations, ie., deletions and nonsense mutations. Immunohistochemical staining indicated that p53 mutations including non-in-frame deletions and nonsense mutations all resulted in no expression of p53 protein. Notably, mutations occurred more frequently in patients suffering from squamous cell carcinoma (SQ). Nine of 31 SQ patients (29%) exhibited deletions or nonsense mutations, suggesting that deletions and nonsense mutations in the p53 gene are involved in the formation of SQ in Taiwan. In addition, mutations occurred more frequently in patients with stage III or IV lung cancer. However, mutations were not correlated with patients' smoking habits. Our data suggest that p53 gene mutation involved in the formation of SQ and distinct environmental factor(s) and/or genetic factor(s) that induced specific short deletions in repeat sequences may be involved in lung tumorigenesis in Taiwan.