Absence of hSNF5/INI1 mutation in human lung cancer
Introduction
Molecular genetic studies of human lung cancers have indicated that inactivation of multiple tumor suppressor genes, including RB1, TP53 and CDKN2A, is required for lung carcinogenesis. Karyotypic studies and comparative genomic hybridization (CGH) analysis have revealed the presence of various abnormalities on chromosome arm 22q in lung cancers [1], [2]. In our previous allelotype studies, loss of heterozygosity (LOH) on chromosome arm 22q was detected in 73% of small cell lung carcinoma (SCLC) [3] and in 47% of non-small cell lung carcinoma (NSCLC) [4]. LOH on 22q was frequently observed in advanced stage NSCLCs, and the incidence of LOH on 22q in brain metastases was significantly higher than that in primary tumors [4]. These results indicate that a tumor suppressor gene on chromosome 22q plays an important role in the acquisition of malignant phenotypes in lung cancers.
The hSNF5/INI1 gene encodes a member of the chromatin-remodeling SWI/SNF multiprotein complexes and maps to 22q11.2. Recently, Versteege et al. [5] reported deletions and somatic mutations of the hSNF5/INI1 gene in 12 of 13 rhabdoid tumors. Biegel et al. [6] also reported that 15 of 29 rhabdoid tumors had homozygous deletions of one or more exons of the hSNF5/INI1 gene and the other 14 tumors had mutations. Germ-line mutations of the hSNF5/INI1 gene were identified in four cases of familial rhabdoid tumors [6]. These findings were fully consistent with the paradigm of the 2-hit recessive model of oncogenesis and supported the hypothesis that hSNF5/INI1 is the malignant rhabdoid tumor suppressor gene. Thus, it is possible that the hSNF5/INI1 gene acts as a tumor suppressor in several other types of human cancers, in particular in cancers with 22q deletions such as lung cancer. In this study, we performed PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis of the entire coding region and intronic splice donor and acceptor sites of the hSNF5/INI1 gene in order to investigate the prevalence of hSNF5/INI1 mutations in lung cancer.
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Cell lines
Fifty lung cancer cell lines, including 33 non-small cell lung carcinomas (NSCLC) and 17 small cell lung carcinomas (SCLC) were used in this study. NSCLC cell lines were A427, A549, PC-3, PC-7, PC-9, PC-10, PC-13, PC-14, Lu99, LC1-Sq, RERF-LCOK, VMRC-LCD, ABC-1, EBC-1, Lu65, LCMS, NCI-H596, NCI-H23, NCI-H157, NCI-H322, NCI-H441, NCI-H520, NCI-H1155, Ma1, Ma2, Ma3, Ma10, Ma12, Ma17, Ma24, Ma25, Ma26 and Ma29. SCLC cell lines were Lu24, Lu134, Lu135, Lu138, Lu139, Lu140, Lu141, NCI-H69, NCI-H82,
Results
PCR-SSCP analysis of the entire coding sequence as well as the splicing donor and acceptor sites in introns was performed to detect mutations of the hSNF5/INI1 gene in 50 lung cancer cell lines. Seven different types of PCR-SSCP variants were detected. Thus, we further determined the sequences of these seven variants. One of the variants was a silent mutation at codon 299 in exon 7, and the remaining six variants were intronic mutations located in introns 1, 5 or 7 (Table 1). Thus, there were
Discussion
Allelic losses on chromosome 22q have been frequently observed in lung, colon, ovary, breast, rhabdoid tumors and meningiomas [8], [9]. Up to the present, two tumor suppressor genes have been identified on chromosome 22q. The NF2 gene, which is responsible for familial neurofibromatosis type 2, maps to 22q12 [10], [11] and is often inactivated in both hereditary and sporadic meningiomas and schwannomas. However, the NF2 gene is not mutated in lung cancer cell lines [4], [12], suggesting that a
Acknowledgements
This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the 2nd-term Comprehensive 10-Year Strategy for Cancer Control, Grants-in-Aid from the Ministry of Health and Welfare for Research on Human Genome and Gene Therapy, and Grants-in-Aid from the Ministry of Health and Welfare and from the Ministry of Education, Science, Sports and Culture, from the Foundation for Promotion of Cancer Research, Japan. We thank the following scientists for providing cell
References (12)
- et al.
Advances in the analysis of chromosome alterations in human lung carcinomas
Cancer Genet. Cytogenet.
(1997) - et al.
A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor
Cell
(1993) - et al.
How many tumor suppressor genes are involved in human lung carcinogenesis?
Carcinogenesis
(1999) - et al.
Allelotype and replication error phenotype of small cell lung carcinoma
Carcinogenesis
(1997) - et al.
Frequent allelic losses on chromosomes 2q
18q, and 22q in advanced non-small cell lung carcinoma. Cancer Res.
(1994) - et al.
Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer
Nature
(1998)
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