Kim S K, Su L K, Oh Y, Kemp B L, Hong W K, Mao L
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Oncogene. 1998 Jan 8;16(1):89-93. doi: 10.1038/sj.onc.1201512.
Loss of heterozygosity (LOH) at chromosome 10q23-q25 is frequent in small cell lung cancer (SCLC), indicating the presence of putative tumor suppressor genes. PTEN/ MMAC1, a newly cloned candidate tumor suppressor gene at 10q23, was mutated in multiple human cancers. We investigated whether mutations of PTEN/MMAC1 play an important role in SCLC tumorigenesis. We examined 16 SCLC cell lines for PTEN/MMAC1 mRNA expression by reverse-transcriptase polymerase chain reaction (RT-PCR) and potential mutations by sequencing analysis of the PTEN/MMAC1 coding region. No mutation was observed in PTEN/MMAC1 cDNAs in 15 cell lines expressing PTEN/MMAC1. One SCLC cell line, DMS79, did not have detectable PTEN/ MMAC1 expression. Importantly, we identified a novel homologue of PTEN/MMAC1, termed PTH2, localized to chromosome 9p21-q13 and containing only ten amino acid substitutions compared with the PTEN/MMAC1 coding region. However, because the putative initiation codon for PTEN/MMAC1 gene was changed to arginine in PTH2, the translational initiation site of PTH2 is very likely to differ from that of the PTEN/MMAC1. PTH2 was expressed in two normal lung tissues and two normal colon tissues, but in only four of 16 SCLC cell lines. A missense mutation in PTH2 was identified in a SCLC cell line that did not express PTEN/MMAC1 mRNA. Our data suggest that inactivation of PTEN/ MMAC1 is a rare event in SCLC tumorigenesis. However, the PTEN/MMAC1 homologue PTH2 may play a role in SCLC tumorigenesis.
10q23 - q25染色体杂合性缺失（LOH）在小细胞肺癌（SCLC）中很常见，这表明存在假定的肿瘤抑制基因。PTEN/MMAC1是新克隆的位于10q23的候选肿瘤抑制基因，在多种人类癌症中发生突变。我们研究了PTEN/MMAC1突变在SCLC肿瘤发生中是否起重要作用。我们通过逆转录聚合酶链反应（RT-PCR）检测了16个SCLC细胞系中PTEN/MMAC1 mRNA的表达，并通过对PTEN/MMAC1编码区进行测序分析检测潜在突变。在15个表达PTEN/MMAC1的细胞系中，未在PTEN/MMAC1 cDNA中观察到突变。一个SCLC细胞系DMS79未检测到PTEN/MMAC1表达。重要的是，我们鉴定了一个新的PTEN/MMAC1同源物，称为PTH2，定位于9p21 - q13染色体，与PTEN/MMAC1编码区相比仅含有10个氨基酸替换。然而，由于PTEN/MMAC1基因的假定起始密码子在PTH2中变为精氨酸，PTH2的翻译起始位点很可能与PTEN/MMAC1不同。PTH2在两个正常肺组织和两个正常结肠组织中表达，但在16个SCLC细胞系中仅在4个中表达。在一个不表达PTEN/MMAC1 mRNA的SCLC细胞系中鉴定出PTH2中的一个错义突变。我们的数据表明，PTEN/MMAC1失活在SCLC肿瘤发生中是一个罕见事件。然而，PTEN/MMAC1同源物PTH2可能在SCLC肿瘤发生中起作用。
