ALTERATIONS OF PTEN MMAC1, A CANDIDATE TUMOR-SUPPRESSOR GENE, AND ITSHOMOLOG, PTH2, IN SMALL-CELL LUNG-CANCER CELL-LINES/

Loss of heterozygosity (LOH) at chromosome 10q23-q25 is frequent in sm all cell lung cancer (SCLC), indicating the presence of putative tumor suppressor genes, PTEN/MMAC1, a newly cloned candidate tumor suppress or gene at 10q23, was mutated in multiple human cancers, We investigat ed whether mutations of PTEN/MMAC1 play an important role in SCLC tumo rigenesis, We examined 16 SCLC cell lines for PTEN/MMAC1 mRNA expressi on by reverse-transcriptase polymerase chain reaction (RT-PCR) and pot ential mutations by sequencing analysis of the PTEN/MMAC1 coding regio n, No mutation was observed in PTEN/MMAC1 cDNAs in 15 cell lines expre ssing PTEN/MMAC1, One SCLC cell line, DMS79, did not have detectable P TEN/MMAC1 expression, Importantly, we identified a novel homologue of PTEN/MMAC1, termed PTH2, localized to chromosome 9p21-q13 and containi ng only ten amino acid substitutions compared with the PTEN/MMAC1 codi ng region, However, because the putative initiation codon for PTEN/MMA C1 gene was changed to arginine in PTH2, the translational initiation site of PTH2 is very likely to differ from that of the PTEN/MMAC1, PTH 2 was expressed in two normal lung tissues and two normal colon tissue s, 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 mR NA, Our data suggest that inactivation of PTEN/MMAC1 is a rare event i n SCLC tumorigenesis, However, the PTEN/MMAC1 homologue PTH2 may play a role in SCLC tumorigenesis.