PTEN Gene Deletions in Patients with Multiple Myeloma.

Abstract

PTEN, a tumor suppressor gene, negatively regulates the anti-apoptotic action of akt phosphorylation. Allelic loss or mutation of this gene has been detected in many solid tumors and more recently in human myeloma cell lines (HMCLs). Expression of PTEN has resulted in growth inhibition and apoptosis of a HMCL, suggesting that it may play a role in the pathogenesis of multiple myeloma (MM). However, the PTEN status in tumor cells from patients with MM has not been determined. Using a triple staining method combining staining for cytoplasmic light chains and fluorescence in situ hybridization (FISH) with chromosome 10-centromere and PTEN-gene specific probes, we analyzed clonal plasma cells from 71 patients with MM, 10 with plasma cell leukemia (PCL) and 10 HMCLs. Hemizygous PTEN deletions were detected in 4 of 71 (5.6%) MM patients, 2 of 10 (20%) PCLs, and 2 of 10 (20%) HMCLs. The percentages of clonal plasma cells containing PTEN deletions ranged from 21–90% (median, 56%). Three of the 4 patients with PTEN deletions were detected at diagnosis with stage III disease (Duire-Salmon) and 1 was detected at relapse. Two patients had IgG kappa, 1 IgG lambda and 1 free lambda light chain. To correlate the PTEN status with other known genetic abnormalities in MM, we investigated 4 MM and 2 PCLs with PTEN deletions using FISH for chromosome13q, p53 status, translocations t(11;14), t(4;14) and t(14;16). One MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. All 4 MM patients with hemizygous PTEN deletions received melphalan based high-dose chemotherapy and autologous stem cell support. Their median overall survival (OS) was 48.1months, and progression free survival (PFS) was 42.8 months as compared to patients without PTEN deletions (OS, not reached, PFS, 25.8 months) (p=0.51 for OS, p=0.67 for PFS). Our results indicate that PTEN deletions are uncommon in MM patients and therefore unlikely represent a primary event for MM. PTEN deletions appear to occur in the advance stage of the disease, and are more frequently involved in PCL or HMCLs suggesting that deletions of PTEN may be associated with disease progression in a subset of MM.