Mutational inactivation of aminoacylase‐1 in a small cell lung cancer cell line

Abstract

Small cell lung cancer (SCLC) cell lines and tumors invariably exhibit loss of heterozygosity (LOH) or, in rare cases, homozygous deletions involving part or all of chromosome arm 3p, suggesting the presence of 1 or more tumor-suppressor genes in this region. The gene encoding aminoacylase-1 (ACY1) is localized on chromosome segment 3p21.1. ACY1 enzymatic activity, protein, and mRNA have been demonstrated to be expressed at either undetectable or very low levels in a group of SCLC cell lines and tumors. The demonstration of mutational inactivation of ACY1 would support the hypothesis that ACY1 inactivation in SCLC confers a selective growth advantage. One of four SCLC cell lines with undetectable Acylenzymatic activity and protein exhibited a compound mutation: nonconservative missense point mutations at codons 195 and 254. No wildtype sequence transcripts were identified in the cell line. Although nonmutational mechanisms for low or undetectable ACY1 enzymatic activity, protein, and mRNA expression are most frequently operant in SCLC, the demonstration of a mutation supports selection for ACY1 inactivation. Analysis of normal liver and a liver metastasis from the same patient from whom the NCI-H711 cell line was derived demonstrated that the mutation was neither germline nor an early event in the development of SCLC. It is of interest that several genes involved in the regulation of intracellular protein degradation are encoded by chromosome band 3p21 and display unusual expression in SCLC. The presence of other loci involved in protein degradation on chromosome band 3p21 and their aberrant expression in SCLC suggest that a variety of mechanisms involved in the normal degradation of intracellular proteins may be perturbed in this neoplasm. Genes Chromosomes Cancer 21:320–325, 1998. Published 1998 Wiley-Liss, Inc.1 This article is a US Government work and, as such, is in the public domain in the United States of America.