Frequent silence of chromosome 9p, homozygous DOCK8, DMRT1 and DMRT3 deletion at 9p24.3 in squamous cell carcinoma of the lung

Abstract

Abstract. Chromosomal alterations are a major genomic force contributing to the development of lung cancer. We subjected 22 cases of squamous cell carcinoma of the lung (SCC) to whole-genome microarray-CGH (resolution, 1 Mb) to identify critical genetic landmarks that might be important mediators in the formation or progression of SCC. On a genome-wide profile, copy number losses (log 2 ratio <-0.25) on chromosome 9p occurred in 72.7% (16/22) of the SCC cases, and the delineated minimal common region was 9p24.3-p21.1. The progression of SCC to advanced stages or poorly differentiated malignancy was significantly associated with an increase in the copy number losses on 9p (P=0.033). More specifically, 2 distinct homozygous deletion (HD) loci (log 2 ratio <-1) were identified as novel loci for candidate tumor suppressor genes (TSGs) in SCC: one, spanning 128 kbp on 9p21.1 [4.5% (1/22)] and the other, spanning approximately 200 kbp on 9p24.3 [13.6% (3/22)]. The HDs at 9p24.3 was found to contain the putative TSG, DOCK8 and 2 possible candidate TSGs, DMRT1 and DMRT3. Quantitative real-time PCR (qRT-PCR) analysis demonstrated the array-CGHdetected potential candidate genes DMRT1, DMRT3 and DOCK8, at 9p24.3 were under-expressed in SCCs. Our study indicated that chromosome 9p loss is the hallmark of SCC, and DMRT1, DMRT3 and DOCK8 genes at 9p24.3 might be of interest for the study of the pathophysiology of SCC as potential targets for therapeutic measures.