High-density marker analysis of 11p15.5 in non-small cell lung carcinomas reveals allelic deletion of one shared and one distinct region when compared to breast carcinomas.

The presence of a non-small cell lung carcinoma (NSCLC)-related gene or genes on chromosome band 11p15.5 is of particular interest, given the specific loss of heterozygosity (LOH) measured in this region for lung as well as many other pediatric and adult neoplasms. We have undertaken high-density polymorphic marker analysis in 30 matched normal and NSCLC tumor samples using 11 PCR-based polymorphic markers positioned approximately every 2-3 cM throughout 11p15.5. These studies have confirmed the presence of two distinct regions of LOH for NSCLC in 11p15.5. In 9 of 13 (69%) tumors with measurable LOH, allelic deletion was restricted to 11p15.5, indicating that whole chromosome 11 loss is not a common event in NSCLC. Furthermore, one-half of these tumors showed independent deletion events for each LOH region, while the remaining tumor regions of LOH extended to include all four markers in between. Only two tumors showed LOH for the more telomeric region alone. Furthermore, the location of these two potentially distinct tumor suppressor genes has been significantly refined to a 3-cM area in the telomeric region between D11S1363 and tyrosine hydroxylase (TH) and a 10-cM area in the more proximal part of 11p15.5 between D11S988 and D11S926. Interestingly, the telomeric region of LOH in NSCLC overlaps with the reported location of one of two breast carcinoma-related tumor suppressor genes, but the proximal allelic deletion area for these two tumor types are clearly distinct. Our studies suggest that chromosome band 11p15.5 harbors a minimum of three separate loci, the loss of which is implicated in these two common adult neoplasms.

A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer.

A novel putative tumor suppressor gene and member of the NF2/ERM/ 4.1 superfamily was isolated using Differential Display PCR (DDPCR) on primary lung tumors. When reintroduced into nonexpressing non-small cell lung carcinoma cell lines, this gene, named DAL-1 (for Differentially expressed in Adenocarcinoma of the Lung), was shown to suppress growth. In addition, significantly reduced expression (>50%) of DAL-1 was measured in 39 primary non-small cell lung carcinoma tumors as compared with patient-matched normal lung tissue. Immunocytochemical staining with a polyclonal anti-DAL-1 antibody localized the protein to the plasma membrane, particularly at cell-cell contact points, a pattern reminiscent of other members of the protein 4.1 superfamily including ezrin and NF2. The data suggest DAL-1 is a novel membrane-associated protein with potential to play an important role in the origin and progression of lung cancer.