-Identification of a candidate gene on chromosome 3p21 potentially involved in early age onset lung cancer Free

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Lung cancer is primarily a disease affecting people over the age of 65. Less than 10% of cases occur in patients younger than 50. Epidemiological studies have provided evidence for the involvement of genetic factors in early onset lung cancer. To identify loci contributing to early age onset lung cancer, we examined loss of heterozygosity at five chromosome regions (3p, 3q, 9p, 17p, and 19p) most commonly affected in lung cancer. Tumors from patients who were less than 50 (young cases) or greater than 79 (elderly cases) at the time of diagnosis were examined. We observed a region on 3p.21 that was more frequently lost in young cases compared to elderly cases (82% vs. 30%, p= 0.02). Further genetic mapping narrowed this region to 2 Mb containing ~70 genes. Significantly, this minimal region of loss was the same region implicated in telomerase suppression in renal cell carcinoma (RCC23) cell lines having an experimentally transferred wild type Ch.3. We performed RT-PCR on 65 of the 70 genes and searched for genes expressed at low level in lung cancers with LOH and at high levels in telomerase suppressed RCC23 cells. We found a cluster of three genes significantly down regulated in lung cancers with LOH. Two of these genes were highly expressed in RCC23 cells with repressed telomerase activity. LOC339834 was the gene most highly up regulated in RCC23 with repressed telomerase expression and the most severely down regulated in lung tumors with LOH in the region. LOC339834 encodes a novel 583 amino acid protein with a coiled-coil domain. Its product shares structural homology to proteins involved in chromosome segregation (CENP-F in human) and telomere maintenance (MLP-1 in yeast). In a majority of lung cancer cell lines and primary lung tumors, it is often methylated at the CpG island within the promoter region and can be re-expressed by demethylation treatment in the cancer cell lines. We sequenced all 11 exons of the LOC339834 gene in 59 lung cancer samples including 18 young cases. We identified five common polymorphic changes that were distributed evenly among all age groups. In contrast, six of the seven singular changes in the gene were observed only in young cases. Our results suggest that LOC339834 is a strong candidate potentially contributing to early age onset lung cancer through telomerase disregulation.