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Loss of Heterozygosity of Chromosome 3p21 Is Associated with Mutant TP53 and Better Patient Survival in Non–Small-Cell Lung Cancer

¹ Department of Genetics and Complex Diseases, and ² Department of Environmental Health, Harvard School of Public Health, and ³ Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts; ⁴ Department of Surgery, Chiba Social Insurance Hospital, Chiba, Japan; ⁵ Department of Surgery, Nara University, Kashihara, Japan; ⁶ Center for Genomics Research, Samsung Biomedical Research Institute, Sungkyunkwan University, Seoul, Republic of Korea; ⁷ Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁸ Laboratory for Molecular Epidemiology, University of California-San Francisco, San Francisco, California

Allelic loss of chromosome region 3p21.3 occurs early and frequently in non–small-cell lung cancer, and numerous tumor suppressor genes at this locus may be targets of inactivation. Using an incident case series study of non–small-cell lung cancer, we sought to determine the prevalence of loss of heterozygosity (LOH) in the 3p21.3 region and to examine the associations between this alteration and patient outcome, exposure to tobacco smoke, occupational asbestos exposure, and additional molecular alterations in these tumors. We examined LOH at 7 microsatellite markers in the chromosome 3p21.3 region, and LOH was present in at least one of the loci examined in 60% (156 of 258) of the tumors, with the prevalence of LOH at individual loci ranging from 15 to 56%. Occupational asbestos exposure and TP53 mutation were significantly associated with more extensive 3p21 LOH. In squamous cell carcinomas, measures of cumulative smoking dose were significantly lower in patients with LOH at 3p21, particularly in TP53 mutant tumors. Examining patient outcome, we found that in squamous cell carcinomas, having any LOH in this region was associated with a better overall survival (log-rank test, P < 0.04). Together, these results indicate that allelic loss at 3p21 can affect patient outcome, and that this loss may initially be related to carcinogen exposure, but that extension of this loss is related to TP53 mutation status and occupational asbestos exposure.

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