Alterations of 9p in squamous cell carcinoma and adenocarcinoma of the lung: association with smoking, TP53, and survival.
Tobacco smoke is well recognized as the major etiological contributor to lung cancer, yet the relationship between tobacco smoke exposure and a specific pattern of molecular abnormalities at somatic loci is less well characterized. We analyzed 100 primary tumors from patients undergoing surgical resection of squamous cell carcinoma and adenocarcinoma of the lung for loss of heterozygosity (LOH) and homozygous deletions at two microsatellite markers in a recombinogenic region of 9p13. We describe the relationship of alterations at these markers with tumor characteristics (both clinical and molecular), patient demographics, survival, and measures of tobacco-smoke exposure. Homozygous deletions in this region occurred in 25% (21/85) and LOH in 33% (28/85) of informative tumors examined. These alterations occurred more often in tumors with intense TP53 protein staining by immunohistochemistry, suggesting that inactivation of the TP53 pathway may contribute to these LOH events. Duration of smoking was greatest in patients with the homozygous deletion, intermediate in patients with LOH, and shortest in patients whose tumor did not demonstrate loss in these markers. Unexpectedly, LOH at 9p13 was a significant predictor of improved survival in patients, while the homozygous deletion was associated with the poorest patient survival. Together, these results suggest that TP53 alteration and long-term tobacco smoke exposure may contribute to genetic alterations at 9p13, and that the mechanism and biologic consequences of allele loss reflect individual biologic differences that determine the extent of loss (LOH or homozygous deletion), such that those patients with the deletion of this region face a more aggressive and deadly disease.
Marsit
Carmen J
CJ
Department of Genetics and Complex Diseases, Harvard School of Public Health, Building I, Room 607, 665 Huntington Avenue, Boston, MA 02115, USA.
Wiencke
John K
JK
Nelson
Heather H
HH
Kim
Duk-Hwan
DH
Hinds
Philip W
PW
Aldape
Kenneth
K
Kelsey
Karl T
KT
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D015999:Multivariate Analysis; D012907:Smoking / Q000009:adverse effects; D016019:Survival Analysis; D013997:Time Factors