Expression of telomere-associated genes as prognostic markers for overall survival in patients with non-small cell lung cancer.
OBJECTIVE
Human telomeres, which are composed of long, repetitive sequences of TTAGGG and a variety of proteins, function as a protective structure capping the ends of chromosomes. Telomere dysfunction plays important roles in cancer initiation and progression. TRF1, TRF2, POT1, and RAP1 are four major telomere proteins that regulate telomere stability and telomere length. We hypothesized that the expression of these genes would have significant predictive value for cancer development and prognosis.


METHODS
We compared the mRNA expression level of TRF1, TRF2, POT1, and RAP1 between tumor and adjacent normal tissues from 148 patients with non-small cell lung cancer using real-time quantitative PCR. We then estimated the prognostic value of the mRNA expression of these genes in tumors.


RESULTS
The expression level of TRF1 was significantly lower in tumor tissues than in adjacent normal tissues (P < 0.0001); no significant difference was found for TRF2, POT1, and RAP1. The expression of RAP1 gene in tumors was highly predictive of overall survival. In the Cox proportional hazards model, patients with higher RAP1 expression were associated with a significantly better survival [hazard ratio (HR), 0.47; 95% confidence interval (95% CI), 0.24-0.91]. This improved survival was more prominent in men (HR, 0.45; 95% CI, 0.22-0.996) and in ever smokers (HR, 0.50; 95% CI, 0.24-1.02). Kaplan-Meier survival curves showed that patients with higher RAP1 expression had significantly longer median survival than patients with lower expression (median = 51.21 versus 15.34 months, P < 0.0009). The expressions of TRF2 in tumor tissues were significantly correlated with tumor grades (P = 0.0114).


CONCLUSIONS
RAP1 expression may be a useful biomarker of tumor progression and survival.
Lin
Xin
X
Departments of Epidemiology and Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA.
Gu
Jian
J
Lu
Charles
C
Spitz
Margaret R
MR
Wu
Xifeng
X
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D015996:Survival Rate; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C440849:POT1 protein, human; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D020827:rap1 GTP-Binding Proteins