Abstract
Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer.
Highlights
Lung cancer is the leading cause of cancer deaths in both men and women in the US and results in more deaths globally than breast, prostate and colon cancers combined [1].While the five year survival rate for early stage non-small cell lung cancer (NSCLC) is above 50% it is less than 5% in patients with metastatic disease [2]
GAGE4 were essentially identical on the small data set, the performance of AKAP4 expression on the larger data set was significantly higher than GAGE4 with an area under the receiver operating characteristic (ROC) curve (AUC)
[18, 19] we found that patients with lung squamous cell carcinomas (LSCC) were more accurately classified than those with lung adenocarcinomas (AC) and that classification accuracy increased with advanced cancer stages, we tested whether the strength of AKAP4 PCR signal correlated with a variety of clinical parameters including www.impactjournals.com/oncotarget
Summary
Lung cancer is the leading cause of cancer deaths in both men and women in the US and results in more deaths globally than breast, prostate and colon cancers combined [1].While the five year survival rate for early stage non-small cell lung cancer (NSCLC) is above 50% it is less than 5% in patients with metastatic disease [2]. Low dose computed tomography www.impactjournals.com/oncotarget normal cells and their aberrant expression in many cancers including NCSLCs make them attractive potential biomarkers [14,15,16]. We first tested whether any of the 116 CT-X genes were differentially expressed in PBMC derived RNA from a discovery set of 12 NSCLC lung cancer patients and 7 control patients with smoking related benign lung diseases including
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