Research Papers:

TBX2 subfamily suppression in lung cancer pathogenesis: a high-potential marker for early detection

Athar A. Khalil, Smruthy Sivakumar, Frances Anthony San Lucas, Tina McDowell, Wenhua Lang, Kazuhiro Tabata, Junya Fujimoto, Yasushi Yatabe, Avrum Spira, Paul Scheet, Georges Nemer _ and Humam Kadara

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Oncotarget. 2017; 8:68230-68241. https://doi.org/10.18632/oncotarget.19938

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Athar A. Khalil1, Smruthy Sivakumar2,3, Frances Anthony San Lucas2, Tina McDowell4, Wenhua Lang4, Kazuhiro Tabata5, Junya Fujimoto4, Yasushi Yatabe6, Avrum Spira7, Paul Scheet2,3, Georges Nemer1,* and Humam Kadara1,2,*

1Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

2Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA

4Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan

6Department of Pathology, Aichi Cancer Center, Nagoya, Japan

7Section of Computational Biomedicine, School of Medicine, Boston University, Boston, Massachusetts, USA

*Contributed equally as co-senior authors

Correspondence to:

Georges Nemer, email: [email protected]

Humam Kadara, email: [email protected]

Keywords: NSCLC, smoking, preneoplasia, airway field of injury, early detection

Received: May 23, 2017     Accepted: July 26, 2017     Published: August 04, 2017


The TBX2 subfamily (TBXs 2, 3, 4 and 5) transactivates or represses genes involved in lung organogenesis. Yet TBX2 subfamily expression in pathogenesis of non-small cell lung cancer (NSCLC), the most common lung malignancy, remains elusive. We sought to probe the expression profile of the TBX2 subfamily in early phases of NSCLC. Expression of TBX2 subfamily was analyzed in datasets of pan-normal specimens as well as NSCLCs and normal lung tissues. TBX2 subfamily expression in matched normal lungs, premalignant hyperplasias and NSCLCs was profiled by transcriptome sequencing. TBX2 subfamily expression was evaluated in the cancerization field consisting of matched NSCLCs and adjacent cytologically-normal airways relative to distant normal lungs and in a dataset of normal bronchial samples from smokers with indeterminate nodules suspicious for malignancy. Statistical analysis was performed using R. TBX2 subfamily expression was markedly elevated in normal lungs relative to other organ-specific normal tissues. Expression of the TBXs was significantly suppressed in NSCLCs relative to normal lungs (P < 10−9). TBX2 subfamily was significantly progressively decreased across premalignant lesions and NSCLCs relative to normal lungs (P < 10−4). The subfamily was significantly suppressed in NSCLCs and adjacent normal-appearing airways relative to distant normal lung tissues (P < 10−15). Further, suppressed TBX2 subfamily expression in normal bronchi was associated with lung cancer status (P < 10−5) in smokers. Our findings suggest that the TBX2 subfamily is notably suppressed in human NSCLC pathogenesis and may serve as a high-potential biomarker for early lung cancer detection in high-risk smokers.

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