A Sensitive NanoString-Based Assay to Score STK11 (LKB1) Pathway Disruption in Lung Adenocarcinoma.

Abstract

INTRODUCTION:

Serine/threonine kinase 11 gene (STK11), better known as liver kinase β1, is a tumor suppressor that is commonly mutated in lung adenocarcinoma (LUAD). Previous work has shown that mutational inactivation of the STK11 pathway may serve as a predictive biomarker for cancer treatments, including phenformin and cyclooxygenase-2 inhibition. Although immunohistochemical (IHC) staining and diagnostic sequencing are used to measure STK11 pathway disruption, there are serious limitations to these methods, thus emphasizing the importance of validating a clinically useful assay.

METHODS:

An initial STK11 mutation mRNA signature was generated using cell line data and refined using three large, independent patient databases. The signature was validated as a classifier using The Cancer Genome Atlas (TCGA) LUAD cohort as well as a 442-patient LUAD cohort developed at Moffitt. Finally, the signature was adapted to a NanoString-based format and validated using RNA samples isolated from formalin-fixed, paraffin-embedded tissue blocks corresponding to a cohort of 150 patients with LUAD. For comparison, STK11 IHC staining was also performed.

RESULTS:

The STK11 signature was found to correlate with null mutations identified by exon sequencing in multiple cohorts using both microarray and NanoString formats. Although there was a statistically significant correlation between reduced STK11 protein expression by IHC staining and mutation status, the NanoString-based assay showed superior overall performance, with a -0.1588 improvement in area under the curve in receiver-operator characteristic curve analysis (p < 0.012).

CONCLUSION:

The described NanoString-based STK11 assay is a sensitive biomarker to study emerging therapeutic modalities in clinical trials.

• Authors: Lu Chen, Brienne E Engel, Eric A Welsh, Sean J Yoder, Stephen G Brantley, Dung-Tsa Chen, Amer A Beg, Chunxia Cao, Frederic J Kaye, Eric B Haura, Matthew B Schabath, W Douglas Cress
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 11 Issue 6 Pg. 838-49 (06 2016) ISSN: 1556-1380 [Electronic] United States
• PMID: 26917230 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Adenocarcinoma (diagnosis, genetics)
• Biological Assay (methods)
• Biomarkers, Tumor (genetics)
• Cohort Studies
• Humans
• Lung Neoplasms (diagnosis, genetics)
• Mutation
• Nanotechnology
• Neoplasm Staging
• Prognosis
• Protein Serine-Threonine Kinases (genetics)
• ROC Curve