A Predictive 7-Gene Assay and Prognostic Protein Biomarkers for Non-small Cell Lung Cancer
Nancy Lan Guo,
Afshin Dowlati,
Rebecca A. Raese,
Chunlin Dong,
Guoan Chen,
David G. Beer,
Justine Shaffer,
Salvi Singh,
Ujala Bokhary,
Lin Liu,
John Howington,
Thomas Hensing,
Yong Qian
Affiliations
Nancy Lan Guo
West Virginia University Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300, United States; Corresponding author at: 2816 HSS, West Virginia University Cancer Institute, Morgantown, WV 26506-9300, United States.
Afshin Dowlati
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, United States
Rebecca A. Raese
West Virginia University Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300, United States
Chunlin Dong
West Virginia University Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300, United States
Guoan Chen
Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944, United States
David G. Beer
Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944, United States
Justine Shaffer
West Virginia University Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300, United States
Salvi Singh
West Virginia University Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300, United States
Ujala Bokhary
Kellogg Cancer Center, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201, United States
Lin Liu
Kellogg Cancer Center, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201, United States
John Howington
Kellogg Cancer Center, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201, United States
Thomas Hensing
Kellogg Cancer Center, NorthShore University HealthSystem, 2650 Ridge Avenue, Evanston, IL 60201, United States
Yong Qian
National Institute of Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, United States
Purpose: This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non-small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic targets. Patients and methods: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples. Results: A 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P < 0.0001) in Kaplan-Meier analyses. In the predicted benefit group, there was a significantly better disease-specific survival in patients receiving adjuvant chemotherapy in both training (P = 0.035) and validation (P = 0.0049) sets. In the predicted non-benefit group, there was no survival benefit in patients receiving chemotherapy in either set. The protein expression of ZNF71 quantified with AQUA scores produced robust patient stratification in separate training (P = 0.021) and validation (P = 0.047) NSCLC cohorts. The protein expression of CD27 quantified with ELISA had a strong correlation with its mRNA expression in NSCLC tumors (Spearman coefficient = 0.494, P < 0.0088). Multiple signature genes had concordant DNA copy number variation, mRNA and protein expression in NSCLC progression. Conclusions: This study presents a predictive multi-gene assay and prognostic protein biomarkers clinically applicable for improving NSCLC treatment, with important implications in lung cancer chemotherapy and immunotherapy. Keywords: Predictive gene assay, Prognostic protein biomarkers, Non-small cell lung cancer (NSCLC), Chemotherapy, Immunotherapy, Precision therapy