Rintaro Noro1, Teruhide Ishigame1, Naomi Walsh2, Kouya Shiraishi3, Ana I Robles1, Bríd M Ryan1, Aaron J Schetter1, Elise D Bowman1, Judith A Welsh1, Masahiro Seike4, Akihiko Gemma4, Vidar Skaug5, Steen Mollerup5, Aage Haugen5, Jun Yokota6, Takashi Kohno3, Curtis C Harris7. 1. Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. 2. Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland; Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland. 3. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. 4. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. 5. Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway. 6. Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain. 7. Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: curtis_harris@nih.gov.
Abstract
INTRODUCTION: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early-stage lung SCC. METHODS: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and examined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta-analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC. RESULTS: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta-analysis of stage I patients. CONCLUSIONS: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection. Published by Elsevier Inc.
INTRODUCTION: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early-stage lung SCC. METHODS: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and examined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta-analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC. RESULTS:Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta-analysis of stage I patients. CONCLUSIONS: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection. Published by Elsevier Inc.
Authors: Fabio Conforti; Laura Pala; Alberto Mantovani; Richard D Gelber; Giuseppe Viale; Aron Goldhirsch; Giuseppe Giaccone; Eleonora Pagan; Vincenzo Bagnardi; Tommaso De Pas; Paola Queirolo; Elisabetta Pennacchioli; Chiara Catania; Emilia Cocorocchio; Pier Francesco Ferrucci; Maristella Saponara; Gianmarco Orsolini; Paola Zagami; Eleonora Nicoló; Filippo De Marinis; Giampaolo Tortora; Emilio Bria; Saverio Minucci; Hadine Joffe; Paolo Veronesi; Jennifer Wargo; Rachel Rosenthal; Charles Swanton Journal: Clin Cancer Res Date: 2021-05-20 Impact factor: 13.801