A Two-Gene Prognostic Classifier for Early-Stage Lung Squamous Cell Carcinoma in Multiple Large-Scale and Geographically Diverse Cohorts.
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.



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.



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.



We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection.
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Rintaro
R
Noro
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Teruhide
T
Ishigame
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.
Naomi
N
Walsh
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Kouya
K
Shiraishi
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Ana I
AI
Robles
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Bríd M
BM
Ryan
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Aaron J
AJ
Schetter
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Elise D
ED
Bowman
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Judith A
JA
Welsh
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Masahiro
M
Seike
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Akihiko
A
Gemma
Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway.
Vidar
V
Skaug
Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway.
Steen
S
Mollerup
Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway.
Aage
A
Haugen
Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
Jun
J
Yokota
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Takashi
T
Kohno
Laboratory of Human Carcinogenesis, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: curtis_harris@nih.gov.
Curtis C
CC
Harris
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
D014408:Biomarkers, Tumor
Biomarker; Gene expression; Lung squamous cell carcinoma; Microarray; Prognostic classifier