Age- and sex-specific genomic profiles in non-small cell lung cancer.
BACKGROUND
Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC).


OBJECTIVE
To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex.


METHODS
Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. All patients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expression signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of activation/deregulation.


METHODS
Patterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with 5-year recurrence-free patient survival.


RESULTS
Low- and high-risk patient clusters/cohorts were identified with the longest and shortest 5-year recurrence-free survival, respectively, within the age and sex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs 42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or older demonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64% vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstrated increased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001) pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001), tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs 22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). All observations were reproducible in split sample analyses.


CONCLUSIONS
Among a cohort of patients with NSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-free survival. These findings require validation in independent patient data sets.
Mostertz
William
W
Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA. anil.potti@duke.edu
Stevenson
Marvaretta
M
Acharya
Chaitanya
C
Chan
Isaac
I
Walters
Kelli
K
Lamlertthon
Wisut
W
Barry
William
W
Crawford
Jeffrey
J
Nevins
Joseph
J
Potti
Anil
A
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009857:Oncogenes / Q000235:genetics; D011379:Prognosis; D012189:Retrospective Studies; D012737:Sex Factors; D016019:Survival Analysis