MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients.
BACKGROUND
MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients.


METHODS
Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database.


RESULTS
MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005).


CONCLUSIONS
The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma.
MacDermed
Dhara M
DM
The Scripps Research Institute and Scripps Translational Science Institute, 3344 N Torrey Pines Court Ste, 300, La Jolla, CA 92037, USA. dharamac@scripps.edu
Khodarev
Nikolai N
NN
Pitroda
Sean P
SP
Edwards
Darrin C
DC
Pelizzari
Charles A
CA
Huang
Lei
L
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D018396:Mucin-1 / Q000378:metabolism*; D051381:Rats; D015996:Survival Rate; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D018396:Mucin-1
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