Deregulation of p27 and cyclin D1/D3 control over mitosis is associated with unfavorable prognosis in non-small cell lung cancer, as determined in 405 operated patients.
BACKGROUND
A large group of interacting molecular factors, involved in epithelial-mesenchymal transition, epidermal growth factor receptor (EGFR) signaling, and G1 mitotic phase, are shown to play an important role in cancerogenesis and progression of non-small cell lung cancer (NSCLC). Since success concerning potential correlations, structural and numeric gene aberrations, and biological risk assessment of these molecular factors are still lacking, combined analysis of a multitude of intertwined factors is currently a promising approach.


METHODS
Cyclins (D1, D2, D3, and E), p21, p27, EGFR, Snail, E-cadherin, beta-catenin, phosphatidylinositol-3' kinase, phosphatase and tensin homologue, phosphorylated Akt, and phosphorylated signal transducer, and activator of transcription-3 were analyzed by immunohistochemistry in 405 surgically resected NSCLC, using a standardized tissue microarray platform. In addition, the gene status of EGFR and cyclin D1 was examined by fluorescence in situ hybridization. Extensive clinical data were acquired, enabling detailed clinicopathologic correlation during a postoperative follow-up period of up to 14 years.


RESULTS
The protein overexpressions of nuclear p27, cyclin D1, cyclin D3, E-cadherin, and EGFR as assessed by immunohistochemistry were all associated with a significant reduction in overall survival time. In addition, cyclin D1 proved especially important, being the only independent molecular tumor-related factor with prognostic significance by multivariable analysis. In analogy to EGFR, recurrent numeric gene aberrations, particularly high-level amplifications, of cyclin D1 were obvious.


CONCLUSIONS
The results emphasize that deregulation of controlling factors of the early G1 phase is of significant oncogenic relevance and may represent a potential treatment target in NSCLC.
Sterlacci
William
W
Hospital Feldkirch, Affiliation of the Medical University Innsbruck, Institute for Pathology, Carinagasse 47, Feldkirch, Austria. william.sterlacci@lkhf.at
Fiegl
Michael
M
Hilbe
Wolfgang
W
Jamnig
Herbert
H
Oberaigner
Wilhelm
W
Schmid
Thomas
T
Augustin
Florian
F
Auberger
Jutta
J
Obermann
Ellen C
EC
Tzankov
Alexandar
A
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis; D055815:Young Adult
C530104:CCND1 protein, human; C534696:CCND3 protein, human; C436291:CDKN1B protein, human; D056743:Cyclin D3; D047908:Intracellular Signaling Peptides and Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27