WWOX expression in different histologic types and subtypes of non-small cell lung cancer.
OBJECTIVE
Non-small cell lung cancer (NSCLC) has heterogeneous histopathologic classification and clinical behavior and very low survival rate. WWOX (WW domain-containing oxidoreductase) is a tumor suppressor gene, and its expression is altered in several cancers. The purpose of this study is to better define the role of WWOX in NSCLC tumorigenesis and progression by determining its pathogenetic and prognostic significance.


METHODS
WWOX protein expression was evaluated by immunohistochemistry in 170 patients with NSCLC (101 squamous cell carcinomas, 66 adenocarcinomas, 3 large cell carcinomas) and was correlated with histopathologic (histotype, subtype, grade, tumor-node-metastasis, stage, index of cell proliferation Ki67/MIB1) and clinical (age, gender, local recurrences, distant metastases, overall survival, and disease-free survival) characteristics.


RESULTS
WWOX expression was absent/reduced in 84.9% of NSCLCs, whereas it was normal in 80.5% of adjacent normal lung tissues. WWOX expression was strongly associated with tumor histology (P=1.1x10(-5)) and histologic grade (P=0.0081): the percentage of cases with absent/strongly reduced WWOX expression was higher in squamous cell carcinomas and in poorly differentiated tumors. Regarding adenocarcinoma, bronchioloalveolar pattern showed normal WWOX expression in 62.5% of the cases, whereas in solid and acinar patterns, a prevalence of cases with absent/very low WWOX expression was observed (79.2% and 50%, respectively). Finally, weak WWOX staining intensity was related to the high index of cell proliferation (P=0.0012).


CONCLUSIONS
Our results suggest that the loss of WWOX expression plays different roles in tumorigenesis of distinct histotypes and subtypes of NSCLC and is related to high aggressiveness (G3; high proliferating activity) of tumors.
Donati
Valentina
V
Department of Surgery, Division of Anatomic Pathology and Cardio-Thoracic Surgery, University of Pisa and Scuola Normale Superiore and Istituto Nazionale di Fisica Nucleare, Section of Pisa, Pisa, Italy. valentina.donati@gmail.com
Fontanini
Gabriella
G
Dell'Omodarme
Matteo
M
Prati
Maria Cristina
MC
Nuti
Simona
S
Lucchi
Marco
M
Mussi
Alfredo
A
Fabbri
Muller
M
Basolo
Fulvio
F
Croce
Carlo Maria
CM
Aqeilan
Rami Ishaq
RI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000737:chemistry; D011379:Prognosis; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000737:chemistry; D000074584:WW Domain-Containing Oxidoreductase
D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human