Prognostic significance of HE4 expression in pulmonary adenocarcinoma

We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty-seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4-positive group (44.6%) was significantly different from that in the negative group (82.3%, p = 0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4-negative group (p = 0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR = 3.7, 95%CI = [1.7–8.4], p = 0.001; HR = 5.5, 95%CI = [1.8–17.2], p = 0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma.

[1]  Christopher P Crum,et al.  Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. , 2005, Cancer research.

[2]  L. Bingle,et al.  The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms , 2002, Oncogene.

[3]  W. Cai,et al.  High resolution analysis of genomic aberrations by metaphase and array comparative genomic hybridization identifies candidate tumour genes in lung cancer cell lines. , 2007, Cancer letters.

[4]  L. Frati,et al.  Ovarian tumor marker HE4 is differently expressed during the phases of the menstrual cycle in healthy young women , 2010, Tumor Biology.

[5]  K. Ohlsson,et al.  Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Roger E Bumgarner,et al.  Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. , 1999, Gene.

[7]  Patrick J Heagerty,et al.  Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms. , 2010, Cancer letters.

[8]  C. Mountain,et al.  Revisions in the International System for Staging Lung Cancer. , 1997, Chest.

[9]  Michèl Schummer,et al.  The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. , 2003, Cancer research.

[10]  Nicole Urban,et al.  Bead-Based ELISA for Validation of Ovarian Cancer Early Detection Markers , 2006, Clinical Cancer Research.

[11]  S. Cross,et al.  WFDC2 (HE4): A potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung , 2006, Respiratory research.

[12]  H. Frierson,et al.  Comprehensive analysis of HE4 expression in normal and malignant human tissues , 2006, Modern Pathology.

[13]  D. Botstein,et al.  Diversity of gene expression in adenocarcinoma of the lung , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Frati,et al.  HE4: a new potential early biomarker for the recurrence of ovarian cancer , 2010, Tumor Biology.

[15]  J. Schröder,et al.  Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. , 1990, The Journal of biological chemistry.

[16]  Y. Yatabe,et al.  Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  P. De Baetselier,et al.  Secretory leukocyte protease inhibitor promotes the tumorigenic and metastatic potential of cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Giovanni Parmigiani,et al.  Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. , 2002, Cancer research.

[19]  Y. Bourbonnais,et al.  Proteins with whey-acidic-protein motifs and cancer. , 2006, The Lancet. Oncology.