Some of them have indirect relationship with the disease pathogenesis

family. WAP four-disulfide core domain 2, the gene encoding HE4, is located on chromosome 20, in a segment frequently amplified in many cancers. Other proteins in this family include Secretory Leukocyte Peptidase Inhibitor, Elafin, and PS20. Members of the WFDC family are characterized by the presence of one or more WFDC domains of approximately 50 amino acids in length that contain eight highly conserved cysteine residues linked by four disulfide bonds. HE4 is a protease inhibitor that was identified in the epithelium of the epididymis and is involved in sperm maturation. The protein shows characteristics of a secretory protein, with a signal peptide followed by a small, acidic, and cysteine-rich polypeptide. Its role in other tissues remains unclear. It has been suggested that it might be involved in the innate immunity defenses of the respiratory tract, nasal and oral cavities and in the development of lung adenocarcinoma. Moreover, HE4 is over-expressed in get (S)-(-)-Blebbistatin ovarian cancer, particularly in serous, clear cell and endometroid epithelial ovarian carcinomas, and is secreted early in the serum of patients with ovarian cancer. Several attempts have been done to characterize ovarian cancer using multi-parametric models of gene expression, including HE4 mRNA . Many publications have shown that the serum levels of HE4 and CA125 can be used for the early detection of ovarian cancer recurrence and to classify patients with a pelvic mass as at high or low risk of ovarian malignancy. Its specificity PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19703900 is higher than that of CA125, especially in early stage disease and in premenopausal women. Serum HE4 level is correlated PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19705642 with tumor stage, age and smoking status. Importantly, it is not elevated in benign gynecological conditions and in endometriosis. However, HE4 is not ovarian cancer-specific. Indeed, WFDC2 is strongly expressed in normal human trachea and salivary glands and, to a lesser extent, in lung, prostate, pituitary gland, thyroid and kidney. Moderate to high levels have also been detected in lung adenocarcinoma and, occasionally, in breast, transitional cell and pancreatic carcinomas. Particularly, HE4 is expressed in most lung adenocarcinomas and in a significant number of squamous, small cell and large cell carcinomas of the lung, suggesting that it could be used as a diagnostic and/or prognostic factor to refine the standard pathologic analysis. Indeed, in lung adenocarcinoma, nodal status and HE4 expression are independent prognostic factors of disease-free and overall survival. Moreover, high serum and pleural effusion concentrations of HE4 were previously observed in NSCLC and Three studies suggested that HE4 could be a potential diagnostic and prognostic marker in NSCLC. The aim of our study was thus to determine the diagnostic and prognostic value of HE4 serum level using 346 samples from a serum biobank dedicated to the validation of biomarkers in lung cancer and following the REMARK guidelines. Materials and Methods Patients Serum samples from 346 consecutive patients with NSCLC referred to the Montpellier– Nmes University Hospital, France, between January 1995 and December 1997 were used for 2 / 13 HE4 in Lung Cancer this study. These samples are part of a large biobank that was started in 1990 to collect serum samples from patients with NSCLC with the goal of determining prospectively the prognostic impact of new serum tumor markers. Specifically, the biobank protocol defined the clinical variables to be recorded, the eligibi