Ovarian Carcinoma: Diagnostic Immunohistochemistry of MUCIN4 (MUC4)

Abstract

Ovarian cancer is the fourth leading cause of cancer deaths among U.S. women and has the highest fatality-to-case ratio of all gynecologic malignancies. It affects > 22,000 women and accounts for > 16,000 deaths every year with a projected 5 year mortality rate exceeding 70% (Jemal et al. 2007). This is, in part, due to the lack of early diagnosis, which makes it one of the most challenging of all cancers to fight. In fact, no observable or defined symptoms of disease are evident until it has metastasized. Therefore, there is a need to develop sensitive and reliable biomarker(s) for early detection, so that the high morbidity and deaths in ovarian cancer patients can be minimized. Current strategies for the detec-tion are based on biochemical markers, such as CA125, and biophysical markers assessed by ultrasound and/or Doppler imaging of the ovaries. The clinical utility of these strategies for early diagnosis, however, is limited due to the lack of specificity and sensitivity.

Mucins have emerged as markers of choice for disease diagnosis and prognosis owing to their aberrant expression in malignant cells and proven functional association of some mucins with the cancer development. To date, 20 human mucins have been identified and categorized into two classes (secreted/gel forming and membrane-bound) based on their structural characteristics and physiological fates (Hollingsworth and Swanson 2004; Singh et al. 2007). Mucins are produced by secretory epithelial cells for the lubrication and protection of ducts and lumen within the human body. However, mucins are also believed to play an important role in the pathogenesis of benign and malignant diseases of secretory epithelial cells (Hollingsworth and Swanson 2004). An aberrant expression of mucins has been reported in a variety of carcinomas. MUC4, which belongs to the membrane-bound mucin family, is aberrantly expressed in several types of carcinomas (Singh et al. 2007; Carraway et al. 2002; Chauhan et al. 2006). It is a multifunctional protein that is implicated in numerous cellular functions including cell adhesion, motility, signal transduction, tissue regeneration and differentiation, and tumor growth and metastasis. The diagnostic significance of MUC4 for ovarian carcinoma was recently evaluated in our laboratory by using immunohistochemical analysis of archival specimens (Chauhan et al. 2006). It was demonstrated that MUC4 could be a potential candidate marker for early diagnosis of epithelial ovarian carcinoma and can be utilized in combination with MUC16 to achieve greater sensitivity for the detection of late-stage tumors signifying the clinical applicability of MUC4 immunohistochemistry.