[Frontiers in Bioscience E3, 625-634, January 1, 2011]

STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis

Karishma Mehra1, Mitra Mehrad, Eleanor Chen1, Geng Ning1, Ronny Drapkin1, Frank D. McKeon2, Wa Xian1,3, Christopher P. Crum2

1Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Department of Cell Biology, Harvard Medical School, 2Department of Pathology, University of Michigan Medical Center, Ann Arbor, 3A-Star Institute of Medical Biology, Singapore

TABLE OF CONTENTS

1. Abstract
2. Introduction 2.1 .Traditional models of ovarian carcinogenesis
3. Changing the landscape: serous tubal intraepithelial carcinoma
3.1. The BRCA model and STICs
3.2. STIC in the general population of ovarian cancers
3.3. Unanswered questions
3.4. Re-visiting high-grade Müllerian carcinomas
4. Emerging precursor candidates in the fallopian tube
4.1. The p53 signature
4.2. Secretory cell outgrowths (SCOUTs): more pathways coming into play?
5. Future directions
References

1. ABSTRACT

The events leading to the most common and most lethal ovarian carcinoma - high grade serous carcinoma - have been poorly understood. However, the detailed pathologic study of asymptomatic women with germ-line BRCA 1 or BRCA2 (BRCA+) mutations has unearthed an early malignancy, serous tubal intraepithelial carcinomas (STIC), which has linked many peritoneal and ovarian serous carcinomas to the fimbria. The distinction between high-grade serous and endometrioid carcinomas continues to narrow, with shared alterations in expression of pTEN, PAX2 and p53. Moreover, the discovery of clonal alterations in p53 in benign tubal epithelium, - p53 signatures - has established a foundation for a serous cancer precursor in the fimbria. We have expanded this entity to include a "generic" secretory cell outgrowth (SCOUT), in the fallopian tube that is associated with altered PAX2. As the repertoire of gene alterations is expanded and its link to serous carcinogenesis clarified, a cogent pathway to high-grade Müllerian carcinomas will emerge. This will challenge conventional thinking about ovarian carcinogenesis but will provide a new template for studies of ovarian cancer prevention.