title: CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis.
abstract: CD44 is a transmembrane hyaluronic acid receptor gene that encodes over 100 different tissue-specific protein isoforms. The most ubiquitous, CD44 standard, has been used as a cancer stem cell marker in ovarian and other cancers. Expression of the epithelial CD44 variant containing exons v8-10 (CD44v8-10) has been associated with more chemoresistant and metastatic tumors in gastrointestinal and breast cancers, but its role in ovarian cancer is unknown; we therefore investigated its use as a prognostic marker in this disease. The gene expression profiles of 254 tumor samples from The Cancer Genome Atlas RNAseqV2 were analyzed for the presence of CD44 isoforms. A trend for longer survival was observed in patients with high expression of CD44 isoforms that include exons v8-10. Immunohistochemical (IHC) analysis of tumors for presence of CD44v8-10 was performed on an independent cohort of 210 patients with high-grade serous ovarian cancer using a tumor tissue microarray. Patient stratification based on software analysis of staining revealed a statistically significant increase in survival in patients with the highest levels of transmembrane protein expression (top 10 or 20%) compared to those with the lowest expression (bottom 10 and 20%) (p = 0.0181, p = 0.0262 respectively). Expression of CD44v8-10 in primary ovarian cancer cell lines was correlated with a predominantly epithelial phenotype characterized by high expression of epithelial markers and low expression of mesenchymal markers by qPCR, Western blot, and IHC. Conversely, detection of proteolytically cleaved and soluble extracellular domain of CD44v8-10 in patient ascites samples was correlated with significantly worse prognosis (p<0.05). Therefore, presence of transmembrane CD44v8-10 on the surface of primary tumor cells may be a marker of a highly epithelial tumor with better prognosis while enzymatic cleavage of CD44v8-10, as detected by presence of the soluble extracellular domain in ascites fluid, may be indicative of a more metastatic disease and worse prognosis.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sosulski
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Heiko
authors.initials: H
authors.lastname: Horn
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Coletti
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vinod
authors.initials: V
authors.lastname: Vathipadiekal
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Castro
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Boston, Massachusetts, United States of America.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Pépin
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D020033:Protein Isoforms