title: Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma.
abstract: Human kallikrein 11 (hK11/trypsin-like serine protease/TLSP, encoded by the KLK11 gene) is a member of the kallikrein family of secreted serine proteases. Recently, we developed a highly sensitive and specific immunoassay for hK11 and found that this protease is expressed in the prostate, stomach and trachea as well as in amniotic fluid and milk of lactating women. Elevated serum hK11 levels were found in 60% of men with prostate cancer and 70% of women with ovarian cancer. Also, hK11 expression was found to be under the regulation of steroid hormones, particularly estrogens, at the level of KLK11 transcription. We hypothesized that hK11 may be implicated in endocrine-related malignancies and serve as a novel prostate and ovarian cancer serological marker. The aim of our study was to examine if hK11 expression in ovarian tumors bears any prognostic significance. The concentration of hK11 (ng per mg of total protein) in 104 ovarian tumor cytosolic extracts was quantified and correlated with clinicopathologic variables and outcome over a median follow-up period of 67 months. Outcome was defined as progression-free survival (PFS) and overall survival (OS). hK11 concentration in ovarian tumor cytosols ranged from 0-21 ng/mg of total protein, with a median of 0.54 ng/mg. An optimal cutoff value of 0.54 ng/mg was selected to categorize tumors as hK11-positive or -negative. hK11-positive tumors were more frequently associated with early stage (Stage I/II) disease, pre-/peri-menopausal status and patients who exhibited complete or partial response to chemotherapy (p < 0.05). Univariate analysis revealed that patients with hK11-positive tumors had a significantly decreased risk of relapse with a hazard ratio (HR) of 0.45 (p = 0.007) and death (HR of 0.34, p = 0.005). Cox multivariate analysis indicated that hK11 was an independent prognostic indicator of OS (HR of 0.41, p = 0.025). Kaplan-Meier survival curves further confirmed that women with hK11-positive tumors have longer PFS and OS (p = 0.005 and p = 0.003, respectively). Similarly, in the subgroup of patients with grade 1-2 tumors, hK11-positivity was associated with higher OS in both univariate and multivariate analysis (HR of 0.23 and 0.17, p < 0.05). Finally, in women with optimal debulking after surgery (<1 cm residual tumor), hK11 positivity was associated with a slower disease progression. These results indicate that hK11 is a novel, independent marker of favorable prognosis in patients with ovarian cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Borgoño
authors.affiliation: Department of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fracchioli
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: George M
authors.initials: GM
authors.lastname: Yousef
authors.affiliation: Department of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy.
authors.forename: Irene A
authors.initials: IA
authors.lastname: Rigault de la Longrais
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Liu-Ying
authors.initials: LY
authors.lastname: Luo
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Antoninus
authors.initials: A
authors.lastname: Soosaipillai
authors.affiliation: Department of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Puopolo
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Grass
authors.affiliation: National Center of Scientific Research "Demokritos", IPC, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Scorilas
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
authors.affiliation: Department of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D012697:Serine Endopeptidases / Q000378:metabolism*; D015996:Survival Rate; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases