title: WWOX tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis.
abstract: WWOX is a bona fide tumour suppressor, with hypomorphic and knockout mouse models exhibiting increased tumour susceptibility. In ovarian cancer cells WWOX transfection abolishes tumourigenicity, suppresses tumour cell adhesion to extracellular matrix and induces apoptosis in non-adherent cells. One-third of ovarian tumours show loss of WWOX expression, and this loss significantly associates with clear cell and mucinous histology, advanced stage, low progesterone receptor expression and poor survival, suggesting that WWOX status affects ovarian cancer progression and prognosis. Genetic variation in other tumour suppressors (e.g. p53 and XPD) is reported to modify cancer progression/outcome, and single nucleotide polymorphisms (SNPs) within the WWOX gene are reported to associate with prostate cancer risk. We previously identified polymorphic variants within WWOX, some of which have potential to affect its expression. We therefore examined a cancer modifier role for these WWOX variants. Eight SNPs, based upon location, frequency and potential to affect WWOX expression, were genotyped in 554 ovarian cancer patients (CGP samples), and associations with pathological and survival data were examined. The CGP samples demonstrated significant associations after Bonferroni correction between Isnp1 and both tumour grade (p(corr)=0.033) and histology (p(corr)=0.046), Isnp8 and tumour grade (p(corr)=0.032) and T1497G and progression-free survival (p(corr)=0.037). None of these positive associations were confirmed in an independent ovarian cancer population (Scotroc1 samples, n=863). While these results may suggest that the associations are false positives, differences between the two populations cannot be excluded, and thus highlight the challenges in validation studies.
authors.affiliation: Ovarian cancer action (HHMT) Research Centre and Section of Molecular Therapeutics, Department of Oncology, Imperial College London Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. a.paige@imperial.ac.uk
authors.forename: Adam J W
authors.initials: AJ
authors.lastname: Paige
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Szymon
authors.initials: S
authors.lastname: Janczar
authors.forename: Jim
authors.initials: J
authors.lastname: Paul
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Taylor
authors.forename: Moira
authors.initials: M
authors.lastname: Stewart
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richardson
authors.forename: Timothy
authors.initials: T
authors.lastname: Perren
authors.forename: Trivadi S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: John F
authors.initials: JF
authors.lastname: Smyth
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human