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.
Eur J Cancer. 2010 Mar;46(4):818-25. doi: 10.1016/j.ejca.2009.12.021. Epub 2010 Jan 13.
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.
WWOX 是一个真正的肿瘤抑制因子，其功能减退和敲除小鼠模型表现出更高的肿瘤易感性。在卵巢癌细胞中，WWOX 的转染可消除致瘤性，抑制肿瘤细胞与细胞外基质的黏附，并诱导非黏附细胞凋亡。三分之一的卵巢肿瘤显示 WWOX 表达缺失，这种缺失与透明细胞和黏液性组织学、晚期、孕激素受体表达水平低以及预后不良显著相关，表明 WWOX 状态影响卵巢癌的进展和预后。据报道，其他肿瘤抑制基因（如 p53 和 XPD）的遗传变异可改变癌症的进展/结果，而 WWOX 基因内的单核苷酸多态性（SNP）与前列腺癌风险相关。我们之前在 WWOX 内发现了多态性变异，其中一些可能影响其表达。因此，我们研究了这些 WWOX 变异体的癌症修饰作用。根据位置、频率和影响 WWOX 表达的潜力，对 554 例卵巢癌患者（CGP 样本）中的 8 个 SNP 进行了基因分型，并对其与病理和生存数据的相关性进行了分析。CGP 样本经 Bonferroni 校正后，Isnp1 与肿瘤分级（p(corr)=0.033）和组织学（p(corr)=0.046）、Isnp8 与肿瘤分级（p(corr)=0.032）和 T1497G 与无进展生存（p(corr)=0.037）之间存在显著相关性。这些阳性关联在另一个独立的卵巢癌人群（Scotroc1 样本，n=863）中均未得到证实。虽然这些结果可能表明这些关联是假阳性，但不能排除两个群体之间的差异，因此凸显了验证研究的挑战。
