文章：

卵巢癌生物学：翻译的新机会

The biology of ovarian cancer: new opportunities for translation

原文发布日期：2009-06-01

DOI: 10.1038/nrc2644

类型: Review Article

开放获取: 否

要点：

1. Several factors make ovarian cancer a difficult disease to treat effectively. Although many patients experience symptoms, these often overlap with other ailments, and many patients are diagnosed after the cancer has metastasized. Ovarian cancer is also heterogeneous — multiple genetic and epigenetic changes are evident in patients with ovarian cancer; however, how such changes are selected for during tumorigenesis is not yet clear.
2. Mutation and loss of TP53 function is one of the most frequent genetic abnormalities in ovarian cancer and is observed in 60–80% of both sporadic and familial cases. Of the 16 candidate tumour suppressor genes identified to date in ovarian cancer, 3 are imprinted genes. Several growth inhibitory genes are also silenced by methylation or imprinting.
3. Inheritance of DNA repair defects contributes to as many as 10–15% of ovarian cancers. The lifetime risk of developing ovarian cancer in mutation carriers varies with the genetic defect (for BRCA1 30–60%, for BRCA2 15–30% and for hereditary non-polyposis colon cancer 7%).
4. At least 15 oncogenes have been implicated in ovarian cancers, and DNA copy number abnormalities have also been found in loci that are known to contain non-coding microRNAs. At least seven signalling pathways are activated in >50% of ovarian cancers, and mutations that affect cell proliferation, apoptosis and autophagy are also evident.
5. Ovarian cancer can be split into two groups on the basis of genetic changes: low-grade tumours with mutations in KRAS, BRAF and PIK3CA, loss of heterozygosity (LOH) on chromosome Xq, microsatellite instability and expression of amphiregulin; and high-grade tumours with aberrations in TP53 and potential aberrations in BRCA1 and BRCA2, as well as LOH on chromosomes 7q and 9p.
6. Changes in cell adhesion and motility also contribute to disease development and metastasis. Adhesion of ovarian cancer cells to the mesothelial cells and to the underlying stroma is mediated by CD44, CA125 and b1 intergrin on the surface of ovarian cancer cells that bind to mesothelin and hyaluronic acid on mesothelial cells, or to fibronectin, laminin and type IV collagen in the underlying matrix.
7. A crucial goal is to identify patients who would benefit from particular targeted therapies. Given the complexity of crosstalk between protein signalling pathways, predicting the impact and efficacy of any one signalling inhibitor is difficult. Inhibition of multiple pathways will almost certainly be required to substantially affect ovarian cancer growth.
8. Effective methods for early detection are needed. Given the prevalence of ovarian cancer, strategies for early detection must have a high sensitivity for early-stage disease (>75%), but an extremely high specificity (99.6%) to attain a positive predictive value of at least 10% (ten operations for each case of ovarian cancer). Using rising values of serum biomarkers such as CA125 to trigger transvaginal sonography is a promising approach.

要点翻译：

1. 多种因素导致卵巢癌成为一种难以有效治疗的疾病。虽然许多患者会出现症状，但这些症状常与其他疾病重叠，且多数患者在癌症转移后才被确诊。卵巢癌还具有异质性——患者体内存在多种明显的遗传和表观遗传改变，然而这些变化在肿瘤发生过程中如何被选择尚不明确。
2. TP53基因突变和功能丧失是卵巢癌中最常见的遗传异常之一，在60%-80%的散发性和家族性病例中均有发现。迄今在卵巢癌中鉴定出的16个候选抑癌基因中，有3个是印记基因。若干生长抑制基因也通过甲基化或印记作用被沉默。
3. DNA修复缺陷的遗传贡献了高达10%-15%的卵巢癌病例。突变携带者罹患卵巢癌的终生风险因基因缺陷类型而异（BRCA1为30%-60%，BRCA2为15%-30%，遗传性非息肉病性结肠癌为7%）。
4. 目前至少有15个癌基因与卵巢癌相关，已知含有非编码microRNA的基因座中也发现了DNA拷贝数异常。至少七条信号通路在超过50%的卵巢癌中被激活，影响细胞增殖、凋亡和自噬的突变也显而易见。
5. 根据遗传学改变可将卵巢癌分为两类：一类为低级别肿瘤，具有KRAS、BRAF和PIK3CA突变，Xq染色体杂合性缺失，微卫星不稳定性及双调蛋白表达；另一类为高级别肿瘤，存在TP53异常及BRCA1/BRCA2潜在异常，并伴有7q和9p染色体杂合性缺失。
6. 细胞黏附和运动性的改变也促进疾病发展和转移。卵巢癌细胞与间皮细胞及下方基质的黏附由癌细胞表面的CD44、CA125和b1整合素介导，这些分子分别与间皮细胞上的间皮素和透明质酸，或基质中的纤连蛋白、层粘连蛋白及IV型胶原结合。
7. 关键目标是识别能从特定靶向治疗中获益的患者群体。鉴于蛋白质信号通路间交互作用的复杂性，预测任一信号抑制剂的效应和疗效十分困难。要显著抑制卵巢癌生长，几乎必然需要多通路联合抑制。
8. 需要建立有效的早期检测方法。考虑到卵巢癌的患病率，早期检测策略必须对早期病变具有高灵敏度（>75%），同时需具备极高特异性（99.6%）才能达到至少10%的阳性预测值（每检出1例卵巢癌需进行十台手术）。利用CA125等血清生物标志物数值升高来触发经阴道超声检查是一种前景广阔的方法。

英文摘要：

Over the past two decades, the 5-year survival for ovarian cancer patients has substantially improved owing to more effective surgery and treatment with empirically optimized combinations of cytotoxic drugs, but the overall cure rate remains approximately 30%. Many investigators think that further empirical trials using combinations of conventional agents are likely to produce only modest incremental improvements in outcome. Given the heterogeneity of this disease, increases in long-term survival might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.

摘要翻译： 

在过去二十年中，由于更有效的手术以及细胞毒药物经验性优化联合治疗，卵巢癌患者的5年生存率已显著提高，但总体治愈率仍约为30%。许多研究者认为，进一步使用传统药物联合的经验性试验可能仅会在结局上带来适度的渐进改善。鉴于该疾病的异质性，通过将分子和细胞层面的最新研究转化为个体化治疗策略及优化早期检测，有望提高长期生存率。

原文链接：

The biology of ovarian cancer: new opportunities for translation