Kuo Kuan-Ting, Mao Tsui-Lien, Jones Siân, Veras Emanuela, Ayhan Ayse, Wang Tian-Li, Glas Ruth, Slamon Dennis, Velculescu Victor E, Kuman Robert J, Shih Ie-Ming
Departments of Pathology, Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Am J Pathol. 2009 May;174(5):1597-601. doi: 10.2353/ajpath.2009.081000. Epub 2009 Apr 6.
Ovarian clear cell carcinoma (CCC) is one of the most malignant types of ovarian carcinomas, particularly at advanced stages. Unlike the more common type of ovarian cancer, high-grade serous carcinoma, ovarian CCC is often resistant to platinum-based chemotherapy, and therefore an effective treatment for this tumor type at advanced stages is urgently needed. In this study, we analyzed 97 ovarian CCCs for sequence mutations in KRAS, BRAF, PIK3CA, TP53, PTEN, and CTNNB1 as these mutations frequently occur in other major types of ovarian carcinomas. The samples included 18 CCCs for which affinity-purified tumor cells from fresh specimens were available, 69 microdissected tumors from paraffin tissues, and 10 tumor cell lines. Sequence mutations of PIK3CA, TP53, KRAS, PTEN, CTNNB1, and BRAF occurred in 33%, 15%, 7%, 5%, 3%, and 1% of CCC cases, respectively. Sequence analysis of PIK3CA in 28 affinity-purified CCCs and CCC cell lines showed a mutation frequency of 46%. Samples with PIK3CA mutations showed intense phosphorylated AKT immunoreactivity. These findings demonstrate that ovarian CCCs have a high frequency of activating PIK3CA mutations. We therefore suggest that the use of PIK3CA-targeting drugs may offer a more effective therapeutic approach compared with current chemotherapeutic agents for patients with advanced-stage and recurrent CCC.
卵巢透明细胞癌（CCC）是卵巢癌中恶性程度最高的类型之一，尤其是在晚期。与更常见的卵巢癌类型——高级别浆液性癌不同，卵巢CCC通常对铂类化疗耐药，因此迫切需要一种针对这种晚期肿瘤类型的有效治疗方法。在本研究中，我们分析了97例卵巢CCC中KRAS、BRAF、PIK3CA、TP53、PTEN和CTNNB1的序列突变情况，因为这些突变在其他主要类型的卵巢癌中经常出现。样本包括18例可从新鲜标本中获得亲和纯化肿瘤细胞的CCC、69例从石蜡组织中显微切割得到的肿瘤以及10株肿瘤细胞系。PIK3CA、TP53、KRAS、PTEN、CTNNB1和BRAF的序列突变分别发生在33%、15%、7%、5%、3%和1%的CCC病例中。对28例亲和纯化的CCC和CCC细胞系进行PIK3CA序列分析，显示突变频率为46%。具有PIK3CA突变的样本显示出强烈的磷酸化AKT免疫反应性。这些发现表明卵巢CCC中PIK3CA激活突变的频率很高。因此，我们建议与目前用于晚期和复发性CCC患者的化疗药物相比，使用靶向PIK3CA的药物可能提供一种更有效的治疗方法。
