Nakayama Kentaro, Nakayama Naomi, Davidson Ben, Katabuchi Hidetaka, Kurman Robert J, Velculescu Victor E, Shih Ie-Ming, Wang Tian-Li
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Cancer Biol Ther. 2006 Jun;5(6):630-4. doi: 10.4161/cbt.5.6.2675. Epub 2006 Jun 9.
Analysis of deleted chromosomal regions in tumors has historically led to the identification of tumor suppressor genes. In this study, we used digital karyotyping, a genome-wide, high-resolution technology, to search for chromosomal deletions in ovarian serous carcinoma, the most lethal gynecological malignancy in women. Five purified ovarian serous carcinomas were analyzed by digital karyotyping and small interstitial deletions at chromosome 17p were identified in two tumor samples. Aligning these two deletions identified an overlapping region that spanned 2.4 Mb which harbored a candidate tumor suppressor gene, mitogen-activated protein kinase kinase-4 (MKK4). Dual-color FISH analysis confirmed homozygous deletion of the MKK4 locus in both samples and RT-PCR demonstrated that both carcinomas lacked MKK4 transcript expression. Loss of heterozygosity of 17p occurred in 24 (86%) of 28 high-grade serous carcinomas including both cases with homozygous MKK4 deletion. Additionally, downregulation of MKK4 expression was found in 96 (75%) of 128 ovarian serous carcinomas as compared to benign ovarian tissues. These findings suggest that homozygous deletion or reduced expression of MKK4 may contribute to the development of ovarian serous carcinoma.
对肿瘤中缺失的染色体区域进行分析，历史上曾促使人们鉴定出肿瘤抑制基因。在本研究中，我们使用了数字核型分析这一全基因组、高分辨率技术，来寻找卵巢浆液性癌（女性中最致命的妇科恶性肿瘤）中的染色体缺失。通过数字核型分析对5例纯化的卵巢浆液性癌进行了分析，并在2个肿瘤样本中鉴定出17号染色体短臂上的小间隙缺失。比对这两个缺失区域，确定了一个跨度为2.4 Mb的重叠区域，该区域含有一个候选肿瘤抑制基因——丝裂原活化蛋白激酶激酶4（MKK4）。双色荧光原位杂交分析证实了两个样本中MKK4基因座的纯合缺失，逆转录聚合酶链反应表明这两种癌均缺乏MKK4转录本表达。在28例高级别浆液性癌中有24例（86%）发生了17号染色体短臂杂合性缺失，包括两例MKK4纯合缺失的病例。此外，与良性卵巢组织相比，在128例卵巢浆液性癌中有96例（75%）发现MKK4表达下调。这些发现表明，MKK4的纯合缺失或表达降低可能促成了卵巢浆液性癌的发生。
