Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas.
Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas.
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DOI：
10.1158/0008-5472.can-08-3913
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Wang TL
中科院分区：
文献类型：
--
作者：
Kuo KT;Guan B;Feng Y;Mao TL;Chen X;Jinawath N;Wang Y;Kurman RJ;Shih IeM;Wang TL
卵巢浆液性癌是最常见和最致命的卵巢癌类型，被认为是由两种不同的分子途径发展而来。高级别（HG）浆液性癌含有频繁的TP53突变，而低级别（LG）癌来自浆液性交界性肿瘤（SBT），并在KRAS/BRAF/ERBB2通路中含有突变。然而，从SBT到LG癌的进展中涉及的分子改变在很大程度上仍然未知。同样，卵巢浆液性癌中肿瘤抑制基因的缺失程度也没有得到很好的研究。为了进一步解决这两个问题，我们使用高密度250K SNP阵列评估了来自37个卵巢浆液性肿瘤（包括SBT、LG和HG肿瘤）的亲和纯化的肿瘤细胞中的DNA拷贝数变化。以DNA拷贝数变化衡量的染色体不稳定指数在HG中显著高于LG浆液性癌。半合子ch1p36缺失在LG浆液性癌中常见，但在SBT中很少见到。该区域含有几个候选肿瘤抑制因子，包括miR-34a。相反，在HG浆液性癌中，鉴定了显著数量的扩增和缺失，包括纯合缺失。在47例HG浆液性癌中，Rb 1、CDKN 2 A/B、CSMD 1和DOCK 4基因座的纯合性缺失最常见，分别占10.6%、6.4%、6.4%和4.3%。除了CDKN 2A/B区，这些纯合性缺失在SBT或LG肿瘤中均不存在。我们的研究提供了HG浆液性癌全基因组纯合性缺失谱，为研究卵巢癌肿瘤抑制因子奠定了分子基础。
Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, was thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations while low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain largely unknown. As well, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well-studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG and HG tumors using high density 250K SNP arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions including homozygous deletions were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4% and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profiles in HG serous carcinomas, serving as a molecular foundation to study tumor suppressors in ovarian cancer.