Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary
Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary
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DOI：
10.1056/nejmoa0902542
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发表时间：
2009-06-25
影响因子：
158.5
通讯作者：
Huntsman, David G.
中科院分区：
文献类型：
--
作者：
Shah, Sohrab P.;Koebel, Martin;Huntsman, David G.
研究背景颗粒细胞瘤（granulosa-cell tumors，GCTs）是卵巢恶性性索间质肿瘤（ovarian sex cord-stromal tumor，SCST）中最常见的一种。这些肿瘤的发病机制尚不清楚。此外，他们的组织病理学诊断可能是具有挑战性的，并没有治愈性的治疗超越surgery.MethodsWe分析了四个成人型GCT使用全转录组配对末端RNA测序。我们确定了推定的GCT特异性突变，这些突变存在于至少三个样本中，但不存在于11个上皮性卵巢肿瘤的转录组、已发表的人类基因组和单核苷酸多态性数据库中。我们通过互补DNA和基因组DNA的直接测序证实了这些变体。然后，我们分析了额外的肿瘤和匹配的正常基因组DNA，使用直接测序相结合，限制性片段长度多态性分析，和TaqMan assays.ResultsAll四个指数GCT有一个错义点突变，402 C-> G（C134 W），FOXL 2，一个基因编码的转录因子，已知是至关重要的粒细胞发育。FOXL 2突变存在于89例额外的成人型GCT中的86例（97%），14例卵泡膜细胞瘤中的3例（21%）和10例青少年型GCT中的1例（10%）。突变是不存在的其他类型的49个SCST和329无关的卵巢或乳腺tumors. ConclusionsWhole转录组测序的四个GCTs确定了一个单一的，经常性的体细胞突变（402 C-> G）FOXL 2，是目前在几乎所有的形态学鉴定的成人型GCTs。突变FOXL 2是成人型GCT发病机制中的潜在驱动因素。
BackgroundGranulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery.MethodsWe analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays.ResultsAll four index GCTs had a missense point mutation, 402C -> G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors.ConclusionsWhole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C -> G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.