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Mutation of FOXL2 in granulosa cell tumors of the ovary

ABSTRACT: We generated paired-end RNA-Seq data using the Illumina Genome Analyzer II platform for four adult granulosa cell tumours (GCTs) of the ovary (1 primary, 3 recurrent). We screened this data for the presence of GCT specific sequence variants and detected a non-synonymous mutation in the FOXL2 gene that was found to be recurrent in 97% of 89 additional GCTs. To measure genomic stability of the four index cases, we generated Affmetrix SNP 6.0 data and analysed these data for copy number changes. Raw sequence reads as well as Affymetrix CEL files are available to applicants.

PROVIDER: EGAS00000000040 | EGA |

REPOSITORIES: EGA

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Mutation of FOXL2 in granulosa-cell tumors of the ovary.

Shah Sohrab P SP Köbel Martin M Senz Janine J Morin Ryan D RD Clarke Blaise A BA Wiegand Kimberly C KC Leung Gillian G Zayed Abdalnasser A Mehl Erika E Kalloger Steve E SE Sun Mark M Giuliany Ryan R Yorida Erika E Jones Steven S Varhol Richard R Swenerton Kenneth D KD Miller Dianne D Clement Philip B PB Crane Colleen C Madore Jason J Provencher Diane D Leung Peter P DeFazio Anna A Khattra Jaswinder J Turashvili Gulisa G Zhao Yongjun Y Zeng Thomas T Glover J N Mark JN Vanderhyden Barbara B Zhao Chengquan C Parkinson Christine A CA Jimenez-Linan Mercedes M Bowtell David D L DD Mes-Masson Anne-Marie AM Brenton James D JD Aparicio Samuel A SA Boyd Niki N Hirst Martin M Gilks C Blake CB Marra Marco M Huntsman David G DG

The New England journal of medicine 20090610 26

<h4>Background</h4>Granulosa-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.<h4>Methods</h4>We 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 ...[more]

PMID: 19516027

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Project description:Stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Loss of the tumor suppressor gene Pten accelerates GCT formation in the CTNNB1 strain. Conversely, expression of oncogenic KRASG12D causes the dramatic arrest of proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice developed early-onset GCTs leading to premature death in a manner similar to theCtnnb1;Pten mutant mice. Moreover, the GCTs in the Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation. Microarray and RT-PCR analyses revealed that ovaries from mice expressing dominant-stable CTNNB1 with either Pten loss or KRAS activation were unpredictably similar. Specifically, gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. Furthermore, the concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis. RT-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovary and testis. Together, these results suggest that KRAS activation and Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. four samples: average of two wild type samples (previously submitted as GSM403220 and GSM403221), beta-Catenin constitutively active mutant, beta-Catenin;Pten double mutant, and beta-Catenin;Kras(G12D) double mutant

Dataset Information

Mutation of FOXL2 in granulosa cell tumors of the ovary

Publications

Mutation of FOXL2 in granulosa-cell tumors of the ovary.

Similar Datasets

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