EGAGenomicsAffymetrix 6.0, Illumina Genome Analyzer IIWhole Genome Sequencinghttps://ega-archive.org/studies/EGAS00000000040EGAEGA study EGAS00000000040Title not providedrestrictedEGA<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 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.<h4>Results</h4>All 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.<h4>Conclusions</h4>Whole-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.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 DGGranulosa Cell, gonad of female reproductive system, Malignant Neoplasm, PFRK, gonada of reproductive system of female organism, gonad of female organism reproductive system, Neoplasms, gonada of female reproductive system, Benign Neoplasm, Tumor, genitalia of female organism gonada., Malignant, Cell, gonada of female organism genitalia, Mutations, gonad of genitalia of female organism, Benign, Ovaries, granulosa cell of ovary, Neoplasm, PINTO, female reproductive system gonad, ovaries, female organism reproductive system gonada, gonada of female organism reproductive system, animal ovary, POF3, Malignancy, gonada of genitalia of female organism, genitalia of female organism gonad, ovum-producing ovary, female gonad, ovarium, gonad of reproductive system of female organism, female organism reproductive system gonad, Benign Neoplasms, gonad of female organism genitalia, Cancers, Granulosa, Malignant Neoplasms, Neoplasias, BPES, AU045128, reproductive system of female organism gonada, female organism genitalia gonada, reproductive system of female organism gonad, Pfrk, ovarian granulosa cell, Cells, BPES1, ovary - animal, ovary, Malignancies, female organism genitalia gonad, Neoplasia, female reproductive system gonada, Cancer, TumorsMGC130048, T-cell leukemia, malignant tumor of the breast, Antemortem Diagnosis, RNA Sequence Determination, Breast Neoplasms, Sequence Determination, adult stage, ovary tumor, RNA Sequence, AGL4, positive regulation by symbiont of host non-apoptotic programmed cell death, QC, vif, A4, Gene Expression Profile, mammary neoplasm, Human Mammary Neoplasms, Profiles, A Genes, Tumor, Diagnosis, granular cell tumour NOS (morphologic abnormality), Probes, Mutations, dmTAF[[II]]230, Techniques, ovarian Sex cord-stromal tumour, cDNA library construction, tumor of the breast, "neoplasm of breast (disorder)" EXACT [SNOMEDCT_2005_07_31:126926005], Method, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, symptoms, pathogenesis, cancer of the breast, Analysis, preoperative procedures, PINTO, adult, treatment, average, A, BC, gamma sarcoglycan, Mammary Neoplasms, malignant neoplasm of breast, OVARY NEOPL, Man (Taxonomy), TFIID TAF250, stimulation by symbiont of host programmed cell death, Analyses, Genomes, cel, Determination, sor Genes, complementary DNA, Q, Human Mammary Carcinomas, F10N7_150, procedures, Sequence Determinations, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, Signatures, paired, sex cord stromal tumor, NEOPL OVARIAN, neoplasm of breast, AU045128, Methodological Studies, breast neoplasm, Expression Signature, cancer of breast, Sex cord-stromal tumour of the ovary, disease management, Therapies, Transcriptomes, AGAMOUS-like 4, gamma-sarcoglycan, cDNA Probes, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, Nucleotide, mammary cancer, Breast 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tubules, Postmortem Diagnosis, General, sex cord-stromal tumour of ovary, Adults, Expression Profile, END, neoplasm of granular cell, Malignant Neoplasm of Breast, granular cell tumor NOS (morphologic abnormality), nucleotides, tumor of breast, Transcriptome Profiles, Ovary Neoplasm, child, ovarian tumour, Carcinomas, Diagnoses and Examination, F14P3.4, Postmortem Diagnoses, vif Genes, Q Genes, Factors, tumour of the breast, POF3, NEOPL BREAST, F14P3_4, signs, common, Ovary Neoplasms, Methodological, breast neoplasm (disease), "mammary neoplasm" RELATED [], CG17603, gamma (35kDa dystrophin-associated glycoprotein), TAF[[II]], Methodological Study, Treatments, Transcription factor, human, ovary neoplasm, DMDA, tumour of breast, Taf250, breast cancer, Pfrk, SR3-5, 35kD dystrophin-associated glycoprotein, activation by symbiont of host programmed cell death, Breast Tumors, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription 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reproductive system gonad, neoplasm of granular cell, granular cell tumor NOS (morphologic abnormality), Genetic Material, Taf[[II]]250, Dmel_CG6393, ovaries, female organism reproductive system gonada, sQC, animal ovary, Col4a-1, TAF[[II]]230, POF3, gonada of genitalia of female organism, female gonad, ovarium, gonad of reproductive system of female organism, gonad of female organism genitalia, INSDC_feature:gene, TAF[II]250, CG17603, disease of cellular proliferation, TAF[[II]], primary structure of sequence macromolecule, DmelCG17603, female organism genitalia gonada, TAF1., Taf250, Pfrk, Material, SR3-5, Indexes, Bal, ovarian granulosa cell, BAL, Cells, cardinality, BPES1, Cistron, ORW1, other neoplasm, GCT, NEOPLASMS BENIGN, Neoplasia, TAF230falseMutation of FOXL2 in granulosa cell tumors of the ovaryWe 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. 2018-05-02 13:50:49EGAS00000000040960619516027EGAD00000000046EGAD00000000047EGAC00000000011