Mutation of FOXL2 in granulosa-cell tumors of the ovary
BACKGROUND: 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. METHODS: We analyzed f...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
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Massachusetts Medical Society
2009
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| Online Access: | http://hdl.handle.net/20.500.11937/31863 |
| _version_ | 1848753502543675392 |
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| author | Shah, S. Köbel, M. Senz, J. Morin, R. Clarke, B. Wiegand, K. Leung, G. Zayed, A. Mehl, E. Kalloger, S. Sun, M. Giuliany, R. Yorida, E. Jones, S. Varhol, Richard Swenerton, K. Miller, D. Clement, P. Crane, C. Madore, J. Provencher, D. Leung, P. DeFazio, A. Khattra, J. Turashvili, G. Zhao, Y. Zeng, T. Glover, J. Vanderhyden, B. Zhao, C. Parkinson, C. Jimenez-Linan, M. Bowtell, D. Mes-Masson, A. Brenton, J. Aparicio, S. Boyd, N. Hirst, M. Gilks, C. Marra, M. Huntsman, D. |
| author_facet | Shah, S. Köbel, M. Senz, J. Morin, R. Clarke, B. Wiegand, K. Leung, G. Zayed, A. Mehl, E. Kalloger, S. Sun, M. Giuliany, R. Yorida, E. Jones, S. Varhol, Richard Swenerton, K. Miller, D. Clement, P. Crane, C. Madore, J. Provencher, D. Leung, P. DeFazio, A. Khattra, J. Turashvili, G. Zhao, Y. Zeng, T. Glover, J. Vanderhyden, B. Zhao, C. Parkinson, C. Jimenez-Linan, M. Bowtell, D. Mes-Masson, A. Brenton, J. Aparicio, S. Boyd, N. Hirst, M. Gilks, C. Marra, M. Huntsman, D. |
| author_sort | Shah, S. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Copyright © 2009 Massachusetts Medical Society. All rights reserved. |
| first_indexed | 2025-11-14T08:25:32Z |
| format | Journal Article |
| id | curtin-20.500.11937-31863 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:25:32Z |
| publishDate | 2009 |
| publisher | Massachusetts Medical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-318632017-09-13T15:18:39Z Mutation of FOXL2 in granulosa-cell tumors of the ovary Shah, S. Köbel, M. Senz, J. Morin, R. Clarke, B. Wiegand, K. Leung, G. Zayed, A. Mehl, E. Kalloger, S. Sun, M. Giuliany, R. Yorida, E. Jones, S. Varhol, Richard Swenerton, K. Miller, D. Clement, P. Crane, C. Madore, J. Provencher, D. Leung, P. DeFazio, A. Khattra, J. Turashvili, G. Zhao, Y. Zeng, T. Glover, J. Vanderhyden, B. Zhao, C. Parkinson, C. Jimenez-Linan, M. Bowtell, D. Mes-Masson, A. Brenton, J. Aparicio, S. Boyd, N. Hirst, M. Gilks, C. Marra, M. Huntsman, D. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Copyright © 2009 Massachusetts Medical Society. All rights reserved. 2009 Journal Article http://hdl.handle.net/20.500.11937/31863 10.1056/NEJMoa0902542 Massachusetts Medical Society restricted |
| spellingShingle | Shah, S. Köbel, M. Senz, J. Morin, R. Clarke, B. Wiegand, K. Leung, G. Zayed, A. Mehl, E. Kalloger, S. Sun, M. Giuliany, R. Yorida, E. Jones, S. Varhol, Richard Swenerton, K. Miller, D. Clement, P. Crane, C. Madore, J. Provencher, D. Leung, P. DeFazio, A. Khattra, J. Turashvili, G. Zhao, Y. Zeng, T. Glover, J. Vanderhyden, B. Zhao, C. Parkinson, C. Jimenez-Linan, M. Bowtell, D. Mes-Masson, A. Brenton, J. Aparicio, S. Boyd, N. Hirst, M. Gilks, C. Marra, M. Huntsman, D. Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title | Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title_full | Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title_fullStr | Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title_full_unstemmed | Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title_short | Mutation of FOXL2 in granulosa-cell tumors of the ovary |
| title_sort | mutation of foxl2 in granulosa-cell tumors of the ovary |
| url | http://hdl.handle.net/20.500.11937/31863 |