The pathognomonic FOXL2 C134W mutation alters DNA-binding specificity

Annaïck Carles; Genny Trigo-Gonzalez; Qi Cao; S. W. Grace Cheng; Michelle Moksa; Misha Bilenky; David G. Huntsman; Gregg B. Morin; Martin Hirst

doi:10.1158/0008-5472.CAN-20-0104

The pathognomonic FOXL2 C134W mutation alters DNA-binding specificity

Annaïck Carles, Genny Trigo-Gonzalez, Qi Cao, S. W. Grace Cheng, Michelle Moksa, Misha Bilenky, David G. Huntsman, Gregg B. Morin, Martin Hirst

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21 Citations (Scopus)

Résumé

The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2^WT- and V5-FOXL2^C134W-inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2^C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2^C134W and identification of unique targets of FOXL2^C134W including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2^C134W drives AGCT by alteringthebindingaffinityofFOXL2-containingcomplexestoengage an oncogenic transcriptional program.

Langue d'origine	English
Pages (de-à)	3480-3491
Nombre de pages	12
Journal	Cancer Research
Volume	80
Numéro de publication	17
DOI	https://doi.org/10.1158/0008-5472.CAN-20-0104
Statut de publication	Published - sept. 1 2020
Publié à l'externe	Oui

Note bibliographique

Funding Information:
This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www. computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support.

Funding Information:
This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www.computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support.

Publisher Copyright:
© 2020 American Association for Cancer Research.

ASJC Scopus Subject Areas

Oncology
Cancer Research

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title = "The pathognomonic FOXL2 C134W mutation alters DNA-binding specificity",

abstract = "The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W-inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W and identification of unique targets of FOXL2C134W including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2C134W drives AGCT by alteringthebindingaffinityofFOXL2-containingcomplexestoengage an oncogenic transcriptional program.",

author = "Anna{\"i}ck Carles and Genny Trigo-Gonzalez and Qi Cao and {Grace Cheng}, {S. W.} and Michelle Moksa and Misha Bilenky and Huntsman, {David G.} and Morin, {Gregg B.} and Martin Hirst",

note = "Funding Information: This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www. computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support. Funding Information: This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www.computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

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doi = "10.1158/0008-5472.CAN-20-0104",

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AU - Carles, Annaïck

AU - Trigo-Gonzalez, Genny

AU - Cao, Qi

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AU - Moksa, Michelle

AU - Bilenky, Misha

AU - Huntsman, David G.

AU - Morin, Gregg B.

AU - Hirst, Martin

N1 - Funding Information: This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www. computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support. Funding Information: This work was supported by Terry Fox Research Institute Program Project grants (#1021 and #1028 to G.B. Morin, D.G. Huntsman, and M. Hirst). This research was enabled, in part by support provided by WestGrid and Compute Canada (www.computecanada.ca) and Canada Foundation of Innovation (#31343 and #31098). The authors also wish to acknowledge Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada for computational resources and support. A full list of funders of infrastructure and research supporting the services accessed is available at www.bcgsc.ca/about/funding_support. Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W-inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W and identification of unique targets of FOXL2C134W including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2C134W drives AGCT by alteringthebindingaffinityofFOXL2-containingcomplexestoengage an oncogenic transcriptional program.

AB - The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W-inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W and identification of unique targets of FOXL2C134W including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2C134W drives AGCT by alteringthebindingaffinityofFOXL2-containingcomplexestoengage an oncogenic transcriptional program.

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The pathognomonic FOXL2 C134W mutation alters DNA-binding specificity

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