HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Helen Ross-Adams; Stephen Ball; Kate Lawrenson; Silvia Halim; Roslin Russell; Claire Wells; Siri H. Strand; Torben F. Ørntoft; Melissa Larson; Sebastian Armasu; Charles E. Massie; Mohammad Asim; Martin M. Mortensen; Michael Borre; Kathryn Woodfine; Anne Y. Warren; Alastair D. Lamb; Jonathan Kay; Hayley Whitaker; Antonio Ramos-Montoya; Adele Murrell; Karina D. Sørensen; Brooke L. Fridley; Ellen L. Goode; Simon A. Gayther; John Masters; David E. Neal; Ian G. Mills

doi:10.18632/oncotarget.12543

HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Helen Ross-Adams, Stephen Ball, Kate Lawrenson, Silvia Halim, Roslin Russell, Claire Wells, Siri H. Strand, Torben F. Ørntoft, Melissa Larson, Sebastian Armasu, Charles E. Massie, Mohammad Asim, Martin M. Mortensen, Michael Borre, Kathryn Woodfine, Anne Y. Warren, Alastair D. Lamb, Jonathan Kay, Hayley Whitaker, Antonio Ramos-MontoyaAdele Murrell, Karina D. Sørensen, Brooke L. Fridley, Ellen L. Goode, Simon A. Gayther, John Masters, David E. Neal, Ian G. Mills

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.

Original language	English
Pages (from-to)	74734-74746
Number of pages	13
Journal	Oncotarget
Volume	7
Issue number	46
DOIs	https://doi.org/10.18632/oncotarget.12543
State	Published - 2016
Externally published	Yes

Keywords

Cancer
EQTL
HNF1B
Ovarian
Prostate

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Ross-Adams, H., Ball, S., Lawrenson, K., Halim, S., Russell, R., Wells, C., Strand, S. H., Ørntoft, T. F., Larson, M., Armasu, S., Massie, C. E., Asim, M., Mortensen, M. M., Borre, M., Woodfine, K., Warren, A. Y., Lamb, A. D., Kay, J., Whitaker, H., ... Mills, I. G. (2016). HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget, 7(46), 74734-74746. https://doi.org/10.18632/oncotarget.12543

@article{93304f7f115a42519384dca1ec44b7d3,

title = "HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer",

abstract = "Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.",

keywords = "Cancer, EQTL, HNF1B, Ovarian, Prostate",

author = "Helen Ross-Adams and Stephen Ball and Kate Lawrenson and Silvia Halim and Roslin Russell and Claire Wells and Strand, \{Siri H.\} and {\O}rntoft, \{Torben F.\} and Melissa Larson and Sebastian Armasu and Massie, \{Charles E.\} and Mohammad Asim and Mortensen, \{Martin M.\} and Michael Borre and Kathryn Woodfine and Warren, \{Anne Y.\} and Lamb, \{Alastair D.\} and Jonathan Kay and Hayley Whitaker and Antonio Ramos-Montoya and Adele Murrell and S{\o}rensen, \{Karina D.\} and Fridley, \{Brooke L.\} and Goode, \{Ellen L.\} and Gayther, \{Simon A.\} and John Masters and Neal, \{David E.\} and Mills, \{Ian G.\}",

year = "2016",

doi = "10.18632/oncotarget.12543",

language = "Ingl{\'e}s",

volume = "7",

pages = "74734--74746",

journal = "Oncotarget",

issn = "1949-2553",

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Ross-Adams, H, Ball, S, Lawrenson, K, Halim, S, Russell, R, Wells, C, Strand, SH, Ørntoft, TF, Larson, M, Armasu, S, Massie, CE, Asim, M, Mortensen, MM, Borre, M, Woodfine, K, Warren, AY, Lamb, AD, Kay, J, Whitaker, H, Ramos-Montoya, A, Murrell, A, Sørensen, KD, Fridley, BL, Goode, EL, Gayther, SA, Masters, J, Neal, DE & Mills, IG 2016, 'HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer', Oncotarget, vol. 7, no. 46, pp. 74734-74746. https://doi.org/10.18632/oncotarget.12543

TY - JOUR

T1 - HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

AU - Ross-Adams, Helen

AU - Ball, Stephen

AU - Lawrenson, Kate

AU - Halim, Silvia

AU - Russell, Roslin

AU - Wells, Claire

AU - Strand, Siri H.

AU - Ørntoft, Torben F.

AU - Larson, Melissa

AU - Armasu, Sebastian

AU - Massie, Charles E.

AU - Asim, Mohammad

AU - Mortensen, Martin M.

AU - Borre, Michael

AU - Woodfine, Kathryn

AU - Warren, Anne Y.

AU - Lamb, Alastair D.

AU - Kay, Jonathan

AU - Whitaker, Hayley

AU - Ramos-Montoya, Antonio

AU - Murrell, Adele

AU - Sørensen, Karina D.

AU - Fridley, Brooke L.

AU - Goode, Ellen L.

AU - Gayther, Simon A.

AU - Masters, John

AU - Neal, David E.

AU - Mills, Ian G.

PY - 2016

Y1 - 2016

N2 - Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.

AB - Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.

KW - Cancer

KW - EQTL

KW - HNF1B

KW - Ovarian

KW - Prostate

UR - https://www.scopus.com/pages/publications/84996798850

U2 - 10.18632/oncotarget.12543

DO - 10.18632/oncotarget.12543

M3 - Artículo

C2 - 27732966

AN - SCOPUS:84996798850

SN - 1949-2553

VL - 7

SP - 74734

EP - 74746

JO - Oncotarget

JF - Oncotarget

IS - 46

ER -

HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Abstract

Keywords

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