Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Dylan M Glubb; Sharon E Johnatty; Michael C J Quinn; Tracy A O'Mara; Jonathan P Tyrer; Bo Gao; Peter A Fasching; Matthias W Beckmann; Diether Lambrechts; Ignace Vergote; Digna R Velez Edwards; Alicia Beeghly-Fadiel; Javier Benitez; Maria J Garcia; Marc T Goodman; Pamela J Thompson; Thilo Dörk; Matthias Dürst; Francesmary Modungo; Kirsten Moysich; Florian Heitz; Andreas du Bois; Jacobus Pfisterer; Peter Hillemanns; Beth Y Karlan; Jenny Lester; Ellen L Goode; Julie M Cunningham; Stacey J Winham; Melissa C Larson; Bryan M McCauley; Susanne Krüger Kjær; Allan Jensen; Joellen M Schildkraut; Andrew Berchuck; Daniel W Cramer; Kathryn L Terry; Helga B Salvesen; Line Bjorge; Penny M Webb; Peter Grant; Tanja Pejovic; Melissa Moffitt; Claus K Hogdall; Estrid Hogdall; James Paul; Rosalind Glasspool; Marcus Bernardini; Alicia Tone; David Huntsman; AGO Study Group

doi:10.18632/oncotarget.18501

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Dylan M Glubb, Sharon E Johnatty, Michael C J Quinn, Tracy A O'Mara, Jonathan P Tyrer, Bo Gao, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, Ignace Vergote, Digna R Velez Edwards, Alicia Beeghly-Fadiel, Javier Benitez, Maria J Garcia, Marc T Goodman, Pamela J Thompson, Thilo Dörk, Matthias Dürst, Francesmary Modungo, Kirsten MoysichFlorian Heitz, Andreas du Bois, Jacobus Pfisterer, Peter Hillemanns, Beth Y Karlan, Jenny Lester, Ellen L Goode, Julie M Cunningham, Stacey J Winham, Melissa C Larson, Bryan M McCauley, Susanne Krüger Kjær, Allan Jensen, Joellen M Schildkraut, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Helga B Salvesen, Line Bjorge, Penny M Webb, Peter Grant, Tanja Pejovic, Melissa Moffitt, Claus K Hogdall, Estrid Hogdall, James Paul, Rosalind Glasspool, Marcus Bernardini, Alicia Tone, David Huntsman, AGO Study Group

Institut for Klinisk Medicin

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Abstract

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p < 1×10^-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

Originalsprog	Engelsk
Tidsskrift	OncoTarget
Vol/bind	8
Udgave nummer	39
Sider (fra-til)	64670-64684
Antal sider	15
ISSN	1949-2553
DOI	https://doi.org/10.18632/oncotarget.18501
Status	Udgivet - 12 sep. 2017

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10.18632/oncotarget.18501Licens: CC BY

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome lociForlagets udgivne version, 1,58 MBLicens: CC BY

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Glubb, D. M., Johnatty, S. E., Quinn, M. C. J., O'Mara, T. A., Tyrer, J. P., Gao, B., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Velez Edwards, D. R., Beeghly-Fadiel, A., Benitez, J., Garcia, M. J., Goodman, M. T., Thompson, P. J., Dörk, T., Dürst, M., Modungo, F., ... AGO Study Group (2017). Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci. OncoTarget, 8(39), 64670-64684. https://doi.org/10.18632/oncotarget.18501

Glubb, DM, Johnatty, SE, Quinn, MCJ, O'Mara, TA, Tyrer, JP, Gao, B, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Velez Edwards, DR, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Thompson, PJ, Dörk, T, Dürst, M, Modungo, F, Moysich, K, Heitz, F, du Bois, A, Pfisterer, J, Hillemanns, P, Karlan, BY, Lester, J, Goode, EL, Cunningham, JM, Winham, SJ, Larson, MC, McCauley, BM, Kjær, SK, Jensen, A, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Salvesen, HB, Bjorge, L, Webb, PM, Grant, P, Pejovic, T, Moffitt, M, Hogdall, CK , Hogdall, E, Paul, J, Glasspool, R, Bernardini, M, Tone, A, Huntsman, D & AGO Study Group 2017, 'Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci', OncoTarget, bind 8, nr. 39, s. 64670-64684. https://doi.org/10.18632/oncotarget.18501

@article{4c9f88b8e3ed4ce5980d8a5db7c470ed,

title = "Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci",

abstract = "We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p < 1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.",

author = "Glubb, {Dylan M} and Johnatty, {Sharon E} and Quinn, {Michael C J} and O'Mara, {Tracy A} and Tyrer, {Jonathan P} and Bo Gao and Fasching, {Peter A} and Beckmann, {Matthias W} and Diether Lambrechts and Ignace Vergote and {Velez Edwards}, {Digna R} and Alicia Beeghly-Fadiel and Javier Benitez and Garcia, {Maria J} and Goodman, {Marc T} and Thompson, {Pamela J} and Thilo D{\"o}rk and Matthias D{\"u}rst and Francesmary Modungo and Kirsten Moysich and Florian Heitz and {du Bois}, Andreas and Jacobus Pfisterer and Peter Hillemanns and Karlan, {Beth Y} and Jenny Lester and Goode, {Ellen L} and Cunningham, {Julie M} and Winham, {Stacey J} and Larson, {Melissa C} and McCauley, {Bryan M} and Kj{\ae}r, {Susanne Kr{\"u}ger} and Allan Jensen and Schildkraut, {Joellen M} and Andrew Berchuck and Cramer, {Daniel W} and Terry, {Kathryn L} and Salvesen, {Helga B} and Line Bjorge and Webb, {Penny M} and Peter Grant and Tanja Pejovic and Melissa Moffitt and Hogdall, {Claus K} and Estrid Hogdall and James Paul and Rosalind Glasspool and Marcus Bernardini and Alicia Tone and David Huntsman and {AGO Study Group}",

year = "2017",

month = sep,

day = "12",

doi = "10.18632/oncotarget.18501",

language = "English",

volume = "8",

pages = "64670--64684",

journal = "OncoTarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

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TY - JOUR

T1 - Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

AU - Glubb, Dylan M

AU - Johnatty, Sharon E

AU - Quinn, Michael C J

AU - O'Mara, Tracy A

AU - Tyrer, Jonathan P

AU - Gao, Bo

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Lambrechts, Diether

AU - Vergote, Ignace

AU - Velez Edwards, Digna R

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Garcia, Maria J

AU - Goodman, Marc T

AU - Thompson, Pamela J

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Modungo, Francesmary

AU - Moysich, Kirsten

AU - Heitz, Florian

AU - du Bois, Andreas

AU - Pfisterer, Jacobus

AU - Hillemanns, Peter

AU - Karlan, Beth Y

AU - Lester, Jenny

AU - Goode, Ellen L

AU - Cunningham, Julie M

AU - Winham, Stacey J

AU - Larson, Melissa C

AU - McCauley, Bryan M

AU - Kjær, Susanne Krüger

AU - Jensen, Allan

AU - Schildkraut, Joellen M

AU - Berchuck, Andrew

AU - Cramer, Daniel W

AU - Terry, Kathryn L

AU - Salvesen, Helga B

AU - Bjorge, Line

AU - Webb, Penny M

AU - Grant, Peter

AU - Pejovic, Tanja

AU - Moffitt, Melissa

AU - Hogdall, Claus K

AU - Hogdall, Estrid

AU - Paul, James

AU - Glasspool, Rosalind

AU - Bernardini, Marcus

AU - Tone, Alicia

AU - Huntsman, David

AU - AGO Study Group

PY - 2017/9/12

Y1 - 2017/9/12

N2 - We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p < 1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

AB - We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p < 1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

U2 - 10.18632/oncotarget.18501

DO - 10.18632/oncotarget.18501

M3 - Journal article

C2 - 29029385

SN - 1949-2553

VL - 8

SP - 64670

EP - 64684

JO - OncoTarget

JF - OncoTarget

IS - 39

ER -

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

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