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

VL - 8

SP - 64670

EP - 64684

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 39

ER -