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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

Brett M. Reid, Jennifer B. Permuth, Y. Ann Chen, Jamie K. Teer, Alvaro N.A. Monteiro, Zhihua Chen, Jonathan Tyrer, Andrew Berchuck; on behalf of the Ovarian Cancer Association Consortium, Georgia Chenevix-Trench; on behalf of the Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, Jennifer A. Doherty, Ellen L. Goode, Edwin S. Iverson, Kate Lawrenson, Celeste L. Pearce, Paul D. Pharoah, Catherine M. Phelan, Susan J. Ramus, Mary Anne Rossing, Joellen M. Schildkraut, Jin Q. Cheng, Simon A. Gayther and Thomas A. Sellers; on behalf of the Ovarian Cancer Association Consortium
Brett M. Reid
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Jennifer B. Permuth
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Y. Ann Chen
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Jamie K. Teer
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Alvaro N.A. Monteiro
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Zhihua Chen
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Jonathan Tyrer
2University of Cambridge, Cambridge, United Kingdom.
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Andrew Berchuck
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Georgia Chenevix-Trench
4QIMR Berghofer Medical Research Institute, Brisbane, Australia.
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Jennifer A. Doherty
5The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
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Ellen L. Goode
6Mayo Clinic, Rochester, Minnesota.
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Edwin S. Iverson
7Duke University, Durham, North Carolina.
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Kate Lawrenson
8Cedars-Sinai Hospital, Los Angeles, California.
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Celeste L. Pearce
9School of Public Health, University of Michigan, Ann Arbor, Michigan.
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Paul D. Pharoah
2University of Cambridge, Cambridge, United Kingdom.
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Catherine M. Phelan
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Susan J. Ramus
10Keck School of Medicine, University of Southern California, Los Angeles, California.
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Mary Anne Rossing
11Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Joellen M. Schildkraut
12University of Virginia, Charlottesville, Virginia.
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Jin Q. Cheng
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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Simon A. Gayther
8Cedars-Sinai Hospital, Los Angeles, California.
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Thomas A. Sellers
1Moffitt Cancer Center & Research Institute, Tampa, Florida.
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  • For correspondence: Thomas.Sellers@moffitt.org
DOI: 10.1158/1055-9965.EPI-16-0341 Published January 2017
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  • Figure 1.
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    Figure 1.

    Proportion of EOC-associated SNPs in lncRNA genes compared with whole genome. Histograms of the proportion of EOC-associated SNPs (P < 1.0 × 10−5) from analysis of (A) main histologic subgroups and (B) serous histology by grade for whole genome (WG), all lncRNA, and ovarian-active lncRNA regions. Significant differences compared with (*) whole-genome and (**) all lncRNA are annotated.

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    Figure 2.

    Ovarian tissue expression and biologic processes of EOC-associated lncRNA genes. A, Expression of 53 EOC-associated lncRNA for 412 ovarian tumor tissues and 35 normal ovarian tissues. B, Heatmap of significant P values (FDR < 15%) for 18 biologic processes associated with 20 of 53 EOC-associated lncRNAs.

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    Figure 3.

    Selected boxplots for significant eQTL within novel regions associated with EOC risk.

Tables

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  • Table 1.

    SNPs associated with EOC risk are enriched in lncRNA genes

    Whole genome (15,159,372 SNPs)13,442 lncRNA genes (1,757,495 SNPs)5,287 ovarian-active lncRNA genes (457,227 SNPs)
    Tumor histologySNPs P < 10−5Independent regionsaSNPs P < 10−5PbIndependent regionsaPcSNPs P < 10−5PdIndependent regionsaPe
    All invasive5,2941301,4640.047720.00058730.009460.043
    Serous5,9221471,5720.044810.0099600.002510.16
     High grade5,3671781,4670.045890.0028990.004500.25
     Low grade1,9161,1042190.483850.64500.701690.15
    • ↵aSNPs with r2 > 0.2 and within a 250-kb distance were grouped into independent regions.

    • ↵bProportion of risk SNPs within lncRNA genes compared with whole-genome distribution. Empirical P values based on 10,000 permutations of lncRNA genes across the whole genome.

    • ↵cProportion of regions overlapping lncRNA genes compared with whole-genome distribution. Empirical P values based on 10,000 permutations of independent regions across the whole genome.

    • ↵dProportion of risk SNPs in ovarian-active lncRNA genes compared with all lncRNAs. Empirical P values based on 10,000 permutations of active/inactive classification of lncRNAs.

    • ↵eProportion of regions overlapping ovarian-active lncRNA genes compared with all lncRNAs. Empirical P values based on 10,000 permutations of independent regions that overlapped lncRNAs.

  • Table 2.

    Novel EOC risk regions (P < 1.0 × 10−5) with allele-specific effects on lncRNA gene expression

    LocusIndependent regions (length, kB)Overlap lncRNAa (ovarian-active?)Top SNPMAFR2OR (95% CI)PSNP hits/eQTL SNPslncRNA eQTL targets (distance, kB)
    11p15.5chr11:2116492-2190591 (74)IGF2-AS (Y)rs3741205 (A>C)0.280.990.93 (0.91–0.94)3.94E−064/2FAM99A (429)
    AC132217.4 (N)
    11p13chr11:36325764-36396678 (71)RP11-514F3.4 (N)rs10501153 (C>T)0.340.820.92 (0.90–0.93)3.76E−0712/8RP11-219O3.2 (50)
    16q21chr16:58944508-59028237 (84)RP11-410D17.2 (Y)rs6499994 (A>G)0.090.710.91 (0.89–0.93)8.57E−0828/4CTB-134F13.1 (-791)
    RP11-430C1.1 (+861)
    16q22.1chr16:67625872-68029739 (404)RP11-167P11.2 (Y)rs12325430 (T>C)0.440.750.92 (0.90–0.93)2.91E−072/2RP11-167P11.2 (0)
    CTC-479C5.10 (Y)
    CTC-479C5.17 (N)
    AC009095.4 (Y)
    chr16:67950613-68429047 (478)RP11-96D1.5 (Y)chr16:68187782 (CT>C)0.400.730.92 (0.90–0.93)2.10E−0711/1RP11-167P11.2 (177)
    RP11-96D1.9 (N)
    RP11-96D1.6 (Y)
    RP11-96D1.7 (Y)
    RP11-96D1.10 (Y)
    RP11-96D1.11 (Y)
    RP11-96D1.3 (Y)
    RP11-67A1.2 (Y)
    CTC-479C5.6 (N)
    CTC-479C5.17 (Y)
    19q13.12-13chr19:38201712-38474127 (272)CTD-2554C21.3 (N)chr19:38451511 (TA>T)0.140.811.12 (1.09–1.15)5.74E−069/7AC012309.5 (459)
    CTD-2554C21.2 (Y)
    CTD-2528L19.6 (N)
    CTC-244M17.1 (N)
    AC016582.2 (N)
    • Abbreviation: R2 = Imputation quality r2.

    • ↵alncRNAs in bold contain SNP hits within their coordinates and non-bolded lncRNAs are in LD with SNP hits.

Additional Files

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  • Supplementary Data

    • Supplemental Tables and Figures - Supplemental Figure S1. Flowchart for epigenomic annotation of lncRNAs. Supplemental Figure S2. Distribution of ovarian tissue histone marks in lncRNA genes. Supplemental Table S1. Study participants for GWAS meta-analysis of epithelial ovarian cancer. Supplemental Figure S3. Distribution of number of EOC risk SNPs for 10,000 permutations of lncRNA-sized regions. Supplemental Table S2. SNPs associated with risk for less common ovarian cancer subtypes are not enriched in lncRNAs. Supplemental Figure S4. Genomic coverage of GENCODE v19 lncRNA genes (n=13,442 with GWAS SNPs). Supplemental Table S3. Density of EOC-associated SNPs in lncRNA genes versus whole genome (All histologies). Supplemental Table S4. Density of EOC-associated SNPs in lncRNA genes by histologic subtype. Supplemental Table S5. Promoter and transcription factor motifs enriched in EOC-associated lncRNA regions. Supplemental Table S6. Biological processes of putative promoter and transcription factors enriched in 53 EOC-associated lncRNA. Supplemental Figure S5. Regional plots for five novel loci associated with EOC risk and expression of lncRNA genes.
    • Supplemental Methods - Density Measures of lncRNA Enrichment at Independent EOC-associated Regions
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Cancer Epidemiology Biomarkers & Prevention: 26 (1)
January 2017
Volume 26, Issue 1
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Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci
Brett M. Reid, Jennifer B. Permuth, Y. Ann Chen, Jamie K. Teer, Alvaro N.A. Monteiro, Zhihua Chen, Jonathan Tyrer, Andrew Berchuck, Georgia Chenevix-Trench, Jennifer A. Doherty, Ellen L. Goode, Edwin S. Iverson, Kate Lawrenson, Celeste L. Pearce, Paul D. Pharoah, Catherine M. Phelan, Susan J. Ramus, Mary Anne Rossing, Joellen M. Schildkraut, Jin Q. Cheng, Simon A. Gayther and Thomas A. Sellers on behalf of the Ovarian Cancer Association Consortium, on behalf of the Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, on behalf of the Ovarian Cancer Association Consortium
Cancer Epidemiol Biomarkers Prev January 1 2017 (26) (1) 116-125; DOI: 10.1158/1055-9965.EPI-16-0341

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Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci
Brett M. Reid, Jennifer B. Permuth, Y. Ann Chen, Jamie K. Teer, Alvaro N.A. Monteiro, Zhihua Chen, Jonathan Tyrer, Andrew Berchuck, Georgia Chenevix-Trench, Jennifer A. Doherty, Ellen L. Goode, Edwin S. Iverson, Kate Lawrenson, Celeste L. Pearce, Paul D. Pharoah, Catherine M. Phelan, Susan J. Ramus, Mary Anne Rossing, Joellen M. Schildkraut, Jin Q. Cheng, Simon A. Gayther and Thomas A. Sellers on behalf of the Ovarian Cancer Association Consortium, on behalf of the Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, on behalf of the Ovarian Cancer Association Consortium
Cancer Epidemiol Biomarkers Prev January 1 2017 (26) (1) 116-125; DOI: 10.1158/1055-9965.EPI-16-0341
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