Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk

Brett M. Reid, Jennifer B. Permuth, Y. Ann Chen, Brooke L. Fridley, Edwin S. Iversen, Zhihua Chen, Heather Jim, Robert A. Vierkant, Julie M Cunningham, Jill S. Barnholtz-Sloan, Steven Narod, Harvey Risch, Joellen M. Schildkraut, Ellen L Goode, Alvaro N. Monteiro, Thomas A. Sellers

Research output: Contribution to journalArticle

Abstract

Background: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results: Three CNVRs were associated (P < 0.01) with EOC risk: two large (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). Conclusions: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. Impact: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.

Original languageEnglish (US)
Pages (from-to)1117-1126
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume28
Issue number7
DOIs
StatePublished - Jan 1 2019

Fingerprint

Genome
Neoplasms
Atlases
DNA Copy Number Variations
Gene Expression
Neoplasm Genes
Genome-Wide Association Study
Ovarian epithelial cancer
Computer Simulation
Down-Regulation
DNA
Research
human CYP2A7 protein

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Reid, B. M., Permuth, J. B., Ann Chen, Y., Fridley, B. L., Iversen, E. S., Chen, Z., ... Sellers, T. A. (2019). Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk. Cancer Epidemiology Biomarkers and Prevention, 28(7), 1117-1126. https://doi.org/10.1158/1055-9965.EPI-18-0833

Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk. / Reid, Brett M.; Permuth, Jennifer B.; Ann Chen, Y.; Fridley, Brooke L.; Iversen, Edwin S.; Chen, Zhihua; Jim, Heather; Vierkant, Robert A.; Cunningham, Julie M; Barnholtz-Sloan, Jill S.; Narod, Steven; Risch, Harvey; Schildkraut, Joellen M.; Goode, Ellen L; Monteiro, Alvaro N.; Sellers, Thomas A.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 28, No. 7, 01.01.2019, p. 1117-1126.

Research output: Contribution to journalArticle

Reid, BM, Permuth, JB, Ann Chen, Y, Fridley, BL, Iversen, ES, Chen, Z, Jim, H, Vierkant, RA, Cunningham, JM, Barnholtz-Sloan, JS, Narod, S, Risch, H, Schildkraut, JM, Goode, EL, Monteiro, AN & Sellers, TA 2019, 'Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk', Cancer Epidemiology Biomarkers and Prevention, vol. 28, no. 7, pp. 1117-1126. https://doi.org/10.1158/1055-9965.EPI-18-0833
Reid, Brett M. ; Permuth, Jennifer B. ; Ann Chen, Y. ; Fridley, Brooke L. ; Iversen, Edwin S. ; Chen, Zhihua ; Jim, Heather ; Vierkant, Robert A. ; Cunningham, Julie M ; Barnholtz-Sloan, Jill S. ; Narod, Steven ; Risch, Harvey ; Schildkraut, Joellen M. ; Goode, Ellen L ; Monteiro, Alvaro N. ; Sellers, Thomas A. / Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk. In: Cancer Epidemiology Biomarkers and Prevention. 2019 ; Vol. 28, No. 7. pp. 1117-1126.
@article{ee517fe2bcc142b9a6995631a5ffd91f,
title = "Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk",
abstract = "Background: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1{\%}) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results: Three CNVRs were associated (P < 0.01) with EOC risk: two large (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). Conclusions: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. Impact: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.",
author = "Reid, {Brett M.} and Permuth, {Jennifer B.} and {Ann Chen}, Y. and Fridley, {Brooke L.} and Iversen, {Edwin S.} and Zhihua Chen and Heather Jim and Vierkant, {Robert A.} and Cunningham, {Julie M} and Barnholtz-Sloan, {Jill S.} and Steven Narod and Harvey Risch and Schildkraut, {Joellen M.} and Goode, {Ellen L} and Monteiro, {Alvaro N.} and Sellers, {Thomas A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/1055-9965.EPI-18-0833",
language = "English (US)",
volume = "28",
pages = "1117--1126",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk

AU - Reid, Brett M.

AU - Permuth, Jennifer B.

AU - Ann Chen, Y.

AU - Fridley, Brooke L.

AU - Iversen, Edwin S.

AU - Chen, Zhihua

AU - Jim, Heather

AU - Vierkant, Robert A.

AU - Cunningham, Julie M

AU - Barnholtz-Sloan, Jill S.

AU - Narod, Steven

AU - Risch, Harvey

AU - Schildkraut, Joellen M.

AU - Goode, Ellen L

AU - Monteiro, Alvaro N.

AU - Sellers, Thomas A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results: Three CNVRs were associated (P < 0.01) with EOC risk: two large (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). Conclusions: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. Impact: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.

AB - Background: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results: Three CNVRs were associated (P < 0.01) with EOC risk: two large (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). Conclusions: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. Impact: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.

UR - http://www.scopus.com/inward/record.url?scp=85068805761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068805761&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-18-0833

DO - 10.1158/1055-9965.EPI-18-0833

M3 - Article

C2 - 30948450

AN - SCOPUS:85068805761

VL - 28

SP - 1117

EP - 1126

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 7

ER -