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9p22.2 卵巢癌易感性位点的功能分析与精细定位。

Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus.

机构信息

Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

University of South Florida Cancer Biology PhD Program, Tampa, Florida.

出版信息

Cancer Res. 2019 Feb 1;79(3):467-481. doi: 10.1158/0008-5472.CAN-17-3864. Epub 2018 Nov 28.

DOI:10.1158/0008-5472.CAN-17-3864
PMID:
30487138
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6359979/
Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, was established as the most likely target gene. We determined the consensus binding sequence for BNC2 , verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies as an ovarian cancer risk gene..

摘要

全基因组关联研究已经确定了 40 个卵巢癌风险位点。然而，这些关联的潜在机制仍难以捉摸。在这项研究中，我们采用了一种双管齐下的方法来识别候选因果 SNP，并评估染色体 9p22.2 上的潜在生物学机制，该区域是卵巢癌易感性的第一个也是最具统计学意义的相关区域。具有等位基因特异性效应的三个转录调控元件和一个支架/基质附着区被表征，并且通过物理 DNA 相互作用， 被确定为最可能的靶基因。我们确定了 BNC2 的共识结合序列，验证了其在 BNC2 ChIP-seq 区域中的富集，并验证了其一组下游靶基因。在超过 15000 例卵巢癌病例和 30000 例对照中进行密集区域基因分型的精细映射，确定了支架/基质附着区中的 SNP 是最有可能的因果变异。这项研究揭示了 9p22.2 上的全面调控景观，并提出了卵巢癌易感性的可能机制。意义：绘制 9p22.2 卵巢癌风险位点图确定 为卵巢癌风险基因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/d029b0b4caef/nihms-1514364-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/ab24551cd51d/nihms-1514364-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/7e3af990f2a8/nihms-1514364-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/0bcc1e45ea1a/nihms-1514364-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/23b78029dd25/nihms-1514364-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/34aa0aba5bee/nihms-1514364-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/d029b0b4caef/nihms-1514364-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/ab24551cd51d/nihms-1514364-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/1a39bc3c7010/nihms-1514364-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/406cba083d71/nihms-1514364-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/7e3af990f2a8/nihms-1514364-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/0bcc1e45ea1a/nihms-1514364-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/23b78029dd25/nihms-1514364-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/34aa0aba5bee/nihms-1514364-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/088b/6359979/d029b0b4caef/nihms-1514364-f0005.jpg

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