Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer

Nature Communications
Matteo D AntonioKelly A Frazer

Abstract

Efforts to identify driver mutations in cancer have largely focused on genes, whereas non-coding sequences remain relatively unexplored. Here we develop a statistical method based on characteristics known to influence local mutation rate and a series of enrichment filters in order to identify distal regulatory elements harboring putative driver mutations in breast cancer. We identify ten DNase I hypersensitive sites that are significantly mutated in breast cancers and associated with the aberrant expression of neighboring genes. A pan-cancer analysis shows that three of these elements are significantly mutated across multiple cancer types and have mutation densities similar to protein-coding driver genes. Functional characterization of the most highly mutated DNase I hypersensitive sites in breast cancer (using in silico and experimental approaches) confirms that they are regulatory elements and affect the expression of cancer genes. Our study suggests that mutations of regulatory elements in tumors likely play an important role in cancer development.Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I h...Continue Reading

References

Apr 11, 2018·Human Molecular Genetics·Adam LavertuRuss B Altman
Apr 26, 2018·Endocrine-related Cancer·Erin E SwinsteadGordon L Hager
Mar 14, 2020·Journal of Cellular and Molecular Medicine·Jing ZhangLixin Xie
Aug 28, 2020·Frontiers in Bioengineering and Biotechnology·Siwen XuYunlong Liu

Citations

Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·W S PearD Baltimore
Dec 23, 1999·Current Opinion in Genetics & Development·A F Smit
Aug 30, 2000·Nature·Charles M PerouD Botstein
Jan 11, 2000·Nucleic Acids Research·S T SherryK Sirotkin
Sep 21, 2007·Bioinformatics·Mark D Robinson, Gordon K Smyth
Oct 13, 2007·Science·Laura D WoodBert Vogelstein
Mar 15, 2008·Cancer Research·Ali Torkamani, Nicholas J Schork
Apr 29, 2008·Nature Medicine·Greg FinakMorag Park
May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
Jun 10, 2009·Bioinformatics·Heng Li1000 Genome Project Data Processing Subgroup
Nov 19, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Skjalg BruheimOystein Fodstad
Jan 30, 2010·Bioinformatics·Aaron R Quinlan, Ira M Hall
Mar 25, 2011·Nature·Michael A ChapmanTodd R Golub
Mar 29, 2011·Nature·Jason ErnstBradley E Bernstein
Oct 8, 2011·Nature Reviews. Cancer·Shigetsugu Hatakeyama
May 23, 2012·Cell·Serena Nik-ZainalBreast Cancer Working Group of the International Cancer Genome Consortium
Jun 23, 2012·Nature·Philip J StephensMichael R Stratton
Jun 23, 2012·Nature·Shantanu BanerjiMatthew Meyerson
Sep 8, 2012·Nature·Robert E ThurmanJohn A Stamatoyannopoulos
Sep 8, 2012·Nature·Shane NephJohn A Stamatoyannopoulos
Sep 8, 2012·Genome Research·Jennifer HarrowTim J Hubbard
Sep 25, 2012·Nature·Cancer Genome Atlas Network
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Nov 28, 2012·American Journal of Human Genetics·Amnon KorenSteven A McCarroll
Jan 26, 2013·Science·Franklin W HuangLevi A Garraway
Feb 12, 2013·Nature Biotechnology·Kristian CibulskisGad Getz
Apr 23, 2013·Current Opinion in Genetics & Development·Malte Spielmann, Eva Klopocki
May 29, 2013·Bioinformatics·Shawn E YostOlivier Harismendy
May 31, 2013·Genome Biology·Matteo D'Antonio, Francesca D Ciccarelli
Jul 23, 2013·Nature Biotechnology·Patrick D HsuFeng Zhang
Aug 16, 2013·Nature·Ludmil B AlexandrovMichael R Stratton
Oct 3, 2013·Scientific Reports·David TamboreroNuria Lopez-Bigas
Oct 8, 2013·PloS One·Chi-Cheng HuangEric Y Chuang
Dec 12, 2013·Breast Cancer Research : BCR·Olivier HarismendyKelly A Frazer
Dec 18, 2013·Nature Biotechnology·Paz PolakShamil R Sunyaev
Mar 13, 2014·Database : the Journal of Biological Databases and Curation·Omer AnFrancesca D Ciccarelli
Apr 11, 2014·Journal of the National Comprehensive Cancer Network : JNCCN·William J GradisharNational Comprehensive Cancer Network Breast Cancer Panel
Sep 10, 2014·Current Protocols in Bioinformatics·Aaron R Quinlan

Related Concepts

Study
Gene Expression Regulation, Neoplastic
Deoxyribonuclease I
Genome
Genes
Telomerase Catalytic Subunit
Genome Assembly Sequence
Neoplasms
Multiple Malignancy
Site

Related Feeds

Cancer Epigenetics and Chromatin (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on chromatin and its role in cancer epigenetics please follow this feed to learn more.

Cancer Epigenetics Chromatin Complexes (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on chromatin complexes and their role in cancer epigenetics.

Breast Cancer: Risk Factors

Breast cancer is a multifactorial disease that is influenced by both environmental and genetic factors. Discover the latest research on the environmental and genetic risk factors for breast cancer here.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

Cancer Genomics

Cancer genomics employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research here.