Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

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Abstract

Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of “looping” by which HPV integrant-mediated DNA replication and recombination may result in viral–host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.

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The Sequence Alignment/Map format and SAMtools

Heng Li, Bob Handsaker, Alec Wysoker … (2009)

Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk

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BEDTools: a flexible suite of utilities for comparing genomic features

Aaron Quinlan, Ira Hall (2010)

Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing web-based methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools Contact: aaronquinlan@gmail.com; imh4y@virginia.edu Supplementary information: Supplementary data are available at Bioinformatics online.

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Fast and accurate long-read alignment with Burrows–Wheeler transform

Heng Li, Richard Durbin (2010)

Motivation: Many programs for aligning short sequencing reads to a reference genome have been developed in the last 2 years. Most of them are very efficient for short reads but inefficient or not applicable for reads >200 bp because the algorithms are heavily and specifically tuned for short queries with low sequencing error rate. However, some sequencing platforms already produce longer reads and others are expected to become available soon. For longer reads, hashing-based software such as BLAT and SSAHA2 remain the only choices. Nonetheless, these methods are substantially slower than short-read aligners in terms of aligned bases per unit time. Results: We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g. the human genome) with a few gigabytes of memory. The algorithm is as accurate as SSAHA2, more accurate than BLAT, and is several to tens of times faster than both. Availability: http://bio-bwa.sourceforge.net Contact: rd@sanger.ac.uk

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Author and article information

Journal

Journal ID (nlm-ta): Genome Res

Journal ID (iso-abbrev): Genome Res

Journal ID (publisher-id): GENOME

Title: Genome Research

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 1088-9051

ISSN (Electronic): 1549-5469

Publication date (Print): February 2014

Volume: 24

Issue: 2

Pages: 185-199

Affiliations

[1 ]Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;

[2 ]Viral Oncology Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;

[3 ]Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA;

[4 ]Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA;

[5 ]Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20814, USA;

[6 ]Center for Cancer Research and Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;

[7 ]Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02115, USA;

[8 ]Department of Otolaryngology–Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA;

[9 ]Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA

Author notes

[10]

These authors contributed equally to this work.

[11]

These authors contributed equally to this work.

[12 ]Corresponding authors E-mail david.symer@ 123456osumc.edu E-mail maura.gillison@ 123456osumc.edu

Article

Medline ID: 9518021

DOI: 10.1101/gr.164806.113

PMC ID: 3912410

PubMed ID: 24201445

SO-VID: ec852a02-83d9-422b-998d-cf3315bc014d

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

History

Date received : 7 August 2013

Date accepted : 17 October 2013

Page count

Pages: 15

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Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

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BIO Integration

Most cited references 83

The Sequence Alignment/Map format and SAMtools

BEDTools: a flexible suite of utilities for comparing genomic features

Fast and accurate long-read alignment with Burrows–Wheeler transform

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