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Mortimer S.A.,University of California at Berkeley | Mortimer S.A.,Guardant Health | Kidwell M.A.,University of California at Berkeley | Doudna J.A.,University of California at Berkeley | And 2 more authors.
Nature Reviews Genetics | Year: 2014

A comprehensive understanding of RNA structure will provide fundamental insights into the cellular function of both coding and non-coding RNAs. Although many RNA structures have been analysed by traditional biophysical and biochemical methods, the low-throughput nature of these approaches has prevented investigation of the vast majority of cellular transcripts. Triggered by advances in sequencing technology, genome-wide approaches for probing the transcriptome are beginning to reveal how RNA structure affects each step of protein expression and RNA stability. In this Review, we discuss the emerging relationships between RNA structure and the regulation of gene expression. © 2014 Macmillan Publishers Limited. All rights reserved. Source


Patent
Guardant Health | Date: 2015-09-22

Disclosed herein in are methods and systems for determining genetic variants (e.g., copy number variation) in a polynucleotide sample. A method for determining copy number variations includes tagging double-stranded polynucleotides with duplex tags, sequencing polynucleotides from the sample and estimating total number of polynucleotides mapping to selected genetic loci. The estimate of total number of polynucleotides can involve estimating the number of double-stranded polynucleotides in the original sample for which no sequence reads are generated. This number can be generated using the number of polynucleotides for which reads for both complementary strands are detected and reads for which only one of the two complementary strands is detected.


The present disclosure provides a system and method for the detection of rare mutations and copy number variations in cell free polynucleotides. Generally, the systems and methods comprise sample preparation, or the extraction and isolation of cell free polynucleotide sequences from a bodily fluid; subsequent sequencing of cell free polynucleotides by techniques known in the art; and application of bioinformatics tools to detect rare mutations and copy number variations as compared to a reference. The systems and methods also may contain a database or collection of different rare mutations or copy number variation profiles of different diseases, to be used as additional references in aiding detection of rare mutations, copy number variation profiling or general genetic profiling of a disease.


The present disclosure provides a system and method for the detection of rare mutations and copy number variations in cell free polynucleotides. Generally, the systems and methods comprise sample preparation, or the extraction and isolation of cell free polynucleotide sequences from a bodily fluid; subsequent sequencing of cell free polynucleotides by techniques known in the art; and application of bioinformatics tools to detect rare mutations and copy number variations as compared to a reference. The systems and methods also may contain a database or collection of different rare mutations or copy number variation profiles of different diseases, to be used as additional references in aiding detection of rare mutations, copy number variation profiling or general genetic profiling of a disease.


News Article
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

What if screening for cancer was as easy as checking your cholesterol? That’s the promise of techniques currently in development that may one day make it possible to detect the earliest stages of cancer with an annual blood draw. So-called “liquid biopsies” involve extracting free-floating cancer cells or cancer DNA from the bloodstream (or in some cases from the urine) to get information about tumors too small or hidden to detect with standard techniques. This could make it possible for clinicians to remotely monitor how cancer patients are responding to treatment, to detect early warning signs of recurrence, and even to pick up the very first signs of cancer in otherwise healthy people. Over the past year, industry excitement surrounding these techniques has accelerated rapidly, with established biotech companies such as Qiagen, Roche and Illumina and a bevy of startups such as Guardant Health and Foundation Medicine competing to commercialize liquid biopsy and bring it to patients within the next few years. While many researchers agree the technology is exciting, the question is: Will liquid biopsies become the next big thing in cancer diagnostics, or will it simply have niche applications? “Right now it’s the Wild West,” said John Witte, Ph.D., who co-directs the cancer genetics program in the UCSF Helen Diller Family Comprehensive Cancer Center and is working to improve the sensitivity of liquid biopsy techniques to help track the development and progression of potentially deadly prostate cancers. “There are a lot of different ways liquid biopsies might be transformative for cancer screening and monitoring, but we’re not yet sure how well the techniques will work. Still, the potential value is enormous and well worth risky ventures.” Currently physicians remove tumor samples surgically or with biopsy needles, then examine the tissue under microscopes or analyze it genetically to make a diagnosis and guide treatment. This approach is expensive, invasive and usually only possible once a tumor has grown large enough to already be a major threat. Worse, cancers often continue to mutate as they spread, meaning that a biopsy of the original tumor may not help to treat invasive metastatic colonies. “Physicians are still often working in the dark,” said Ash Alizadeh, M.D., Ph.D., a Stanford hematologist and oncologist who has been a leader in the development of liquid biopsy techniques over the past decade and currently consults for Roche Diagnostics. “Even once we identify a tumor using a scan, the seriousness and extent of the cancer in the patient’s body is often still murky.” This is why researchers, clinicians and diagnostic companies are so eager to develop technology that can allow them to analyze tumors without an invasive procedure. There are two main targets of liquid biopsy currently in development: The older and more well-established technique involves filtering blood samples for rare circulating tumor cells (CTCs) that have been shed by a tumor and can be recognized using common molecular markers present on the surface of many types of cancer cells. The DNA of these cells can be used to learn about mutations underlying the patient’s cancer, or the cells themselves can be cultured and used to identify personalized cancer drugs. Several companies are already offering such tests, and hundreds of clinical trials are currently in the pipeline. Though researchers have been working on CTC liquid biopsies for decades, many attempts at clinical applications have so far been disappointing – in part, because not all cancer types produce recognizable CTCs. Even where scientists know what CTCs should look like, finding a few of these exceedingly rare cells among millions of blood cells is a major challenge – even more so at the earliest stages of the disease. More recently, researchers have made progress on the considerably harder feat of reliably detecting so-called “cell-free” circulating tumor DNA (ctDNA). These techniques, which rely on matching blood-borne DNA fragments to the genetic sequences of known tumor mutations, can theoretically be performed much more quickly and with greater sensitivity than CTC liquid biopsies and have recently spurred highly touted liquid biopsy efforts by companies like Illumina. “The technique has suddenly become hot because new sequencing technology has made it seem possible for the first time,” said Pamela Paris, Ph.D., a UCSF cancer genomicist who uses CTC liquid biopsies in her research to link specific prostate and bladder cancer mutations to effective drugs. However, there are still kinks to be worked out, Paris cautioned. For instance, fragmentary ctDNA on its own contains less information than fully intact cancer cells. In addition, since ctDNA is thought to be released by dead or dying cells, there’s a chance it could bias clinical results, preferentially providing information about the weakest cancer cells while allowing the most problematic, treatment-resistant cells to remain undetected. The future of liquid biopsy techniques largely depends on how well researchers and major biotechnology companies are able to scale up the technology behind them and prove that it can be both cost-effective and reliable, researchers said. For instance, most ctDNA techniques still miss a significant fraction of the DNA molecules present in the blood – too many to be confident that they can reliably rule out the presence of lurking cancer DNA. “The big challenge is the numbers,” Witte said. “Accurately detecting tumor mutations via ctDNA requires substantially more thorough or deeper gene sequencing than what is currently used for tumors themselves.” However, Witte said, even if it proves more difficult than anticipated to use liquid biopsy for early diagnosis in healthy people, the techniques will probably achieve extremely valuable but more niche uses: aiding researchers’ quest to link cancer genomics with cancer treatment and allowing clinicians to track the progression of certain later-stage cancers – with pancreatic, ovarian, colorectal, melanoma, breast and lung cancers considered among the most promising candidates for immediate benefit. “It’s important to maintain healthy skepticism,” Witte said, “But right now I’d say most researchers are cautiously optimistic.”

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