Cloud-based access to the fully sequenced genomes of 10,000 pediatric patients with cancer

Genomics Data Could Lead to New Treatments for Children

BY BETH FAND INCOLLINGO

PUBLISHED MARCH 12, 2019

St. Jude Children’s Research Hospital is offering cloud-based access to the fully sequenced genomes of 10,000 pediatric patients with cancer, in the hopes that sharing the information will lead to the highest possible number of treatment breakthroughs.

Called the Pediatric Cancer Genome Project (PCGP), the growing set of data, categorized by cancer type, is meant to help researchers at the Memphis facility and beyond understand the genetic mutations that drive pediatric cancers and find new drugs to treat the diseases.

In whole-genome sequencing, a child’s normal and tumor genes are sequenced and then compared. Mutations that are present in a child’s tumor but not his or her normal genes may be driving the disease, and could be good candidates to target with drugs, said Jinghui Zang, Ph.D., chair of the Department of Computational Biology at St. Jude.

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A discussion of the limitations of a single, static reference genome

Buffalo gave us spicy wings and the ‘book of life.’ Here’s why that’s undermining personalized medicine

“The human reference genome, largely completed in 2001, has achieved near-mythic status. It is “the book of life,” the “operating manual for Homo sapiens.” But the reference genome falls short in ways that have become embarrassing, misleading, and, in the worst cases, emblematic of the white European dominance of science — shortcomings that are threatening the dream of genetically based personalized medicine.“

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Disease risk estimates need more samples from more populations (Genome Biology)

Genetic disease risks can be misestimated across global populations

Michelle S. Kim, Kane P. Patel, Andrew K. Teng, Ali J. Berens, and Joseph Lachance

Genome Biology (Research article)

Accurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of genome-wide association studies (GWAS), and extensive computer simulations to identify how genetic disease risks can be misestimated. In contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. 

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50,000 Human Exomes at the UK Biobank

New genetic data on 50,000 UK Biobank participants made available to the global health research community

A vast tranche of new UK Biobank genetic data becomes available to health researchers today, offering an unprecedented resource to enhance understanding of human biology and aid in therapeutic discovery.

The exome sequence data of 50,000 UK Biobank participants were generated at the Regeneron Genetics Center through a collaboration between UK Biobank, Regeneron (US) and GSK (UK) and are linked to detailed health records, imaging and other health-related data. Regeneron is also leading a consortium of biopharma companies (including Abbvie, Alnylam, AstraZeneca, Bristol-Myers Squibb, Biogen, Pfizer and Takeda) to complete exome sequencing of the remaining 450,000 UK Biobank participants by 2020. In addition, GSK has committed a £40 million investment to initiatives, such as UK Biobank, that harness advances in genetic research in the development of new medicines

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Big players dominate global Liver Cancer diagnostics for foreseeable future

The Global Liver Cancer Diagnostic Market to 2025 - Leading Players are Illumina, Qiagen, F. Hoffmann-La Roche, Siemens Healthcare, and Thermo Fisher Scientific

Dublin, March 08, 2019 (GLOBE NEWSWIRE) -- The "Liver Cancer Diagnostic Market Size, Share & Trends Analysis Report By Screening Type (Biopsy, Endoscopy, Laboratory Tests, Imaging), By Region (North America, APAC, Europe), And Segment Forecasts, 2019 - 2025"report has been added to ResearchAndMarkets.com's offering.

The global liver cancer diagnostics market size is expected to reach USD 15.4 billion by 2025. The market is projected to expand at a CAGR of 8.1% over the estimated time period.

Rise in disease incidence coupled with growing demand for novel diagnosis products are thrusting the growth of the market. Hepatocellular Carcinoma (HCC) is the most common type of primary liver cancer in adults. It is among the common causes of death in people with liver cirrhosis and the third-leading cause of cancer deaths across the globe. Poor survival rate and lack of therapies has made this disease a crucial health issue worldwide.

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Single-cell sequencing reveals important cancer mutation signatures (original article)

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

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Potential to remove HIV from infected cells

‘Molecular scissors’ successfully remove HIV genes from all tissues in infected monkeys

The top story from the Conference on Retroviruses and Opportunistic Infections (CROI 2019) in Seattle this week has been a likely second HIV cure. However, the cure involved an expensive and risky therapy – a bone-marrow transplant – that would never be broadly applicable.

Just as significant in the long term may be a study reported in the same session that used much more benign technology to achieve what may be a cure in monkeys.

A team of researchers at Temple University in Philadelphia, USA, has removed the retroviral genes from the cells of monkeys infected with SIV, the monkey analogue of HIV. The researchers found that the gene-snipping enzyme they used, contained within the shell of a common cold-type virus so that it could simulate an infection and enter cells, successfully removed the SIV genes from a majority – and possibly all – cells in all the monkeys’ organs where levels were measured, including hard-to-access ones such as the brain.

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Let's now worry about designer babies ...

The Dawn of Intelligent Designer Babies

While selecting or editing embryos in favour of certain attributes may seem like a phenomenon of the distant future, the company Genomic Prediction in the United States has recently announced their advanced technology that would allow parents to screen for several complex traits, most controversially being low intelligence. This process would give the option of excluding embryos during in vitro fertilisation (IVF) that have a high risk of having “mental disability,” defined as an IQ of 25 points below average. While Genomic Prediction explicitly states that this will not be used to select for embryos with the potential for abnormally high intelligence, co-founder Stephen Hsu claims it is entirely feasible and states “I think people are going to demand that. If we don’t do it, some other company will.”

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Human disease models made in frogs with CRISPR

Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system

Abstract

Precise single-base editing in Xenopus tropicalis would greatly expand the utility of this true diploid frog for modeling human genetic diseases caused by point mutations. Here, we report the efficient conversion of C-to-T or G-to-A in X. tropicalis using the rat apolipoprotein B mRNA editing enzyme catalytic subunit 1–XTEN–clustered regularly interspaced short palindromic repeat–associated protein 9 (Cas9) nickase–uracil DNA glycosylase inhibitor–nuclear localization sequence base editor [base editor 3 (BE3)]. Coinjection of guide RNA and the Cas9 mutant complex mRNA into 1-cell stage X. tropicalis embryos caused precise C-to-T or G-to-A substitution in 14 out of 19 tested sites with efficiencies of 5–75%, which allowed for easy establishment of stable lines. Targeting the conserved T-box 5 R237 and Tyr C28 residues in X. tropicalis with the BE3 system mimicked human Holt-Oram syndrome and oculocutaneous albinism type 1A, respectively. Our data indicate that BE3 is an easy and efficient tool for precise base editing in X. tropicalis.—Shi, Z., Xin, H., Tian, D., Lian, J., Wang, J., Liu, G., Ran, R., Shi, S., Zhang, Z., Shi, Y., Deng, Y., Hou, C., Chen, Y. Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system.

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Increasing CRISPR efficiency, and specificity with zinc-finger proteins (original article)

Diversifying the structure of zinc finger nucleases for high-precision genome editing

Abstract—Genome editing for therapeutic applications often requires cleavage within a narrow sequence window. Here, to enable such high-precision targeting with zinc-finger nucleases (ZFNs), we have developed an expanded set of architectures that collectively increase the configurational options available for design by a factor of 64. These new architectures feature the functional attachment of the FokI cleavage domain to the amino terminus of one or both zinc-finger proteins (ZFPs) in the ZFN dimer, as well as the option to skip bases between the target triplets of otherwise adjacent fingers in each zinc-finger array. Using our new architectures, we demonstrate targeting of an arbitrarily chosen 28 bp genomic locus at a density that approaches 1.0 (i.e., efficient ZFNs available for targeting almost every base step). We show that these new architectures may be used for targeting three loci of therapeutic significance with a high degree of precision, efficiency, and specificity.

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New insights into tissue-localized immunity in lung transplants

Generation and persistence of human tissue-resident memory T cells in lung transplantation

Tissue-resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess.  By studying donor and recipient T cells in transplanted lungs, Snyder et al. have provided a rare glimpse into the generation and maintenance of human TRM. Whereas donor T cells were barely detectable in blood within 10 weeks after transplantation, donor TRM were abundant and persisted in transplanted lungs for more than a year. Recipient T cells infiltrating the lung gradually acquired TRM profiles over time as determined by analyses of T cells from bronchoalveolar lavages. In this 20-patient cohort, persistence of donor lung TRM correlated with improved clinical outcome, although further studies are needed to understand their role in graft retention.

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CRISPR-based gene therapy, speculating about a time-table

We’re still a long way from using gene-editing for medical conditions?

Gene editing has been in the news lately due to an ethically reckless experiment in which human embryos were subjected to an inefficient form of gene editing. The subjects, now born, gained uncertain protection from HIV in exchange for a big collection of potential risks. A large number of ethicists and scientists agreed that this isn't the sort of thing we should be using gene editing for.

Gene editing will likely always come with a bit of risk; when you're cutting and pasting DNA in millions of cells, extremely rare events can't be avoided. So the ethical questions come down to how we can minimize those risks and what conditions make them worth taking.

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Centers for Medicare & Medicaid Services cancer sequencing dust-up

CMS Acknowledges Stakeholder Concerns Over Decision Not to Cover Germline NGS in Early Cancer Patients

NEW YORK (GenomeWeb) – The Centers for Medicare & Medicaid Services issued a notice this week acknowledging the confusion over its coverage policy for germline next-generation sequencing for cancer patients.

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Single-molecule quantum sequencing method for detecting Anti-Cancer drug incorporation into DNA

DNA is small. Really, really, small. So, when researchers want to study the structure of a single-stranded DNA, they can’t just pull out their microscopes: they have to get creative.

In a study published this week in Scientific Reports, researchers from Japan’s Osaka University explain how they came up with a really small solution to the challenge of studying anti-cancer drugs incorporated into single strands of DNA.

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Next-next generation tool for improving traditional chemotherapies

Direct Analysis of Incorporation of an Anticancer Drug into DNA at Single-Molecule Resolution

Identifying positions at which anticancer drug molecules incorporate into DNA is essential to define mechanisms underlying their activity, but current methodologies cannot yet achieve this. The thymidine fluorine substitution product trifluridine (FTD) is a DNA-damaging anticancer agent thought to incorporate into thymine positions in DNA. This mechanism, however, has not been directly confirmed. Here, we report a means to detect FTD in a single-stranded oligonucleotide using a method to distinguish single molecules by differences in electrical conductance. Entire sequences of 21-base single-stranded DNAs with and without incorporated drug were determined based on single-molecule conductances of the drug and four deoxynucleosides, the first direct observation of its kind. This methodology may foster rapid development of more effective anticancer drugs.

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More than four possible bases, more coverage

Scientists Have Created Synthetic DNA with 4 Extra Letters

A couple billion years ago, four molecules danced into the elegant double-helix structure of DNA, which provides the codes for life on our planet. But were these four players really fundamental to the appearance of life — or could others have also given rise to our genetic code?

A new study, published today (Feb. 20) in the journal Science, supports the latter proposition: Scientists have recently molded a new kind of DNA into its elegant double-helix structure and found it had properties that could support life.

But if natural DNA is a short story, this synthetic DNA is a Tolstoy novel.

The researchers crafted the synthetic DNA using four additional molecules, so that the resulting product had a code made up from eight letters rather than four. 

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Increased CRISPR specificity by limiting expression

Scientists sharpen their molecular scissors and expand the gene editing toolbox

Wake Forest Institute for Regenerative Medicine (WFIRM) scientists have figured out a better way to deliver a DNA editing tool to shorten the presence of the editor proteins in the cells in what they describe as a "hit and run" approach.

CRISPR (clustered regularly interspaced short palindromic repeats) technology is used to alter DNA sequences and modify gene function. CRISPR/Cas9 is an enzyme that is used like a pair of scissors to cut two strands of DNA at a specific location to add, remove or repair bits of DNA. But CRISPR/Cas9 is not 100 percent accurate and could potentially cut unexpected locations, causing unwanted results.

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Cancer mutation characterization with machine learning (original article -- very cool)

Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models

Loss of DNA repair mechanisms can leave specific mutation signatures in the genomes of cancer cells. To identify cancers with broken DNA-repair processes, accurate methods are needed for detecting mutation signatures and, in particular, their activities or probabilities within individual cancers. In this paper, we introduce a class of statistical modeling methods used for natural language processing, known as “topic models”, that outperform standard methods for signature analysis. We show that topic models that incorporate signature probability correlations across cancers perform best, while jointly analyzing multiple mutation types improves robustness to low mutation counts.

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Synthetic DNA suggests other bases might be out there

Synthetic DNA could help with search for alien life

Scientists have long suggested that if life exists beyond Earth, the processes behind it may be entirely different from everything we know.

On Thursday, researchers announced that they were able to create a DNA-like molecular system that can store and transmit information. It's not a life form, but the genetic system represents what an alternative to DNA-based life may resemble.

It could also help scientists keep a different picture in mind when searching for life elsewhere in the universe.

Smart stats make use of large-scale health insurance claims

Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes

We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h2 = 0.311) and shared environmental variance (c2 = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (varSES = 0.002), daily air quality (varAQI = 0.0004), and average temperature (vartemp = 0.001) overall, as well as for individual phenotypes. We found significant heritability and shared environment for a number of comorbidities (h2 = 0.433, c2 = 0.241) and average monthly cost (h2 = 0.290, c2 = 0.302). All results are available using our Claims Analysis of Twin Correlation and Heritability (CaTCH) web application.

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