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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Population-specific structural variation

Genome maps across 26 human populations reveal population-specific patterns of structural variation

Abstract—Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

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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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Alzheimers insights from the desk of the NIH Director, Dr. Francis Collins

Largest-Ever Alzheimer’s Gene Study Brings New Answers

Predicting whether someone will get Alzheimer’s disease (AD) late in life, and how to use that information for prevention, has been an intense focus of biomedical research. The goal of this work is to learn not only about the genes involved in AD, but how they work together and with other complex biological, environmental, and lifestyle factors to drive this devastating neurological disease.

It’s good news to be able to report that an international team of researchers, partly funded by NIH, has made more progress in explaining the genetic component of AD. Their analysis, involving data from more than 35,000 individuals with late-onset AD, has identified variants in five new genes that put people at greater risk of AD [1]. It also points to molecular pathways involved in AD as possible avenues for prevention, and offers further confirmation of 20 other genes that had been implicated previously in AD.

The results of this largest-ever genomic study of AD suggests key roles for genes involved in the processing of beta-amyloid peptides, which form plaques in the brain recognized as an important early indicator of AD. They also offer the first evidence for a genetic link to proteins that bind tau, the protein responsible for telltale tangles in the AD brain that track closely with a person’s cognitive decline.

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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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EU pathway for improve rare disease identification and treatment

New EU platform to support better rare disease diagnosis and treatment

The European Commission is launching a new online knowledge-sharing platform to support better diagnosis and treatment for more than 30 million Europeans living with a rare disease.

Currently a vast amount of data on patients with specific conditions is scattered across Europe in about 600 'registries' – databases that hold information on patients with specific conditions. Data is not collected EU-wide and there are no shared standards to analyse the information that is available on rare diseases. The new European Platform on Rare Diseases Registration will bring this data together supporting the quality research that can enhance diagnosis and treatment outcomes - helping to improve the lives of patients and their families.

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EU Genomics sector has some reliable bets

10 European Genomics Companies to Watch Out For

Next generation sequencing has revolutionized the biotech industry and genomics technology has changed dramatically over the last few years. There are many interesting European genomics companies, but here are 10 we thought especially worthy of mention.

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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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Mutation bursts associated with cancer -- a very good summary

Researchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage—mutational fingerprints that represent the origins of cancer—were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious.

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Original article here …

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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Insights into how prostate cancers become resistant, and new potential targets (original article)

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

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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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3 Technologies That Could Create Trillion-Dollar Markets Over the Next Decade

Go back to the typical household in 1950, and you would see much that you would recognize: washing machines, vacuum cleaners, cars, TVs. But go back 50 years earlier, to 1900, and most of us would find a world that was utterly foreign, and exhausting. Daily chores like cooking and washing took hours of backbreaking labor. That’s because in the early 20th century, electricity and internal combustion completely changed how we live, transforming our cities, our homes, how we shop, eat, work, and just about every other facet of daily existence.

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We’re on the cusp of a similar point today, except it is not just two technologies that are poised to change the world, but three of them: gene editing, new computing architectures, and materials science are just beginning to make the leap from lab to market. Taken together, these could be as transformative as electricity and internal combustion, which kicked off a 50-year productivity boom.

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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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