Mapping the pharmacogenomic drug response landscape

Encircling the regions of the pharmacogenomic landscape that determine drug response

Adrià Fernández-Torras, Miquel Duran-Frigola & Patrick Aloy

Genome Medicine (Research Article)

Background

The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize drug combinations, and point to new therapeutic biomarkers. However, the inherent complexity of transcriptional signatures, with thousands of differentially expressed genes, makes them hard to interpret, thus giving poor mechanistic insights and hampering translation to clinics.

Methods

To simplify drug signatures, we have developed a network-based methodology to identify functionally coherent gene modules. Our strategy starts with the calculation of drug-gene correlations and is followed by a pathway-oriented filtering and a network-diffusion analysis across the interactome.

Results

We apply our approach to 189 drugs tested in 671 cancer cell lines and observe a connection between gene expression levels of the modules and mechanisms of action of the drugs. Further, we characterize multiple aspects of the modules, including their functional categories, tissue-specificity, and prevalence in clinics. Finally, we prove the predictive capability of the modules and demonstrate how they can be used as gene sets in conventional enrichment analyses.

Conclusions

Network biology strategies like module detection are able to digest the outcome of large-scale pharmacogenomic initiatives, thereby contributing to their interpretability and improving the characterization of the drugs screened.

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A high-quality raspberry genome assembly is on its way

BerryWorld Plus wins KeyGene’s genome-for-free contest

KeyGene is pleased to announce that BerryWorld Plus has won the genome-for-free contest, organised on the occasion of the Genome Insights meetup on 21 March 2019 in Wageningen. The raspberry breeders at BerryWorld Plus will receive a high-quality genome assembly of a genotype of their choice.  BerryWorld Plus was selected because they are a leader in considering state-of-the-art technology to accelerate the development of premium, healthy raspberries. With this high-quality genomic resource, raspberry breeding can now fully benefit from KeyGene’s ample experience and state of the art technologies.

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Hope in the fight against Glioblastoma

New Strategies Take On the Worst Cancer—Glioblastoma

““The most common form of malignant brain cancer—called a glioblastoma—is notoriously wily and considered the deadliest human cancer. Glioblastomas charge their way into normal brain tissue diffusely and erratically, making them surgical nightmares. And they mutate at such a rapid rate that most currently available cancer treatments can't keep up with them. Even neighboring tumor cells can be genetically distinct, and therefore hard to target with a single therapy. 

Survival rates from glioblastomas enjoyed a modest bump in the 1980s when radiation became a standard part of the treatment protocol. Patients could expect to live for nearly another year after diagnosis, up from just four to six months. The introduction of the chemotherapy drug temozolomide in the 2000s increased survival another few months. But since then patient survival rates have stalled… many experts insist the key to beating glioblastoma will entail personalizing care to a patient’s individual tumor and the particular molecular signature of a cancer.

One method of testing cancer therapies, including glioblastomas, has been so-called “ex vivo” cancer models, in which malignant cells are probed in the lab. Also known as tumor “avatars,” they allow researchers to test a drug on patients’ cancer cells before introducing it into their bodies. A number of ex vivo models have been tried over the years: culturing tumor cells in Petri dishes; grafting them into animal models; even growing “organoids” (three-dimensional tumors grown on a supporting matrix). These techniques have seen varying success depending on the tumor type at hand, but none have proven especially helpful for glioblastoma.

A report on new research technology published recently in the journal Nature Biomedical Engineering may address the limitations of previous ex vivo approaches. In short, researchers have concocted a glioblastoma-on-a-chip. Chip-based models of various organs and diseases—including many cancers—have debuted in the last few years. They are constructed by lining a plastic microchip with live human cells that mimic a particular organ or disease in order to simplify, cheapen and increase the efficiency of drug testing. The Wyss Institute at Harvard University and other groups have made impressive headway in developing a number of chip-based biologic models. Chip models of the lung, the intestine, skin, bone marrow ALS—even the blood-brain barrier—have been tested.”

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The Banana Genome Browser is Online

This may not be particularly useful for most readers, but you should check it out simply because it is the Banana Genome Hub.

Check it out …

Where mutations are not tolerated: a good summary of an outstanding study

Big datasets pinpoint new regions to explore the genome for disease

A dataset of more than 100,000 individuals allows researchers to identify genetic regions that are intolerant to change and may underlie developmental disorders.

Imagine rain falling on a square of sidewalk. While the raindrops appear to land randomly, over time a patch of sidewalk somehow remains dry. The emerging pattern suggests something special about this region. This analogy is akin to a new method devised by researchers at University of Utah Health. They explored more than 100,000 healthy humans to identify regions of our genes that are intolerant to change. They believe that DNA mutations in these "constrained" regions may cause severe pediatric diseases.

"Instead of focusing on where DNA changes are, we looked for parts of genes where DNA changes are not," said Aaron Quinlan, Ph.D., associate professor of Human Genetics and Biomedical Informatics at U of U Health and associate director of the USTAR Center for Genetic Discovery. "Our model searches for exceptions to the rule of dense genetic variation in this massive dataset to reveal constrained regions of genes that are devoid of variation. We believe these regions may be lethal or cause extreme phenotypes of disease when mutated."

While this approach is conceptually simple, only recently has there been enough human genomes available to make it happen. These new, invariable stretches may reveal new disease-causing genes and can be used to help pinpoint the cause of disease in patients with developmental disorders. The results of this study are available online in the December 10 issue of the journal Nature Genetics.

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Targeting Brain Tumors with Single-Cell RNA-seq

Brain Tumors Through the Single-Cell RNA Sequencing Lens: Researcher Interview with Mario Suvà

Read Peggy Wang’s interview with Mario Suvà for the National Cancer Institute. Dr. Suvà is an assistant professor of pathology at Massachusetts General Hospital and Harvard Medical School, an Institute Member at the Broad Institute, and uses single-cell RNA sequencing as a discovery tool for understanding brain cancer. Lean more about his work and this powerful new approach to understanding this important disease…

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New advance increasing the effectiveness of immunotherapies for cancer treatment

Harnessing T-cell “stemness” could enhance cancer immunotherapy

A new study led by scientists in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI) sheds light on one way tumors may continue to grow despite the presence of cancer-killing immune cells. The findings, published March 29, 2019, in Science, suggest a way to enhance the effectiveness of immunotherapies for cancer treatment. NCI is part of the National Institutes of Health.

Dying cancer cells release the chemical potassium, which can reach high levels in some tumors. The research team reported that elevated potassium causes T cells to maintain a stem-cell-like quality, or “stemness,” that is closely tied to their ability to eliminate cancer during immunotherapy. The findings suggest that increasing T cells’ exposure to potassium—or mimicking the effects of high potassium—could make cancer immunotherapies more effective.

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BRCA Challenge creates database for fighting cancer

BRCA Exchange aggregates data on thousands of BRCA variants to inform understanding of cancer risk

A global resource that includes data on thousands of inherited variants in the BRCA1 and BRCA2 genes is available to the public. The BRCA Exchange was created through the BRCA Challenge, a long-term demonstration project initiated by the Global Alliance for Genomics and Health (GA4GH) to enhance sharing of BRCA1 andBRCA2 data. The resource, available through a website and a new smartphone appExit Disclaimer, allows clinicians to review expert classifications of variants in these major cancer predisposition genes as part of their individual assessment of complex questions related to cancer prevention, screening, and intervention for high-risk patients. 

The five-year BRCA Challenge project was funded in part by the National Cancer Institute (NCI), part of the National Institutes of Health, and through the Cancer Moonshot℠. A paper detailing the development of the BRCA Exchange was published January 8, 2019, in PLOS Genetics. READ MORE …

The world needs more Geneticists

Study Finds Shortage of Medical Geneticists

Genomics plays an increasingly important role in how we treat cancer. Genomic analyses can tell us who is at highest risk of developing cancer as well as how to treat someone’s cancer in the most precise and effective way possible. “Targeted drugs for cancer happen in 2 different ways,” says Michael Watson, PhD, founder and executive director of the American College of Medical Genetics and Genomics, Bethesda, Maryland. “Some drugs are molecularly targeted, so knowing the specific tumor genetics allows you to identify the best drug for the tumor. But there is also germline pharmacogenetics — someone can have a gene in their own DNA that alters how they will metabolize various drugs.” Understanding and interpreting these genetic differences factor into an oncologist’s decision regarding the best therapeutic approach to pursue.

But oncologists aren’t always trained in the newest genomic tests and technologies, which change rapidly as science in this area continues to advance at a dizzying pace. They often rely on collaboration with medical geneticists, who may work in the laboratories that run somatic cancer testing as well as serve patients clinically themselves, particularly by treating patients who may have a known genetic risk for cancer, such as disruptions in the BRCA1 or BRCA2 genes. Access to these specialist physicians will be a crucial component of cancer care in the future.

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Common variants in ovarian tumors

Identifying Genetic Similarities in Tumors May Shed Light on Spread of Ovarian Cancer

Researchers define the genetic characteristics of ovarian tumors-- information that could lead to new opportunities for personalized therapy and may explain why screening programs for the disease haven’t been successful.

BY KATIE KOSKO

Yale Cancer Center researchers have defined the genetic characteristics of ovarian tumors, information that could lead to new opportunities for personalized therapy, according to study findings published in Proceedings of the National Academy of Science.

The team examined 64 primary, 41 metastatic and 17 recurrent tumors from 77 patients and then matched them with normal DNA by whole-exome sequencing, which is a technique for sequencing all the protein-coding region of genes in a genome.

The researchers identified several genes, including c-MYC and PIK3CA, that are frequently mutated in primary-metastatic and chemotherapy-resistant ovarian tumors.

In addition, about half of the patients harbored a germinal (inherited) or somatic (an alteration in DNA that occurs after conception) damaging mutation in a repair gene involved in predisposition to ovarian cancer.

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CRISPR cuts 13,000 times in one cell

Genome engineers made more than 13,000 CRISPR edits in a single cell

Rewriting Life

A team at George Church’s Harvard lab wants to redesign species with large-scale DNA changes.

by Antonio Regalado (MIT Technology Review)

Since its invention, CRISPR has let scientists introduce DNA changes at specific locations in a genome. Often these precise changes are made one at a time.

Perhaps not for much longer. A team at Harvard University says it has used the technique to make 13,200 genetic alterations to a single cell, a record for the gene-editing technology.

The group, led by gene technologist George Church, wants to rewrite genomes at a far larger scale than has currently been possible, something it says could ultimately lead to the “radical redesign” of species—even humans. Large-scale gene editing of this sort has been tried before. In 2017, an Australian team led by Paul Thomas peppered the Y chromosome of mice with edits and succeeded in blasting it out of existence. That strategy is being eyed as a potential treatment for Down syndrome, a genetic disorder caused by an extra chromosome.

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Promise of cheap and fast CRISPR-based diagnostics

Handheld CRISPR device to enable faster diagnosis of genetic disease

A team of researchers in the US has developed a handheld device that diagnoses genetic diseases at point-of-care. Called CRISPR-Chip, the device combines a deactivated clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 protein with electronic transistors to identify genetic mutations in DNA samples without the need for amplification or replication of the DNA segment using the polymerase chain reaction (PCR).

Avoiding the time-consuming PCR step is expected to enable the use of CRISPR-Chip for genetic testing in a doctor’s office or field work setting, rather than sending samples to a laboratory.

The method can also be used to assess the accuracy of gene-editing techniques.

The researchers included scientists from the University of California, Berkeley (UC Berkeley) and the Keck Graduate Institute (KGI) of The Claremont Colleges.

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And watch the promo video HERE …

NGS-heavy investigation of Neuropsychiatric Disease

Illumina, University of Copenhagen to Study Genetic Evolution of Neuropsychiatric Disease

NEW YORK (GenomeWeb) – Illumina said today that it is working with the Lundbeck Foundation GeoGenetics Centre at the University of Copenhagen to study how infectious pathogens influenced the evolutionary history of certain mental and neurological disorders.

An international, multi-disciplinary team including specialists in ancient genomics, neurogenetics, population genetics, archaeology, linguistics, and brain health will create two subsets of genomics data: one consisting of 5,000 ancient human genomes, and another consisting of ancient pathogen DNA associated with human diseases. Both datasets will be made publicly available.

The research team will use Illumina's NovaSeq 6000 system with S4 flow cells to sequence up to 20 billion ancient DNA fragments every two days, Illumina said.

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Functional genomics of Diabetes SNPs

Risk variants disrupting enhancers of TH1 and TREG cells in type 1 diabetes

Peng Gao, Yasin Uzun, Bing He, Sarah E. Salamati, Julie K. M. Coffey, Eva Tsalikian, & Kai Tan

PNAS (Research Article)

Functional interpretation of noncoding genetic variants identified by genome-wide association studies is a major challenge in human genetics and gene regulation. We generated epigenomics data using primary cells from type 1 diabetes patients. Using these data, we identified and validated multiple novel risk variants for this disease. In addition, our ranked list of candidate risk SNPs represents the most comprehensive annotation based on T1D-specific T-cell data. Because many autoimmune diseases share some genetic underpinnings, our dataset may be used to understand causal noncoding mutations in related autoimmune diseases.

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Mushroom multicellularity illuminated by gene expression analysis

Transcriptomic atlas of mushroom development reveals conserved genes behind complex multicellularity in fungi

Krisztina Krizsán, Éva Almási, Zsolt Merényi, Neha Sahu, Máté Virágh, Tamás Kószó, Stephen Mondo, Brigitta Kiss, Balázs Bálint, Ursula Kües, Kerrie Barry, Judit Cseklye, Botond Hegedüs, Bernard Henrissat, Jenifer Johnson, Anna Lipzen, Robin A. Ohm, István Nagy, Jasmyn Pangilinan, Juying Yan, Yi Xiong, Igor V. Grigoriev, David S. Hibbett, and László G. Nagy

PNAS (Research Article)

Complex multicellularity is a major evolutionary innovation in the history of life. Mushroom-forming fungi (Agaricomycetes) represent one of the most diverse complex multicellular clades, yet the genetic bases and evolutionary origins of their multicellular development are hardly known. We used readouts of gene expression in six species to find genes with a dynamic expression during the development of fruiting bodies. Comparisons across species and to 200 fungal genomes identified the gene families with a conserved expression dynamics in multicellular fruiting bodies and their ancient evolutionary origins. These data outline the major multicellularity-related and developmental processes of mushrooms, including the role of transcriptional reprogramming, gene coexpression networks, and alternative splicing, and reveal significant convergence with other complex multicellular lineages.

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Paternal mitochondrial contributions may be just as rare as we always thought

Extraordinary claims require extraordinary evidence in the case of asserted mtDNA biparental inheritance

Antonio Salas, Sebastian Schoenherr, Hans Jurgen Bandelt, View ORCID ProfileAlberto Gomez-Carballa, & Hansi Weissensteiner

bioRxiv (Research Article)

Abstract—A breakthrough article published in PNAS by Luo et al. (2018) challenges a central dogma in biology which states that the mitochondrial DNA (mtDNA) is inherited exclusively from the mother. By sequencing the mitogenomes of several members of three independent families, the authors inferred an unprecedented pattern of biparental inheritance that requires the participation of an autosomal nuclear factor in the molecular process. However, a comprehensive analysis of their data reveals a number of issues that must be carefully addressed before challenging the current paradigm. Unfortunately, the methods section lacks any description of sample management, validation of their results in independent laboratories was deficient, and the reported findings have been observed at a frequency at complete variance with established evidence. Moreover, the remarkably high (and unusually homogeneous) levels of heteroplasmy reported can be readily detected using classical techniques for DNA sequencing. By reassessing the raw sequencing data with an alternative computational pipeline, we report strong correlation to the NextGENe results provided by the authors on a per sample base. However, the sequencing replicates from the same donors show aberrations in the variants detected that need further investigation to exclude contributions from other sources or methodological artifacts. Finally, applying the principle of reductio ad absurdum, we demonstrate that the nuclear factor invoked by the authors would need to be extraordinarily complex and precise in order to preclude linear accumulation of mtDNA lineages across generations. We discuss alternate scenarios that explain findings of the same nature as reported by Luo et al., in the context of in-vitro fertilization and therapeutic mtDNA replacement ooplasmic transplantation.

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Good review of major microbial genome web portals

A Comparison of Microbial Genome Web Portals

Peter D. Karp, Natalia Ivanova, Markus Krummenacker, Nikos Kyrpides, Mario Latendresse, Peter Midford, Wai Kit Ong, Suzanne Paley, & Rekha Seshadri

Frontiers in Microbiology (Research Article)

Microbial genome web portals have a broad range of capabilities that address a number of information-finding and analysis needs for scientists. This article compares the capabilities of the major microbial genome web portals to aid researchers in determining which portal(s) are best suited to their needs. We assessed both the bioinformatics tools and the data content of BioCyc, KEGG, Ensembl Bacteria, KBase, IMG, and PATRIC. For each portal, our assessment compared and tallied the available capabilities. The strengths of BioCyc include its genomic and metabolic tools, multi-search capabilities, table-based analysis tools, regulatory network tools and data, omics data analysis tools, breadth of data content, and large amount of curated data. The strengths of KEGG include its genomic and metabolic tools. The strengths of Ensembl Bacteria include its genomic tools and large number of genomes. The strengths of KBase include its genomic tools and metabolic models. The strengths of IMG include its genomic tools, multi-search capabilities, large number of genomes, table-based analysis tools, and breadth of data content. The strengths of PATRIC include its large number of genomes, table-based analysis tools, metabolic models, and breadth of data content.

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Is CRISPR a National Security Threat?

National Security Implications of Gene Editing

“CRISPR-Cas9 is here and now, he pointed out. “Gene editing has a number of near term and longer term ramifications that … have implications for national security, intelligence and defense,” he said.

If the research goes clandestine, the technology could be used to modify various physiological functions in humans both before birth and perhaps key operational points or optimized points after birth, he said.

With genomic knowledge of weaknesses and susceptibilities to certain diseases, populations could be targeted in order to cause instability in societies.”

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FDA slows down CRISPR

Gene Editing Promise Stalled at FDA

The FDA is currently claiming regulatory authority over gene-edited livestock based on a decades-old administrative decision related to older transgenic biotechnology, where a foreign gene is inserted into an animal’s genome. Gene editing is making simple changes or deletions within an animal’s native genome.

NPPC is pushing for regulatory oversight by the USDA. The USDA has already established the right regulatory framework by adopting a risk-based approach to reviewing potential genetic changes in plants. It easily could adapt that approach for livestock and regulate gene-edited animals under the Animal Health Protection Act. 

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One-stop shopping for your gene-editing needs

Brand new CRISPR/Cas9 Platform: One-stop Gene Knockout/knockin Service for Precise Gene Editing

New York, Mar 25th, 2019 - Creative Biogene, as a leading provider focuses on offering professional products and services to accelerate gene research, recently announces the brand new CRISPR/Cas9 Platform, which provides comprehensive gene editing services and products. With talented and experienced scientists, Creative Biogene can offer more reliable and professional service to support gene editing projects.

Read the whole press release here …