Specificity helps with cancer outcome prediction, therapies

Acute Erythroleukemia Genomic Subtypes Help Predict Outcomes, Suggest Therapies

NEW YORK (GenomeWeb) – A new genomic analysis of acute erythroid leukemia (AEL) has uncovered recurrent tumor gene mutation and expression profiles, including genomic features that appear to coincide with outcomes for patients affected by the rare, difficult-to-treat form of acute myeloid leukemia (AML).

"These results mark a new era in understanding and treatment of AEL, an aggressive leukemia that has been plagued by diagnostic controversy and poor outcomes," senior author Charles Mullighan, a pathology researcher and co-leader of the St. Jude Children's Research Hospital's hematological malignancies program, said in a statement. 

As they reported online today in Nature Genetics, Mullighan and colleagues performed whole-genome, exome, targeted, and transcriptome sequencing on samples from 159 pediatric or adult AEL patients treated at sites around the world, comparing the somatic mutations and gene expression patterns they found to those in samples from more than 1,900 individuals with non-AEL conditions — from other forms of AML to myelodysplastic syndrome.

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Origins and Evolution of Mental Health Genetic Variants

Illumina and the Lundbeck Foundation GeoGenetics Centre Collaborate to Generate One of the Largest Ancient Genome Datasets to Decode the Genetic Origins and Evolution of Mental Health Issues

SAN DIEGO--(BUSINESS WIRE)--Illumina (NASDAQ:ILMN) and the Lundbeck Foundation GeoGenetics Centre at the University of Copenhagen, Denmark partner to explore the relationship between the evolutionary history of select mental and neurological disorders and infectious pathogens. One of the first projects of its kind worldwide, the endeavor aims to acquire new knowledge in terms of the medical and biological understanding of special factors underlying the development of human neuropsychiatric diseases through the ages. Ultimately, the project may provide a new approach to the development of medicines and other therapeutic treatments for mental and neurological conditions.

Where do brain disorders come from? In an effort to shed light on the role of microbes in the pathogenesis of neuropsychiatric illnesses, such as Alzheimer’s disease and schizophrenia, Professor Eske Willerslev and his team will build one of the largest genomic datasets of its kind, by complete DNA mapping of thousands of ancient Eurasian human remains. The data will be obtained from bones and teeth, the oldest remains dating back 10,000 years.

The international, multi-disciplinary team of scientists, which includes specialists in ancient genomics, neuro-genetics, population genetics, archaeology, linguistics, and experts in brain health, among others, will focus on creating two unique subsets of genomic data. The first panel is a 5,000 ancient human genomes panel. The second panel will consist of ancient pathogen DNA that is associated with human diseases. Both panels, which will be made publicly available, will together advance our understanding of the evolution of disease variance and its interaction with the human genome and pathogen pressure. The project will generate and analyze one of the largest sets of ancient human and pathogen genome panels ever created.

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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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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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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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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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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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Gene interactions are a potential key to personalized medicine

Gene interactions identified as personalized medicine’s missing link

“The ability to affordably sequence genomes has prompted numerous predictions about the rise of personalised medicine, however so far this has failed to come to pass. But in research published today, scientists have identified gene interactions as the key barrier to this medical revolution taking off.

Personalised medicine, where individuals are prescribed pharmaceuticals based on their own genetic makeup, has been raised as a possibility since the Human Genome Project was completed in 2003. It was thought that as more people had their genomes sequenced scientists would unearth genes responsible for predispositions to specific diseases, which would enable medication to be tailored to individuals.

However, while tens of thousands of people around the world have now had their genomes sequenced, it has not produced the clear genetic interactions initially predicted. And the reason for this is gene interactions: how different genes impact each other in the results and responses they produce.”

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Liquid Biopsies help with Lung Cancer Diagnostics

Illumina-Sponsored Study Finds Liquid Biopsy Complements Tissue-Based Genotyping in Lung Cancer

NEW YORK (GenomeWeb) – The Illumina-sponsored Actionable Genome Consortium reported this week that cell-free DNA-based tumor genotyping for non-small cell lung cancer patients is concordant with tissue tumor-based genotyping most of the time and could be particularly useful in cases where acquiring a tissue biopsy is not feasible.

The group, which includes researchers from Memorial Sloan Kettering Cancer Center, Dan-Farber Cancer Center, MD Anderson Cancer Center, Grail, and Illumina, published its study this week in Annals of Oncology.

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Abbot gets clearance for Alinity Molecular Diagnostics

Abbott Receives CE Mark for Alinity Molecular Diagnostics System, Assays

“NEW YORK (GenomeWeb) – Abbott announced today that it has received CE marking for its Alinity molecular diagnostics system and assays, which are now available in countries that recognize the designation.

The firm said that its molecular system will help clinicians who are struggling to keep up with demand for infectious disease testing.

The MDx platform offers a number of initial assays, including virology testing for human immunodeficiency virus type 1, hepatitis B virus, and hepatitis C virus; sexual health-related testing for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium, or a CT/NG/TV/MG panel; and high-risk human papillomavirus testing.“

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microRNA and cancer therapy

Scientists home in on microRNA processing for novel cancer therapies

“More than a decade of research on the mda-7/IL-24 gene has shown that it helps to suppress a majority of cancer types, and now scientists are focusing on how the gene drives this process by influencing microRNAs. Published this week in the journal Proceedings of the National Academy of Sciences, the findings could potentially have implications beyond cancer for a variety of cardiovascular and neurodegenerative diseases caused by the same microRNA-driven processes.”

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Great story about the application of evolutionary principles to fight cancer

A CLEVER NEW STRATEGY FOR TREATING CANCER, THANKS TO DARWIN

ROXANNE KHAMSI (WIRED)

“Even if cancer therapies kill most of the cells they target, a small subset can survive, largely thanks to genetic changes that render them resistant. In advanced-stage cancer, it’s generally a matter of when, not if, the pugnacious surviving cells will become an unstoppable force. Gatenby thought this deadly outcome might be prevented. His idea was to expose a tumor to medication intermittently, rather than in a constant assault, thereby reducing the pressure on its cells to evolve resistance.“

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Microbiome may predict preterm births

Spontaneous Preterm Birth Clues Identified in Cervicovaginal Microbiome

NEW YORK (GenomeWeb) – A University of Pennsylvania and University of Maryland team has identified microbial community features and host immune features in the cervix and vagina that appear to coincide with spontaneous preterm birth risk.

Based on targeted sequence data and enzyme-linked immunosorbent assay (ELISA) data that provided a look at cervicovaginal microbial community members and immune protein levels, respectively, in hundreds of women with or without preterm birth, the researchers pinned down half a dozen microbial community types and identified seven taxa with apparent ties to spontaneous preterm birth.

Together with host immune protein levels, the microbiome data provided clues to preterm birth biology, the authors noted in its study, out in Nature Communications today. Moreover, they suggested that it may eventually be possible to develop therapeutic approaches that tap into microbiome or immune features associated with the condition.

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Genome vs Exome sequencing in reference to cancer

Q&A With Mark B. Gerstein, PhD, on Diagnostic Genomic vs Exomic Sequencing

“Mark Gerstein, PhD, is Albert L Williams Professor of Biomedical Informatics and professor of molecular biophysics and biochemistry, and of computer science at the Yale School of Medicine in New Haven, Connecticut. He is also codirector of the Yale Program in Computational Biology & Bioinformatics.

Dr Gerstein spoke with Cancer Therapy Advisor about the diagnostic use of whole-genome compared with whole-exome next-generation sequencing to search for gene mutations that are thought to contribute to the risk of cancer and other diseases.1-3“

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