Applying genomic meta-analyses to understand disease

Wanted: More Data, the Dirtier the Better

by Esther Landhuis, Quanta Magazine 

“To distill a clear message from growing piles of unruly genomics data, researchers often turn to meta-analysis — a tried-and-true statistical procedure for combining data from multiple studies. But the studies that a meta-analysis might mine for answers can diverge endlessly. Some enroll only men, others only children. Some are done in one country, others across a region like Europe. Some focus on milder forms of a disease, others on more advanced cases. Even if statistical methods can compensate for these kinds of variations, studies rarely use the same protocols and instruments to collect the data, or the same software to analyze it. Researchers performing meta-analyses go to untold lengths trying to clean up the hodgepodge of data to control for these confounding factors.”

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Strata Oncology using NGS for advanced cancer

Strata Oncology Launches Expanded StrataNGS for Patients with Advanced Cancer

ANN ARBOR, Mich., March 19, 2019 /PRNewswire/ -- Strata OncologyTM, a leading precision oncology company, today announced the launch of version 3.0 of StrataNGSTM, its pan-cancer assay for solid tumors. The updated 500-gene assay utilizes DNA and RNA from tumor samples to detect all clinically actionable biomarkers — including microsatellite instability (MSI), tumor mutational burden (TMB), and PD-L1 — recommended by leading guidelines, in a single test. Test results are provided in a streamlined report that facilitates rapid, confident interpretation and identification of potential treatment options and clinical trials.

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Somatic histone mutations occur in >4% of diverse tumour types and in crucial regions of histone proteins

The expanding landscape of ‘oncohistone’ mutations in human cancers

Benjamin A. Nacev, Lijuan Feng, John D. Bagert, Agata E. Lemiesz, JianJiong Gao, Alexey A. Soshnev, Ritika Kundra, Nikolaus Schultz, Tom W. Muir, & C. David Allis

Nature (Research Article)

Abstract

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical ‘oncohistone’ mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory ‘acidic patch’ of histones H2A and H2B, or are predicted to disrupt the H2B–H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.

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Immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion

Neoantigen-directed immune escape in lung cancer evolution

Rachel Rosenthal, Elizabeth Larose Cadieux, Roberto Salgado, Maise Al Bakir, David A. Moore, Crispin T. Hiley, Tom Lund, Miljana Tanić, James L. Reading, Kroopa Joshi, Jake Y. Henry, Ehsan Ghorani, Gareth A. Wilson, Nicolai J. Birkbak, Mariam Jamal-Hanjani, Selvaraju Veeriah, Zoltan Szallasi, Sherene Loi, Matthew D. Hellmann, Andrew Feber, Benny Chain, Javier Herrero, Sergio A. Quezada, Jonas Demeulemeester, Peter Van Loo, Stephan Beck, Nicholas McGranahan, Charles Swanton & The TRACERx consortium

Nature (Research Article)

Abstract

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.

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New CRISPR Diagnostics Firm

Broad, Wyss Institute Researchers Launch CRISPR Dx Firm Sherlock Biosciences

NEW YORK (GenomeWeb) – Engineering biology startup Sherlock Biosciences announced today that it has launched with initial financing of $35 million and licenses to foundational CRISPR and synthetic biology technology from the Broad Institute and Harvard's Office of Technology Development…

Sherlock will use engineering biology tools, including CRISPR and synthetic biology, to develop a new generation of molecular diagnostics that can rapidly deliver accurate results for a vast range of needs in virtually any setting and at low cost, the company said.

The financing includes a $17.5 million non-dilutive grant and an investment from the Open Philanthropy Project, as well as funds from additional undisclosed investors.

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Combination therapy for cancer therapy

Functional Genomics Approach To Identify New Combination Therapies For Cancer Treatment

“In our recent publication in Science Advances, we describe the use of an in vivo-based functional genomics screen to identify genes whose inhibition potentiates a response to anti-PD-1 immunotherapy. Specifically, we define a novel mechanism whereby targeting the collagen receptor, discoidin domain receptor 2 (DDR2), elicits a significantly enhanced response to immune checkpoint blockade with PD-1 inhibitors. Of specific note is the observation this combination is robust across multiple tumor models including melanoma, sarcoma, breast, bladder and colon cancer indicating that DDR2 expression is an important and broadly used mechanism by cancer cells to escape checkpoint blockade therapy“

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Setback for myeloma therapy Venclexta

Roche, AbbVie forced to slam brakes on myeloma studies of star drug Venclexta after researchers flag higher risk of death

“Two heavyweight pharma players today said they’ve been forced to stop recruiting patients for all ongoing studies involving Venclexta (venetoclax) for multiple myeloma. Roche and AbbVie say the drug arm has been linked to a higher rate of death than the control group, prompting the FDA to issue a partial hold ordering them to suspend any new patient recruitment for the blood cancer trials until they can sort out what is happening.“

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Distinguishing amplification artifacts from biologically derived somatic mutations in single-cell sequencing data

Linked-read analysis identifies mutations in single-cell DNA-sequencing data

Craig L. Bohrson, Alison R. Barton, Michael A. Lodato, Rachel E. Rodin, Lovelace J. Luquette, Vinay V. Viswanadham, Doga C. Gulhan, Isidro Cortés-Ciriano, Maxwell A. Sherman, Minseok Kwon,  Michael E. Coulter, Alon Galor, Christopher A. Walsh & Peter J. Park

Nature Genetics (Research Article)

Whole-genome sequencing of DNA from single cells has the potential to reshape our understanding of mutational heterogeneity in normal and diseased tissues. However, a major difficulty is distinguishing amplification artifacts from biologically derived somatic mutations. Here, we describe linked-read analysis (LiRA), a method that accurately identifies somatic single-nucleotide variants (sSNVs) by using read-level phasing with nearby germline heterozygous polymorphisms, thereby enabling the characterization of mutational signatures and estimation of somatic mutation rates in single cells.

Space-Herpes, just what the world needs now

Space Travel Causes Viruses To 'Resurrect' Inside Astronauts

“It seems space travel has a very unexpected side effect – herpes.

NASA scientists discovered that dormant herpes viruses lurking inside more than half of astronauts aboard the International Space Station (ISS) and Space Shuttle "resurrected" after time spent in space. The results have been published in Frontiers in Microbiology.

Fortunately, very few went on to develop symptoms. However, the study authors warn, virus reactivation rates appear to increase as time goes on – an observation that could pose a major challenge to missions to Mars and further into deep space. “

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ALS Awards for target discovery and therapy development

TARGET ALS AWARDS SIX INNOVATIVE RESEARCH TEAMS WITH ADDITIONAL TARGET DISCOVERY FUNDS

New York City – Target ALS is pleased to announce that it has awarded target discovery and development funding to six research consortia that are working toward the development of ground-breaking therapeutic approaches to treating ALS.

In 2016 – 2017, Target ALS provided multi-year grants to a number of unique research consortia to encourage ALS research ideation and active involvement from both the pharma/biotech industry as well as the most talented new investigators in the field. In a historic first, either a pharma/biotech researcher or a new investigator led each team. These teams were awarded funding for a range of novel projects from early stage target discovery to the development of new therapeutic approaches.

A wave of creative thinking and collaboration followed. Indeed, many projects have led to the development of new, ground-breaking therapeutic approaches while others are advancing our understanding of pathophysiology of ALS.  In response to this growing momentum, the Target ALS Independent Review Committee (IRC) granted six of the most promising collaborative projects an additional year of funding.

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Exome sequencing reveals molecular features of the pediatric variants of follicular lymphoma

Molecular Characterization of Pediatric Follicular Lymphoma

“Pediatric follicular lymphomas involve interactions in MAPK and G-protein protein receptor signaling pathways, according to results of a new study. This study, published online in Haematologica, identified a number of novel mutations and signaling pathways associated with pediatric follicular lymphomas.

Classic follicular lymphoma, an indolent B-cell lymphoma, is very rare in children, whereas pediatric-type nodal follicular lymphoma (PTNFL) and primary follicular lymphoma of the testis (PFLT) occur more frequently in this population compared with adults. While the molecular landscape of classic follicular lymphoma has been more thoroughly studied, comparatively little is known about the molecular features of the pediatric variants of follicular lymphoma.”

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Personalis introduces new universal cancer immunogenomics platform, ImmunoID NeXT™

Personalis, Inc. to Present at ICI-IO Combinations Summit 2019

MENLO PARK, Calif.--(BUSINESS WIRE)--Personalis Inc., a leader in advanced genomics for precision oncology, today announced that they are scheduled to present at ICI-IO Combinations Summit 2019 in Boston on Wednesday, March 20, 2019 at 2:30 PM, EDT.

The presentation, entitled “Challenges and Solutions: Enabling multidimensional tumor immunogenomics for advancing biomarker discovery,” will introduce Personalis’ new universal cancer immunogenomics platform, ImmunoID NeXT™. In addition to an overview, the presentation will also highlight how this platform can be used to overcome the challenges facing immuno-oncology translational and clinical researchers. By deriving new insights through our industry leading NGS analysis platform, ImmunoID NeXT provides solutions to enable the development of safer, more effective precision oncology therapeutics and combinations.

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Improve clinical care for Ovarian cancer using multiple genome sequences

Simultaneous Sequencing of Paired Germline and Somatic Specimens Enhanced Clinical Care in Ovarian Cancer

In a small sample of women with ovarian cancer for whom simultaneous next-generation DNA sequencing was performed on paired germline and tumor specimens, test results influenced clinical decision-making for nearly 25% of patients. This study was presented at the Society of Gynecologic Oncology (SGO)’s 50th Annual Meeting on Women’s Cancer.

Targeted sequencing using the BROCA test, a gene panel designed for patients with a suspected hereditary cancer predisposition, was performed between July 2017 and July 2018 on paired peripheral blood (germline) and ovarian cancer tumor specimens (somatic) for 36 women with newly diagnosed ovarian cancer and 7 women with recurrent disease. Tumor specimens were obtained from surgical specimens, biopsy, or cytology in 72.1%, 25.6%, and 2.3% of cases, respectively.

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Chinese gene editing therapies are developing

China’s race to test ‘mutation-free’ gene-editing technology on cancer patients

BEIJING — China could be just over a year away from clinical trials of a new gene-editing therapy with an unprecedented high level of safety, according to a team of Chinese scientists involved in the research programme.

The scientists said the research, based on groundbreaking work published in the journal Science earlier this month, could help save the lives of many patients battling deadly diseases including cancer.

The existing genome-editing method works like a shotgun, breaking up a large numbers of genome strands and sometimes missing its intended target, causing unnecessary damage to cells.

The new tool under development in China targets and swaps individual “letters” in the DNA with extreme precision, avoiding cuts to the strands and significantly reducing the risk of unexpected mutations.

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Linking development and disease

Putting developmental diseases on the map

Most people use a map to understand the physical world around them. Now, genetic researchers have a map of their own to understand how developmental diseases work at the genetic level.  

In a recent study, UW graduate student Junyue Cao and Dr. Malte Spielmann from the Max Planck Institute profiled approximately 2 million cells from 61 mice embryos between 9 and 14 days old, resulting in a digital representation of how each cell type develops and its gene expression changes.

When a gene is between 9 and 14 days old, most cells that underlie major developmental diseases can be studied, according to Cao. With further application, Cao believes his study can be used as a reference to help other researchers understand how genetic diseases like autism, breast cancer, and parkinson’s disease develop in humans.

“If we can use this to comprehensively categorize the different cell states and their composition in disease or [the] aging process, then potentially, we can fully understand how they are generated in development and why there are different diseases and aging,” Cao said.

Cao and his team collected the largest single-cell dataset, Mouse Organogenesis Cell Atlas (MOCA), which consists of distinctions between individual cells. This dataset has recently been published and in this publication, the team created a genetic map of organ development.

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T-cell modification with CRISPR-Cpf1

Researchers engineer immune cells to fight cancer

Deep in the cells of the human immune system, DNA is constantly being replicated, transcribed and even mutated — but rarely does it change dramatically. Like every other living organism, humans and their genes developed from millions of years of evolutionary pruning.

But to Yale microbiologists, altering the entire genomes of T-cells — the body’s main offensive weapon against diseases such as cancer — is as simple as putting together a Lego set.

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Cancer cells switch to fast food

Researchers find epigenetic loss that changes how cells obtain energy from cancer

It has been known for decades that cancer cells have an altered metabolism, and it is seen in several biochemical pathways and in particular, in the way they get energy for their survival.

If healthy cells use the mitochondrial respiratory chain, tumors use aerobic glycolysis, a process that allows them to take energy quickly but depending on glucose. This phenomenon - known as the Warburg effect - is caused by several changes that take place during cell transformation.

Now, a new article describes an epigenetic injury found in human tumours which creates this altered path to take energy from the cancer. The study, published in Journal of Clinical Investigation Insight, is a new research carried out by the group led by Manel Esteller, professor of Genetics of the Faculty of Medicine and Health Sciences of the University of Barcelona (UB), ICREA researcher, coordinator of the Cancer Epigenetics and Biology Program at IDIBELL, and director of the Josep Carreras Institute.

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Population genomic and evolutionary modeling analyses find QTL relevant to global health (BMC Genomics)

Population genomic and evolutionary modeling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

Stephen R. Doyle†Email authorView ORCID ID profile, Christopher J. R. Illingworth†, Roz Laing, David J. Bartley, Elizabeth Redman, Axel Martinelli, Nancy Holroyd, Alison A. Morrison, Andrew Rezansoff, Alan Tracey, Eileen Devaney, Matthew Berriman, Neil Sargison, James A. Cotton,and John S. Gilleard

BMC Genomics (Research Article)

Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved.

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Goals for improving cancer treatment in children

Ushering in the next generation of precision trials for pediatric cancer

Steven G. DuBois, Laura B. Corson, Kimberly Stegmaier, and Katherine A. Janeway

Science (Review article)

Abstract—Cancer treatment decisions are increasingly based on the genomic profile of the patient’s tumor, a strategy called “precision oncology.” Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.

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EGFR is required for regeneration

Study uncovers genes that control process of whole-body regeneration

When it comes to regeneration, some animals are capable of amazing feats. If you cut off a salamander’s leg, it will grow back. When threatened, some geckos drop their tails to distract their predator, only to regrow them later.

Other animals take the process even further. Planarian worms, jellyfish, and sea anemones can actually regenerate their bodies after being cut in half.

Led by Assistant Professor of Organismic and Evolutionary Biology Mansi Srivastava, a team of researchers is shedding new light on how animals pull off the feat, along the way uncovering a number of DNA switches that appear to control genes for whole-body regeneration. The study is described in a March 15 paper in Science.

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