Category Archives: Genome

Irene Blat, a senior director at Genuity Science, discusses how the intersection of data, engineering, genetics and more will be crucial to the future of healthcare.

The future of healthcare will need the right mix of skills and cross-disciplinary collaboration. Irene Blat, senior director of data products and analytics at Genuity Science, is particularly familiar with that. Throughout her career, she has worked with clinicians, geneticists, software engineers and more to drive progress in genomics.

Here, she discusses her passion for problem solving and why mentors have been crucial to her journey.

One of the biggest surprises has been realising the value of collaborative teamwork in tackling these different spaces IRENE BLAT

I have had a passion for life sciences since my early years. I loved experimenting in science class and being able to test, learn and improve. What really solidified my path into life sciences was an undergraduate experience I had working in an immunology lab. We would modify genetic sequences to better understand how immune cells were able to adapt their responses depending on the invaders they were fighting.

The way we measured the response was by looking at thousands of cells with a laser to see how the markers they expressed on their surface had changed based on the genetic changes to their sequence. This generated a lot of data that we then had to analyse.

One of the best aspects of experimenting was recording the data and then looking for and identifying patterns. The thrill of gaining insights into one more piece of the puzzle was what really drove me to continue my career in exploring genetics to better understand and potentially treat diseases.

My interest in genetics was what led me to my first job working at the Broad Institute in Cambridge, Massachusetts. At the time, it was an early data revolution in the life sciences where the human genome had just been sequenced a few years earlier and we were learning a wealth of information about healthy and disease states.

My role was to generate thousands of gene expression profiles of cells that had been treated with different drugs and then look for patterns in the cells responses to the drugs. We were looking for ways to link these genetic patterns to diseases to match them to a potential therapeutic compound. Here, I learned that the human cell is a very complex system and requires combing through lots of data to better understand how all the subtle changes in a cell work together to produce altered states.

Working with these large datasets put me on a path to look for opportunities where I could leverage the power of data to better understand complex biological systems.

For me, my career path has not been linear. I have taken risks and explored new opportunities to expand my experience where I could be impactful. Since joining Genuity, I have been fortunate to contribute to the R&D, product management and commercial aspects of the business with, at times, steep learning curves that have taken me out of my comfort zone.

What I have learned about myself is that I enjoy the challenge of learning something new and being able to leverage previous experiences to bring an original perspective to the company needs. While the subject matter might change, the concepts and learnings are still applicable across the organisation.

One of the biggest surprises has been realising the value of collaborative teamwork in tackling these different spaces. In graduate school, my work was focused on a very specific topic and in my career Ive been hired into very specific roles. But what has enabled me to move between different fields has really been collaborating and learning from other people.

Ive learned not to be afraid to ask questions and really take the opportunity to learn from others in the field. Then I have to take time to synthesise all these learnings to put forward a hypothesis that I can share with my colleagues for feedback and input. Basically, its a team effort and the more diverse the team the better the ideas.

I have had the good fortune of having many outstanding mentors throughout my career who see potential in me through my work ethic and dedication. I am grateful for having mentors who have encouraged me to take on bigger risks by giving me their vote of confidence. In particular, I have had strong female mentors who are excellent leaders and have leaned in throughout their careers.

Being able to learn from their experiences and listening to their guidance has been valuable in helping me decide where to go next in my career. The best mentors are the ones that give the gift of their time and my career has been shaped by the time of several great mentors in my life.

I really enjoy problem solving. In this role, I spend a lot of time thinking of creative ways to solve new problems. I also enjoy working through these problems in collaboration with our talented team. I have a deep appreciation for the value of sharing ideas and approaches with others from different backgrounds.

At Genuity Science, I have worked in teams with clinicians, geneticists, software engineers, bioinformaticians and data scientists who each bring their own expertise to the table. These types of cross-functional teams enable problem solving in a way that would not be possible if we all worked in silos.

What is even more exciting is that our team grows when we engage in collaborations with our customers. Our customers bring strong experiences in drug development that nicely complement our internal expertise in genomics discovery to help advance new therapies to the clinic. There are so many people to learn from both internal and external to our organisation and thats what makes my job exciting Im always learning!

I am a passionate learner. As I look back on how I landed at Genuity Science, the common thread is that every role I have had provided me the opportunity to learn. In this role, we are working at the cutting edge of how to analyse large clinical and genomic datasets. We have to iterate and adapt our analytical tools to solve increasingly complex biological problems.

My flexibility in adapting with the needs of the problem has also helped me in looking at problems in different ways. Since my early days in the lab, I recognised I had a lot of perseverance and grit. Sometimes you have to try multiple approaches before you find a path forward, but it is incredibly rewarding when you gain a new insight into a problem that was unsolved. Thats what keeps me motivated to continue trying.

At Genuity Science, the leadership team has encouraged me to explore the commercial boundaries which are well outside my original scientific training. Being able to inform commercial engagements with my deep scientific understanding has significantly broadened my skillset and resulted in exciting partnerships for the company.

Genuity has supported me in attending trainings and conferences where I was able to learn more about the commercial space as well as gain the opportunity to observe others in action. This has been a great development opportunity for me.

If you enjoy a challenge and like to learn, then a career in data analytics will not disappoint you. You have to be willing to take risks and fail but also learn from the failures and apply the lessons to the next challenge. The greatest reward is seeing how this work can ultimately have an impact on patient lives.

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The role of a data-analytics director in genomic discovery - Siliconrepublic.com

This article was originally published here

Sci Rep. 2020 Nov 20;10(1):20243. doi: 10.1038/s41598-020-76791-y.

ABSTRACT

Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and smoking status. TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR. EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance. DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.

PMID:33219256 | DOI:10.1038/s41598-020-76791-y

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Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib - DocWire...

Dublin, Nov. 19, 2020 (GLOBE NEWSWIRE) -- The "Genomic Cancer Panel and Profiling Markets by Cancer and Germline/Somatic Type with Screening Potential Market Size, Customized Forecasting/Analysis, and Executive and Consultant Guides 2021-2025" report has been added to ResearchAndMarkets.com's offering.

This report provides data that analysts and planners can use. Hundreds of pages of information including a complete list of Current 2020 United States Medicare Fee Payment Schedules to help understand test pricing in detail.

Forecast demand for new testing regimes or technologies. Make research investment decisions. Existing laboratories and hospitals can use the information directly to forecast and plan for clinical facilities growth.

Cancer Gene Panels and Genomic Profiling are quickly changing the diagnosis and treatment of cancers. The market is moving out of a specialized niche and going mainstream as Oncologists begin routinely using information on the hundreds of genes related to cancer. The market is exploding as physicians use all the information they can get in the battle against cancer. And there is a lot of information to be had. But the COVID-19 Pandemic has impacted the market.

Comprehensive panels, genomic profiling, high-risk breast cancer panels. Learn all about how players are jockeying for position in a market that is being created from scratch. And some players are already taking the lead. It is a dynamic market situation with enormous opportunity where the right diagnostic with the right support can command premium pricing. And the science is developing at the same time creating new opportunities with regularity. And the cost of sequencing continues to fall.

The report includes detailed breakouts for 18 Countries and 4 Regions.

Key Topics Covered:

Cancer Panel Market - Strategic Situation Analysis & COVID Update

1. Introduction and Market Definition 1.1 What are Cancer Gene Panels and Profiling? 1.2 The Sequencing Revolution 1.3 Market Definition 1.4 Methodology 1.5 A Spending Perspective on Clinical Laboratory Testing 1.5.1 An Historical Look at Clinical Testing

2. Market Overview 2.1 Players in a Dynamic Market 2.1.1 Academic Research Lab 2.1.2 Diagnostic Test Developer2.1.3 Instrumentation Supplier 2.1.4 Distributor and Reagent Supplier 2.1.5 Independent Testing Lab2.1.6 Public National/regional lab 2.1.7 Hospital lab 2.1.8 Physician Office Labs 2.1.9 Audit Body 2.1.10 Certification Body2.2 Oncogenomics2.2.1 Carcinogenesis2.2.2 Chromosomes, Genes and Epigenetics 2.2.2.1 Chromosomes 2.2.2.2 Genes 2.2.2.3 Epigenetics 2.2.3 Cancer Genes 2.2.4 Germline vs Somatic 2.2.5 Gene Panels, Single Gene Assays and Multiplexing 2.2.6 Genomic Profiling 2.2.7 The Comprehensive Assay 2.2.8 Changing Clinical Role 2.2.9 The Cancer Screening Market Opportunity2.3 Cancer Management vs. Diagnosis 2.3.1 The Role of Risk Assessment 2.3.2 Diagnosis 2.3.3 Managing 2.3.4 Monitoring 2.4 Phases of Adoption - Looking into The Future 2.5 Structure of Industry Plays a Part 2.5.1 Hospital Testing Share 2.5.2 Economies of Scale2.5.2.1 Hospital vs. Central Lab 2.5.3 Physician Office Lab's 2.5.4 Physician's and POCT

3. Market Trends3.1 Factors Driving Growth3.1.1 Level of Care 3.1.2 Companion Dx 3.1.3 Immuno-oncology 3.1.4 Liability3.1.5 Aging Population3.2 Factors Limiting Growth3.2.1 State of knowledge3.2.2 Genetic Blizzard. 3.2.3 Protocol Resistance3.2.4 Regulation and coverage 3.3 Instrumentation and Automation 3.3.1 Instruments Key to Market Share 3.3.2 Bioinformatics Plays a Role 3.4 Diagnostic Technology Development3.4.1 Next Generation Sequencing Fuels a Revolution 3.4.2 Single Cell Genomics Changes the Picture 3.4.3 Pharmacogenomics Blurs Diagnosis and Treatment3.4.4 CGES Testing, A Brave New World 3.4.5 Biochips/Giant magnetoresistance based assay

4. Cancer Panels & Profiles Recent Developments 4.1 Recent Developments - Importance and How to Use This Section 4.1.1 Importance of These Developments 4.1.2 How to Use This Section

5. Profiles of Key Players

6. The Global Market for Cancer Gene Panels and Profiles

7. Global Cancer Gene Panels & Profiles Markets - By Type of Cancer 7.1 Comprehensive Panels & Profiles 7.2 Breast Cancer Gene Testing 7.3 Colorectal Cancer Gene Testing7.4 Gynecological Cancer Gene Testing 7.5 Blood Cancer Gene Testing 7.6 Prostate Cancer Gene Testing 7.7 Lung Cancer Gene Testing7.8 Other Cancer Gene Testing

8. Global Cancer Gene Testing Markets - Germline and Somatic 8.1 Global Market Somatic 7.3 Global Market Germline

9. Potential Market Opportunity Sizes 9.1 Potential Cancer Screening by Country: Lung, Breast & Colorectal 9.2 Potential Cancer Screening by Country: Prostate, Other Cancer & All Cancer 9.3 Potential Market Size - Cancer Diagnosis 9.4 Potential Market Size - Therapy Selection

Appendices

For more information about this report visit https://www.researchandmarkets.com/r/5bx3ai

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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Global Genomic Cancer Panel and Profiling Markets Report 2021-2025: The Market is Moving Out of a Specialized Niche and Going Mainstream -...

Hidden in plain sight, a group of scientists in Porirua some wearing lab coats, some more at home in jeans carry out some of the most important work in the fight against Covid-19.

Genomic sequencing is at the heart of contact tracing, although most New Zealanders hadnt heard those words until after the first wave.

ESR Bioinformatics lead Dr Joep de Ligt and his team, Dr Una Ren and Matt Storey, work around the clock to map the chain of transmission for every single case of Covid-19 in New Zealand.

Their building is straight out of the 1980s, a warren of corridors and stairwells. There are drawings by de Ligts kids on the bookshelf, a small 3D model of a coronavirus molecule on the next shelf.

READ MORE:* Covid-19: Covid Tracer app is a form of protection, expert says* Covid-19: How Auckland's 'mystery' coronavirus case was genome sequenced* Covid-19: Non-stop late nights, public pressure for genome sequencing team tracing coronavirus cases

ROSA WOODS/Stuff

ESR bioinformatics lead Dr Joep de Ligt demonstrates the software which maps the chains of transmission of local cases, just like a complex family tree.

These scientists knew from the beginning this work would be important. During the first lockdown they tested samples, mapped chains of transmission, and added to their database, funding it all themselves.

Then they laid all their data on the table at the Ministry of Health, and explained how they could help.

The ministry now relies on this work, and funds it jointly with the Ministry of Business, Innovation and Employments Covid-19 Innovation Acceleration Fund.

At the moment, ESR in Wellington is the main player in this field. Samples can be sequenced elsewhere, but the results are usually sent to Wellington for analysis and mapping.

ROSA WOODS/Stuff

The robot responsible for pipetting and mixing solutions with the inert virus capable of doing 84 at a time at the ESR lab in Porirua.

Equipment is easy to obtain, but the people with expertise are invaluable, and scarce.

New Zealand can say weve sequenced nearly every case, de Ligt said. That meant a near-conclusive map of cases, with every chain of transmission shown as a line on a diagram, like a family tree.

Other countries around the world were doing this too. Australia and some smaller Pacific islands were also able to track every case and map them.

But for countries overwhelmed with thousands of cases a day, it wasnt a priority. The United Kingdom was sequencing about 30 per cent of its cases, de Ligt said impressive considering its volume of daily cases could reach more than 20,000.

New Zealand was in a sweet spot; a manageable amount of cases, with real value to be gained by knowing where they came from.

Dom Thomas/Getty Images

Joep de Ligt talks to Prime Minister Jacinda Ardern about the different Covid-19 genomes in New Zealand, during an ESR tour in August. (File photo)

The first sequence was produced on March 9. Since then, ESR had done the bulk of the work 1289 of a total 1296 sequences with one other by Otago University, and sic by Massey University.

The case of the Auckland AUT student who tested positive on November 12 was the fastest turnaround so far in New Zealand and, according to de Ligt, likely the fastest in the world.

Overseas, a sample could take anywhere from 24 to 48 hours to sequence. In New Zealand, with the pedal to the floor, it took around 10 hours.

Since samples often travelled from around the country to the lab in Wellington, ESR is planning to equip and train the teams in its Christchurch and Auckland centres to perform the same service, to shorten delivery times even further.

This would also provide alternatives if something happened to the Wellington base, be it disastrous like an earthquake or fire, or simple as a power outage.

ROSA WOODS/Stuff

A Covid-19 molecule, shown here as an enlarged 3D replica, has spikes on the outside which attach themselves to a human cell, and transfer their contents RNA.

When a coronavirus sample lands in the hands of ESR scientists, taken by swabbing the nose and throat of a person with symptoms, it has already tested positive for Covid-19.

The person it came from should already be in self-isolation, and perhaps there is already some indication of whom they caught it from.

Or perhaps everyone is scratching their heads, workplaces thrust into lockdown, and staff at the Ministry of Health are calling hushed, hurried meetings.

RNA, like DNA, is a long ladder of chemical compounds; adenine (A), uracil (U), guanine (G) and cytosine (C). They pair up to form a double helix structure, A always joining with U, and C with G.

These letters change due to mutation. Because of the way Covid-19 RNA mutates, scientists know they can expect a change in the code once every two weeks.

The closer one persons virus resembles another known case, the more likely it is they caught it from that person.

Last week, the AUT students sample was identical to another known case.

ROSA WOODS/Stuff

De Ligt and his team spend most of their time in the office rather than the lab, comparing one sequence to the next.

A positive sample begins its quest for an answer by being turned from a live form of the virus, into one which cannot infect people.

According to ESR chief scientist Dr Brett Cowan, we explode it, and then we cook it. Simple, when you put it like that.

Cowan spends a lot of his time explaining things in layman's terms. While it can be interesting to the public, more importantly, it helps if those co-ordinating health responses and contact tracing understand the process.

The membrane around the outside of the virus is burst open, spilling the genetic data. The spikes on the membranes surface are the parts that latch onto human cells, and allow the RNA, the code of the virus, to transfer and infect. Without the membrane, the RNA cant enter a cell.

The sample is then heated to a temperature that will damage everything but the RNA a second line of defence.

ROSA WOODS/Stuff

ESR chief scientist Dr Brett Cowan, holding a 3D printed replica of the virus Covid-19, is well-versed in explaining the science of viruses to the public.

Once the sample is no longer infectious, the RNA is isolated from the other junk collected in a sample pollen, dust, or bacteria in the nose of the test subject.

The only part of the sample they were interested in, said de Ligt, was the RNA. We dont want to learn about the person.

In any sample, there isnt enough RNA present to produce a result at this stage. The RNA needs to be replicated millions, if not billions of times.

Then a robot transfers the virus into a cocktail of chemicals. This machine, which costs around $30,000, can transfer up to 84 samples at a time thats a sample of inert Covid-19 RNA from 84 different people.

For a country like New Zealand, which rarely had more than a handful of positive cases a day, the robot was not intended to speed up the process.

Rather, it meant everything was done systematically, with no risk of mixed-up samples. Some samples are still pipetted by hand such as the single case of the AUT student.

The next stage is to run it through a machine called a GridION, which costs around $100,000, and can sequence the RNA into the string of As, Us, Cs, and Gs.

The machine spits out the code, and the scientists move in to analyse the results.

ROSA WOODS

Coding is a big part of the process. Here, de Ligt enters the data from the machine into the mapping program, to see the bigger picture of community transmission.

By comparing one sequence with every other on file, they can pinpoint the person it most closely resembles, and then the epidemiologists and contact tracing teams take over.

We take data, and turn it into actionable intelligence, Cowan said. We have the end of the chain, and sequencing gives us the beginning.

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Covid-19: Behind the scenes of genomic sequencing in Wellington's own backyard - Stuff.co.nz

WASHINGTON, Nov. 17, 2020 /PRNewswire/ -- Seven leading diagnostics companies andlaboratory service providers have formed the Access to Comprehensive Genomic Profiling Coalition (ACGP). The goal of the organization is to collectively advocate for appropriate broad U.S. health insurance coverage of comprehensive genomic profiling (CGP) for patients living with advanced cancer. The current members of ACGP are Exact Sciences (NASDAQ: EXAS), Foundation Medicine, Illumina (NASDAQ: ILMN), LabCorp (NYSE: LH), QIAGEN (NYSE: QGEN), Roche Diagnostics (SIX: RO, ROG:OTCQX: RHHBY), and Thermo Fisher Scientific (NYSE: TMO).

CGP testingperformed soon after a diagnosis of advanced cancer betterinforms medical management, including treatment decisions and patient care, which can improve clinical outcomes. In advocating for coverage of CGP, ACGP will educate health insurers and other healthcare stakeholders about the clinical utility and economic value of CGP.

CGP tests assess the genomic alterations within a patient's cancer to help physicians make more informed decisions about personalized treatment approaches. Using next-generation sequencing (NGS) with a tissue biopsy or a blood sample, this testing method can detect the four main classes of alterations known to drive cancer growth: base substitutions, insertions and deletions, copy number alterations (CNAs), and rearrangements or fusions. These tests can reveal clinically relevant alterations and biomarkers in the tumor's DNA and RNA. This helps identify patients who could respond to specific targeted therapies and immunotherapy that can be more effective and may have fewer side effects.Healthcare professionals can use CGP to help predict patient benefit across multiple targeted therapies and cancer indications, with benefits in progression-free survival for patients with non-small cell lung cancer (NSCLC) as one example.1

"Cancer is a disease of the genome, not solely the tissue. Tumor profiling hasevolved tremendously in the last decade," said Jim Almas, MD, vice president and national medical director of clinical effectiveness atLabCorp, and the chairman of ACGP. "The manufacturers and laboratories forming the coalition have produced incredible assays to help identify the mutations driving advanced cancers, leading patients to better care through targeted cancer treatments."

Despite evidence of the benefits of this approach, some health insurers still use an outdated framework to evaluate coverage for CGP, creating a disparity in access across patient populations. Many commercial insurance plans do not cover this type of testing, while public or government plans like Medicare do.Limited insurance coverage options may prevent some treating physicians from ordering CGP for their patients.

"There is no question that obstacles to coverage have inhibited physicians from ordering comprehensive genomic profiling," said Almas."Additionally, we believe some clinicians are not aware of the advantages of a comprehensive testing approach and the benefits of one CGP test to provide genomic profiling, detect microsatellite instability and tumor mutational burden, and help physicians identify clinical trials for which patients may be candidates."

To learn more about ACGP, go to http://www.accesstoCGP.com

1: Singal G, Miller PG, Agarwala V, et al. Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database.JAMA.2019;321(14):1391-1399.

SOURCE Access to Comprehensive Genomic Profiling

http://www.accesstoCGP.com

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Leading Diagnostics Companies Join Forces to Establish the Access to Comprehensive Genomic Profiling Coalition (ACGP) - PRNewswire

Ye-Jin Lee,1 SeungHo Choi,2 Sung-Youn Kwon,2 Yunhwan Lee,2 Jung Kyu Lee,3 Eun Young Heo,3 Hee Soon Chung,3,4 Deog Kyeom Kim3,4

1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 2Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984 Korea; 3Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Boramae-Gil 41, Dongjak-gu, Seoul 156-707, Republic of KoreaTel +82-2-870-3207Fax +82-2-831-0714Email kimdkmd@gmail.com

Background: Identifying the genetic basis of airflow limitation is one of the most interesting issues for understanding chronic obstructive pulmonary disease (COPD) pathophysiology. Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association study (GWAS), especially in patients with moderate to severe COPD; genetic susceptibility for airflow limitation in the early COPD phase has not been widely studied.Objective: We investigated the genetic variants in early COPD.Methods: The present study analyzed Gene-environment interaction and phenotype (GENIE) cohort that included participants who received health screening examination. The association between single nucleotide polymorphism (SNP) and susceptibility to early COPD (FEV1 predicted 50% and FEV1/FVC < 0.7) was tested.Results: A total of 130 patients with early COPD and 3478 controls (1700 ever smokers and 1778 never smokers) were recruited. When compared with the total controls, certain SNPs (rs2818103, rs875033, rs9354627, rs34552148) on chromosome 6 were included at the top of our list (p= 5.6 10 7 9.6 10 6) although they did not reach genome-wide significance. When compared with the never smoker controls, two SNPs (rs2857210, rs2621419) of the HLA-DQB2 gene class were persistently associated with susceptibility to early COPD.Conclusion: Certain SNPs located on chromosome 6 or the HLA-DQB2 gene were the top-scoring SNPs for the association with susceptibility to early COPD in the Korean GENIE cohort.

Keywords: early chronic obstructive pulmonary disease, genome-wide association study, single nucleotide polymorphism, SNP, HLA-DQ gene

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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A Genome-Wide Association Study in Early COPD: Identification of One M | COPD - Dove Medical Press

In 1986, geneticist Thomas Roderick, Ph.D., sat with about 10 colleagues in a bar in Bethesda, Maryland, discussing all-things biology. After a few rounds of drinks, Roderickis said to havethrown out a new term for the study and comparison of genomes across species: "genomics." The term then appeared in scientific literature for the first time a year later.

Genomics now a household word was greatly elevated in stature in October 1990 with the worldwide launch of the Human Genome Project. This month marks the 30th anniversary of the endeavor, biology's audacious odyssey that deciphered the first sequence of the 3 billion DNA letters making up the human genetic blueprint the human genome.

The project showed that humans have 99.9% identical genomes, and it set the stage for developing a catalog of human genes and beginning to understand the complex choreography involved in gene expression. The growing knowledge about the structure and function of the human genome is now regularly used in biotechnology and medicine.

"The Human Genome Project transformed the way we study our biology and medicine. From accessing a genome sequence at the click of a mouse, performing newborn genome sequencing in an intensive care unit or the group's revolutionary decision to share the data with all, the Project's intentions and goals have spilled into how we do science today," said Francis Collins, M.D., Ph.D., National Institutes of Health director.

From accessing a genome sequence at the click of a mouse, performing newborn genome sequencing in an intensive care unit or the group's revolutionary decision to share the data with all, the Project's intentions and goals have spilled into how we do science today.

Thirty years after this historic launch, the field of genomics continues to expand significantly, building upon the Human Genome Project's successes.

Generating the first human genome sequence required actively sequencing human DNA for 6-8 years; today, scientists can sequence a human genome in a day. Such fast human genome sequencing allows physicians to make quick diagnoses of rare genetic disorders in acute settings.

Another notable achievement since the end of the Human Genome Project is the reduced cost of sequencing a human genome. That price has dropped from a billion dollars to mere hundreds, thanks to federal investments used to develop new technologies for DNA sequencing.

"This 30-year milestone is not only an opportunity to reflect on past accomplishments, but a time to look ahead," said Eric Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI). "Over the last 30 years, NHGRI has regularly partnered with the research community to create strategic visions for each phase of human genomics. To commemorate the Human Genome Project's launch 30 years ago, we chose this month to publish NHGRI's new vision for human genomics, a product of the last two-plus years of strategic planning.

To commemorate the Human Genome Project's launch 30 years ago, we chose this month to publish NHGRI's new vision for human genomics, a product of the last two-plus years of strategic planning.

NHGRI has published two strategic visions since the end of the Human Genome Project, in2003and2011. NHGRI will unveil its 2020 Strategic Vision in late October.

Visit genome.gov/2020SVto learn more.

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The Human Genome Project turns the big 3-0! - National Human Genome Research Institute

When the brain forms a memory of a new experience, neurons called engram cells encode the details of the memory and are later reactivated whenever we recall it. A new MIT study reveals that this process is controlled by large-scale remodeling of cells' chromatin.

This remodeling, which allows specific genes involved in storing memories to become more active, takes place in multiple stages spread out over several days. Changes to the density and arrangement of chromatin, a highly compressed structure consisting of DNA and proteins called histones, can control how active specific genes are within a given cell.

"This paper is the first to really reveal this very mysterious process of how different waves of genes become activated, and what is the epigenetic mechanism underlying these different waves of gene expression," says Li-Huei Tsai, the director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

Asaf Marco, an MIT postdoc, is the lead author of the paper, which appears today in Nature Neuroscience.

Epigenomic controlEngram cells are found in the hippocampus as well as other parts of the brain. Many recent studies have shown that these cells form networks that are associated with particular memories, and these networks are activated when that memory is recalled. However, the molecular mechanisms underlying the encoding and retrieval of these memories are not well-understood.

Neuroscientists know that in the very first stage of memory formation, genes known as immediate early genes are turned on in engram cells, but these genes soon return to normal activity levels. The MIT team wanted to explore what happens later in the process to coordinate the long-term storage of memories.

"The formation and preservation of memory is a very delicate and coordinated event that spreads over hours and days, and might be even months -- we don't know for sure," Marco says. "During this process, there are a few waves of gene expression and protein synthesis that make the connections between the neurons stronger and faster."

Tsai and Marco hypothesized that these waves could be controlled by epigenomic modifications, which are chemical alterations of chromatin that control whether a particular gene is accessible or not. Previous studies from Tsai's lab have shown that when enzymes that make chromatin inaccessible are too active, they can interfere with the ability to form new memories.

To study epigenomic changes that occur in individual engram cells over time, the researchers used genetically engineered mice in which they can permanently tag engram cells in the hippocampus with a fluorescent protein when a memory is formed. These mice received a mild foot shock that they learned to associate with the cage in which they received the shock. When this memory forms, the hippocampal cells encoding the memory begin to produce a yellow fluorescent protein marker.

"Then we can track those neurons forever, and we can sort them out and ask what happens to them one hour after the foot shock, what happens five days after, and what happens when those neurons get reactivated during memory recall," Marco says.

At the very first stage, right after a memory is formed, the researchers found that many regions of DNA undergo chromatin modifications. In these regions, the chromatin becomes looser, allowing the DNA to become more accessible. To the researchers' surprise, nearly all of these regions were in stretches of DNA where no genes are found. These regions contain noncoding sequences called enhancers, which interact with genes to help turn them on. The researchers also found that in this early stage, the chromatin modifications did not have any effect on gene expression.

The researchers then analyzed engram cells five days after memory formation. They found that as memories were consolidated, or strengthened, over those five days, the 3D structure of the chromatin surrounding the enhancers changed, bringing the enhancers closer to their target genes. This still doesn't turn on those genes, but it primes them to be expressed when the memory is recalled.

Next, the researchers placed some of the mice back into the chamber where they received the foot shock, reactivating the fearful memory. In engram cells from those mice, the researchers found that the primed enhancers interacted frequently with their target genes, leading to a surge in the expression of those genes.

Many of the genes turned on during memory recall are involved in promoting protein synthesis at the synapses, helping neurons strengthen their connections with other neurons. The researchers also found that the neurons' dendrites -- branched extensions that receive input from other neurons -- developed more spines, offering further evidence that their connections were further strengthened.

Primed for expression

The study is the first to show that memory formation is driven by epigenomically priming enhancers to stimulate gene expression when a memory is recalled, Marco says.

"This is the first work that shows on the molecular level how the epigenome can be primed to gain accessibility. First, you make the enhancers more accessible, but the accessibility on its own is not sufficient. You need those regions to physically interact with the genes, which is the second phase," he says. "We are now realizing that the 3D genome architecture plays a very significant role in orchestrating gene expression."

The researchers did not explore how long these epigenomic modifications last, but Marco says he believes they may remain for weeks or even months. He now hopes to study how the chromatin of engram cells is affected by Alzheimer's disease. Previous work from Tsai's lab has shown that treating a mouse model of Alzheimer's with an HDAC inhibitor, a drug that helps to reopen inaccessible chromatin, can help to restore lost memories.

Reference: Marco A, Meharena HS, Dileep V, et al.Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble. Nat. Neurosci. 2020. doi:10.1038/s41593-020-00717-0

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Genomic analysis using circulating cell-free tumor DNA (ctDNA) was highly concordant with, and complementary to, tissue genomic analysis among patients with advanced renal cell carcinoma (mRCC), according to results of a retrospective study presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Exclusive GAs [genomic alterations] found on both platforms suggests tumor evolution over time and treatment, which may assist in guiding treatment selection in mRCC, Zeynep Zengin, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, and presenter of the study, said.

The single-center, retrospective studied analyzed data from 847consecutive patients with stage IIIB to IV RCC who underwent ctDNA testing using the Guardant360 next-generation sequencing (NGS) assay. Serial assessment of ctDNA was performed on a subset of 39 patients. GAs detected by ctDNA NGS were compared with GAs detected by NGS or whole-exome sequencing of tissue DNA with commercially available platforms (Foundation Medicine and Ashion Analytics, respectively). The median time between the ctDNA and tissue testing was 15.3 months.

Among the ctDNA samples, 72% harbored 1 or more GA, with the most frequent genes affected including TP53 at 37%, VHL at 22%, and EGFR at 6%.

Alterations along the mTOR pathway were also well represented, including PTEN, PIK3CA, and NF1, Dr Zengin said. She noted that approximately 6% of patients harbored mutations in DNA repair genes, such as BRCA1, BRCA2, ATM, and CDK12.

Serial analysis of ctDNA demonstrated that the frequency of GAs in EGFR and PTEN increased over time.

Among the tissue DNA samples, the most frequent genes with GAs was VHL at 63.8%, PMBRM1 at 44.7%, and SETD2 at 39.1%. Both PMBRM1 and SETD2 were not evaluated by the ctDNA assay.

A total of 154 GAs were detected across both ctDNA and tissue DNA assay, when including only the genes assessed by the ctDNA assay. Of these GAs, 17.4% were identified by both tests, whereas 38.8% were detected only in blood and 43.8% were detected only in tissue.

The overlap increased when samples were stratified by the amount of time between their collections. When samples were collected within 6 months of each other, the overlap was 39.3%, whereas samples collected more than 6 months apart had an overlap of 10.8%.

The concordance was high between the tests, with a cumulative rate of 96.2%.

Dr Zengin concluded that concordance analysis suggests that ctDNA and tissue-based genomic profiling are complementary.

Disclosures: Multiple authors declared affiliations with industry. Please refer to the original abstract for a full list of disclosures.

Read more of Cancer Therapy Advisors coverage of the ESMO Virtual Congress 2020 by visiting the conference page.

Reference

Zengin ZB, Weipert C, Hsu J, et al. Assessment of circulating cell-free tumor DNA (ctDNA) in 847 patients (pts) with metastatic renal cell carcinoma (mRCC) and concordance with tissue-based testing. Presented at: European Society for Medical Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Abstract 701O.

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ctDNA Concordant with Tissue Genomic Analysis in RCC - Cancer Therapy Advisor

Alexander Heinl Image: American biochemist Jennifer A. Doudna, left, and the French microbiologist Emmanuelle Charpentier, right, Frankfurt, Germany.

LONDON Two women were awarded the Nobel Prize in chemistry Wednesday for their pioneering work on genome editing, which has the life-saving potential to be used to cure genetic diseases.

"This year's prize is about re-writing the code of life," said Secretary General Gran K. Hansson for the Royal Swedish Academy of Sciences, as he awarded the prize to American biologist Jennifer Doudna and French microbiologist Emmanuelle Charpentier.

Only five women have previously won the chemistry prize, which has been awarded 111 times between 1901 and 2019 to 183 people.

Doudna and Charpentier developed a type of genetic scissor called the CRISPR/Cas9 used "to change the DNA of animals, plants and microorganisms with extremely high precision," according to the chemistry prize committee.

The "revolutionary" method has contributed to new cancer therapies and has the potential to be used in curing inheritable diseases.

"It has not only revolutionized basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments," said Claes Gustafsson, chair of the chemistry committee, in a statement.

In addition to making major developments to genetic research, Charpentier told the news conference by phone that she hopes the prize encourages girls to pursue science.

"I wish that this will provide a positive message to show them in principle woman in science can also be awarded prizes but more importantly, women in science can also have an impact for the research they're performing," she said.

Last year's chemistry award went to American chemist John B. Goodenough, British American chemist M. Stanley Whittingham and Japanese chemist Akira Yoshino for their development of the long-life lithium-ion battery.

The prestigious prize was established by the Swedish inventor Alfred Nobel who dictated in his will that it would honor "those who, during the preceding year, have conferred the greatest benefit to humankind."

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Winners are given a Nobel diploma and medal, and share the prize money of 10 million Swedish kronor (more than $1.1 million).

The other prizes still to be delivered in the coming days are for outstanding work in the fields of literature, peace and economics.

The Associated Press contributed to this report.

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'Re-writing the code of life': Nobel chemistry prize goes to genome editing pioneers - msnNOW