Diversity in Clinical Genetics Remains Poorly Defined

Diversity in Clinical Genetics Remains Poorly Defined but the Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group is working to address this important issue. In clinical genetics and genomics, many approaches depend on the ability to identify genetic variation that appears to be non-randomly distributed in a population. However, genetic variation often clusters in ways that reflect how peoples’ ancestors were grouped together. These historical associations are often summarized by the terms Race, Ethnicity, and Ancestry but what these terms mean, both semantically and biologically, are still very unclear. The paper below provides no clear solutions but is an excellent introduction and discussion of this problem and the challenges we face in addressing it.

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures

Abstract

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.

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Here’s a link to the group that published this paper: https://www.clinicalgenome.org/working-groups/ancestry/

One minute review of CRISPR-Cas9 Possibilities by FastCo

Gene-editing patents have increased tenfold in just four years. Here’s what the technology could cure

“CRISPR-Cas9 is a method for quickly and accurately editing the genome of virtually any living thing… “

Article by Adam Bluestein / Illustration by Jamie Cullen

Five myths about measurement error in epidemiological research

Five myths about measurement error in epidemiological research

This isn’t a genomics paper but genomics and epidemiology are often natural bedfellows—and we all should be taking epidemiology a little more seriously these days.

Abstract

Epidemiologists are often confronted with datasets to analyse which contain measurement error due to, for instance, mistaken data entries, inaccurate recordings and measurement instrument or procedural errors. If the effect of measurement error is misjudged, the data analyses are hampered and the validity of the study’s inferences may be affected. In this paper, we describe five myths that contribute to misjudgments about measurement error, regarding expected structure, impact and solutions to mitigate the problems resulting from mismeasurements. The aim is to clarify these measurement error misconceptions. We show that the influence of measurement error in an epidemiological data analysis can play out in ways that go beyond simple heuristics, such as heuristics about whether or not to expect attenuation of the effect estimates. Whereas we encourage epidemiologists to deliberate about the structure and potential impact of measurement error in their analyses, we also recommend exercising restraint when making claims about the magnitude or even direction of effect of measurement error if not accompanied by statistical measurement error corrections or quantitative bias analysis. Suggestions for alleviating the problems or investigating the structure and magnitude of measurement error are given.

Thank you for reading!

A Primer on Cancer from the NIH National Cancer Institute

Here is an excellent resource for understanding and explaining cancer, directly from the National Institute of Health National Cancer Institute.

A dividing breast cancer cell. Credit: National Cancer Institute / Univ. of Pittsburgh Cancer Institute

What is Cancer? A Collection of Related Diseases

Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues.Cancer can start almost anywhere in the human body, which is made up of trillions of cells. Normally, human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place.

When cancer develops, however, this orderly process breaks down. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors.

Many cancers form solid tumors, which are masses of tissue. Cancers of the blood, such as leukemias, generally do not form solid tumors.

Cancerous tumors are malignant, which means they can spread into, or invade, nearby tissues. In addition, as these tumors grow, some cancer cells can break off and travel to distant places in the body through the blood or the lymph system and form new tumors far from the original tumor.

Unlike malignant tumors, benign tumors do not spread into, or invade, nearby tissues. Benign tumors can sometimes be quite large, however. When removed, they usually don’t grow back, whereas malignant tumors sometimes do. Unlike most benign tumors elsewhere in the body, benign brain tumors can be life threatening.

Differences between Cancer Cells and Normal Cells

Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive. One important difference is that cancer cells are less specialized than normal cells. That is, whereas normal cells mature into very distinct cell types with specific functions, cancer cells do not. This is one reason that, unlike normal cells, cancer cells continue to divide without stopping.

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Evolution of Cancer Cell Chromosomes Visualized using Organoids

This is free art suggesting “mutation”.

Tumor cell populations are full of mutations, mutations that provide genetic diversity that can allow some to survive chemotherapeutic agents. A series of single nucleotide changes may lead to tumor growth but most dramatic changes in genome composition, and increases in genetic variation, occur after tumor cells begin replicating without regard for their chromosome number and composition. This chromosomal instability creates variation in tumors, allowing for the most aggressive subpopulations to proliferate and generating a diverse pool of genotypes—all of which need to be wiped out if the cancer is to be eradicated. While it has been possible to identify the effects of chromosomal instability (wide-spread aneuploidy) for a long time, studying the mechanisms directly has been difficult given the limited amount of genome sampling and karyotyping (chromosome imaging) that was possible compared to the amount of change in tumors.

A recent paper by Bolhaqueiro et al. describes a technological advance for studying chromosome instability that involves genetically engineering cancer cells to express fluorescent proteins that label chromosomes and culturing those cells into organoids, 3D clusters that more accurately mimic how cell grow in vivo than cells in a flat culture. This approach allows rapid single cell karyotyping and imaging of chromosome behavior during cell division. Paired with single cell sequencing, the direct study of the chromosome instability in organoids may have broad applicability. Cancer cells all start with a fairly similar toolkit and undergo a finite number of replications, so with sufficient study more of their vulnerabilities become apparent and possible to target.

Below is the introduction and link to a longer summary of the Bolhaqueiro article; the original article is interesting but longer, geared towards an expert audience, and behind a paywall.

Watching cancer cells evolve through chromosomal instability

Chromosomal abnormalities are a hallmark of many types of human cancer, but it has been difficult to observe such changes in living cells and to study how they arise. Progress is now being made on this front.

Sarah C. Johnson & Sarah E. McClelland (2019) Nature

The genomes of cancer cells are littered with mutations (errors in individual nucleotides), some of which might contribute to growth of the cancer by activating tumour-promoting genes called oncogenes, or by switching off genes belonging to a class known as tumour suppressors, which fight cancer. Yet, arguably even more important are the genomic abnormalities that occur in tumour cells on a much larger scale. For example, such a cell might contain anomalous numbers of entire chromosomes (a situation termed aneuploidy). As the tumour evolves, chromosomal abnormalities can vary between neighbouring cancer cells. This suggests that chromosomal changes can occur by repeated chromosomal ‘shuffling’ during each cell division, resulting in a high rate of genomic change, termed chromosomal instability.

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Unproven Stem Cell Therapies Earn Traction and Criticism

This an interesting article about the some of efforts in take advantage of Stem Cell therapies happening in China, and some of actions being taken to slow these efforts down to a responsible rate.

China urged to abandon plan to sell unproven cell therapies

David Cyranoski, Nature

An international stem-cell body says the country’s proposed law could put patients at risk.

An international group of stem-cell researchers is urging China to cancel draft regulations that would permit some hospitals to sell therapies developed from patients’ own cells, without approval from the nation’s drug regulator.

The International Society for Stem Cell Research (ISSCR) sent a statement outlining its concerns to Jiao Hong, director of China’s National Medical Products Administration in Beijing, on 20 May. The society, which is based in Skokie, Illinois, represents more than 4,000 scientists, clinicians and ethicists around the world.

“We are deeply concerned that China’s newly proposed regulations will provide incentives for hospitals to market unsafe and ineffective interventions directly to consumers. This has the potential to harm the people of China, undermine public health and discredit the international standing of the Chinese regenerative medicine community,” warns the statement, which was signed by society president Doug Melton.

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You are a collection of clones

Every cell in your body has almost the same DNA as all the others. Mutations accrue with each cell division, so swaths of tissues can be traced back to the same parent cell because they all share the same distinguishing mutations. The patches of more closely related cells are clones, specifically “somatic clones” because they are all in the same body. The importance of clonal variation within individuals is becoming more explicitly recognized, but we have been worrying about them for a long time: cancer is what we call the unregulated growth of somatic clones. Detecting somatic clones before they become diseased is getting easier and we are beginning to understand the processes that help keep abnormal clones in line. Hopefully this shift in perspective will help medicine advance and help people to live longer and healthier lives.

For a good introduction to somatic mosaicism, written for a very broad audience, there is an excellent article, in the New York Times by Carl Zimmer.

For more advanced reading, here is a recent article from Science describing how gene expression analyses were used to show that large clonal populations are spread across essentially all normal healthy tissues, but the most mutations were found in the skin, lung, and esophagus—potentially explaining why these tissues are so prone to cancer.

Yizhak et al. (2019) RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science

Here is a review article on how neighboring cells with different mutations compete with each other and how this kind of battle contributes to cancer.

Di Gregorio et al. (2016) Cell Competition and Its Role in the Regulation of Cell Fitness from Development to Cancer. Developmental Cell

The Limits of What DNA Can Predict

Read the tweetorial, it isn’t too complex …

Want remarkably clear insights into genetics and public health with a bare minimum of reading? Well, some corners of Twitter have recently become an incredible resource if you’re interested in learning something about predictive statistics, epidemiology, genomics, and population genetics. There are no better examples of this than the tweetorials that Dr. Cecile Janssen posts. Dr. Janssen is a professor of translational epidemiology in the department of Epidemiology of the Rollins School of Public Health, Emory University, and her website, like her posts, contains insightful guides for thinking critically about DNA sequence data, heritability and health.

If you would like some key insights into predicting complex traits from DNA in a handful of tweets, follow this link: Why it is so hard to predict complex diseases and traits from DNA?

For a slightly longer read, here’s her article from WIRED on how DNA is best applied: DNA tells great stories -- about the past, not future

And a more advanced read, still aimed at a fairly general audience: Designing babies through gene editing: science or science fiction?

Heavy Data Science Startup, Tempus, Brings in $200 Million in New Funding

Tempus, a health technology building massive data sets of cancer-related information, knowledge-bases, has acquired an additional $200 million in funding. This injection of cash brings the Chicago based startup’s valuation to $3.1 billion and is reportedly intended to permit increased growth and the investigation of additional pathologies, such as diabetes and depression. With moves like this, Tempus seems like it’s worth watching. Read More at Forbes

Personalized medicine approaches designed with Fruit Flies

The promise of personalized medicine has been limited by at least two factors: 1) the power of our models—including our ability to get and process data, and 2) our ability to test potential therapeutic solutions in meaningful biological systems, rapidly and systematically, before testing in humans. While we’re seeing rapid and predictable improvements with the power of our models corresponding improvements in how we test therapies have been less consistent. Even if you have a good, genome-level understanding of an individual’s cancer, there is no guidebook for what treatment will be effective against that particular type of cancer. One promising approach has been to use fruit flies (Drosophila) genetically-modified with similar mutational loads as cancer patients to test the efficacy of drug combinations for suppressing tumor growth.

Ross Cagan is an exceptionally creative researcher who leads a lab at the Icahn School of Medicine at Mount Sinai and has been using fruit flies to develop personalized medicine approaches for over 10 years. This week, the Cagan lab published one of the first examples of clinically effective therapies based on such an approach, with lead author Dr. Erdem Bangi (see below for abstract and link). This article describes how Drosophila were screened for effective drug combinations for inhibiting tumors with a similar composition and complexity as a terminally ill colorectal cancer patient’s tumors, and how a specific drug combination was identified and used to effectively shrink the patient’s tumors. Though this treatment did not provide a permanent cure, it did appear to extend the patient’s life and is important proof that this type of approach can be effective.

Excellent, more in-depth summaries can be found HERE and HERE and HERE, so check them out.

The original article, with its somewhat difficult to penetrate title…

Bangi, E., et al. (2019) A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Science Advances

Abstract

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

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Thank you for reading!

Promising result in Cancer Vaccine Clinical Trial

Mount Sinai Researchers Develop Treatment That Turns Tumors Into Cancer Vaccine Factories

Researchers at Mount Sinai have developed a novel approach to cancer immunotherapy, injecting immune stimulants directly into a tumor to teach the immune system to destroy it and other tumor cells throughout the body. 

The “in situ vaccination” worked so well in patients with advanced-stage lymphoma that it is also undergoing trials in breast and head and neck cancer patients, according to a study published in Nature Medicine in April.

The treatment consists of administering a series of immune stimulants directly into one tumor site.  The first stimulant recruits important immune cells called dendritic cells that act like generals of the immune army. The second stimulant activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells. This immune army learns to recognize features of the tumor cells so it can seek them out and destroy them throughout the body, essentially turning the tumor into a cancer vaccine factory.

“The in situ vaccine approach has broad implications for multiple types of cancer,” said lead author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “This method could also increase the success of other immunotherapies such as checkpoint blockade.”

After testing the lymphoma vaccine in the lab, it was tested in 11 patients in a clinical trial. Some patients had full remission from months to years. In lab tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy, the type of immunotherapy responsible for the complete remission of former President Jimmy Carter’s cancer and the focus of the 2018 Nobel Prize in Medicine.

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Thank you for reading!

The first step towards a "Cancer Dependency Map"

That most cancers use the same set of molecular tools is a very powerful idea, but it has been hard to figure out what these tools are and how to target them. Follow the link below for a quick, and enthusiastic, summary of genome-scale CRISPR–Cas9 screens of 324 human cancer cell lines from 30 cancer types with the goal of developing a new, diverse and more effective portfolio of cancer drug targets.

'Dismantling cancer' reveals weak spots

James Gallagher, BBC News

Scientists have taken cancer apart piece-by-piece to reveal its weaknesses, and come up with new ideas for treatment. A team at the Wellcome Sanger Institute disabled every genetic instruction, one at a time, inside 30 types of cancer. It has thrown up 600 new cancer vulnerabilities and each could be the target of a drug.Cancer Research UK praised the sheer scale of the study.

The study heralds the future of personalised cancer medicine. At the moment drugs like chemotherapy cause damage throughout the body. One of the researchers is Dr Fiona Behan, whose mother died after getting cancer for the second time.

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Another helpful summary of the recent paper linking jumping genes to cancer

A recent post discussed an important paper that demonstrated an association between transposable elements, aka ‘jumping genes’, and cancer. Transposable elements are an important but often forgotten class of mutagen that can contribute to genome instability and may disrupt genes and their expression. The original article has an outstanding abundance of data and is not easy reading. The article below provides an accessible summary that’s worth reading if you aren’t an expert in genomics.

Cancer: Scientists find 129 'jumping genes' that drive tumor growth

Catharine Paddock, Medical News Today

In cancer research, scientists usually look for cancer genes by scouring the genome for altered sequences — or mutations — in DNA. But a new study has now revealed that jumping genes, which customary sequencing overlooks, are also important drivers of tumor growth.

Scientists at the Washington University School of Medicine in St. Louis, MO, found that jumping genes are widespread in cancer and promote tumor growth by forcing cancer genes to remain switched on.

They analyzed 7,769 tumor samples from 15 different types of cancer and found 129 jumping genes that can drive tumor growth through their influence on 106 different cancer genes.

The jumping genes were functioning as "stealthy on-switches" in 3,864 of the tumors that the team analyzed. These tumors came from breast, colon, lung, skin, prostate, brain, and other types of cancer.

A recent Nature Genetics paper gives a full account of the study.

Cancer signaling studies take a page from Genetics methods

The following article provides insights into the promise of applying quantitative approaches in the context of tumor tissues and clinical environments. Genetics approaches have dominated cancer research because they generate such an abundance of data ( and because the methodology is so widely and readily generalizable). While genetic variations clearly play an important role in cancer, deviant signaling drives cancer progression and signaling molecules are the targets of most chemotherapeutics. This highlights the importance of understanding cancer signaling pathways with data-rich and quantitatively rigorous methods, similar to those used in genetics. The following article in Science Signaling discusses this topic and is both thorough and accessible. —RPR

Why geneticists stole cancer research even though cancer is primarily a signaling disease

Michael B. Yaffe, Science Signaling

Abstract—Genetic approaches to cancer research have dramatically advanced our understanding of the pathophysiology of this disease, leading to similar genetics-based approaches for precision therapy, which have been less successful. Reconfiguring and adapting the types of technologies that underlie genetic research to dissect tumor cell signaling in clinical samples may offer an alternative road forward.

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Thank you for reading!

What your genome won't tolerate

This is one of those projects that’s so clearly interesting and important that it’s surprising nobody has done it already: specifically, this is a very thorough and well-executed analysis of all the places in the human genome that do not appear to tolerate being mutated. If you have access, it’s worth reading. —RPR

Measuring intolerance to mutation in human genetics

Zachary L. Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella & Molly Przeworski

Nature Genetics (Research Article)

Abstract—In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples—genes that appear ‘intolerant’ to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency.

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Chemotherapy and Immune Response, Complex Therapeutic Terrain

Chemotherapy-Stimulated Immune Response: An Open Debate

Jonathan Goodman, Cancer Therapy Advisor

“A recent review suggested that chemotherapy may prime cancer to respond to checkpoint inhibition.1 According to the review, which was published in the Annals of Oncology earlier this year, this may occur for a variety of reasons, depending primarily on the mechanism of action of the chemotherapy in question. 

In the past, these predictions may have been surprising to researchers in oncology, as chemotherapy was previously thought to be immunosuppressive. Yet, the authors argue, the effects of chemotherapy can “induce favorable immunogenic conditions within the tumor microenvironment, which may be difficult to achieve by just targeting immune cells.” 

In this setting, chemotherapy functions as the first part of a 2-stage evolutionary trap, where in the first stage clinicians actively select for a tumor microenvironment in which checkpoint blockade is most likely to be effective. With cyclophosphamide, for example, immunogenic cell death may be induced, and the drug may lead to dendritic cell homeostasis.2,3 Both are favorable immunomodulatory effects that may lead to an improved immune response —especially, it appears, when checkpoint blockade is used. 

A recent editorial published in the Annals of Oncology, however, suggests that the notion of turning “cold” tumors “hot” may be a misconception.4 This, according to a study author, Thomas Helleday, PhD, professor of translational oncology and director of the Sheffield Cancer Centre at the University of Sheffield, England, is for several key reasons, each of which has to do with the selective processes caused by chemotherapeutics.“

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New Database of Dog Genomes

Researchers create the largest global catalog of variations in the dog genome

By Prabarna Ganguly, Ph.D.
Science Writer/Editor, NHGRI

In 2019, 'King' the Wire Fox Terrier won the Westminster Dog Show in Madison Square Garden, having competed against 2,800 dogs from 203 breeds. The sheer number of dog breeds points toward the major role played by genetics in shaping such variation in dogs.

In a new study, researchers at the National Human Genome Research Institute (NHGRI) have generated the largest catalog of genetic variants associated with physical traits for domesticated dog breeds. The findings, published in Nature Communication, will help researchers assess if variants associated with dog body structure, behavior and life span could also be implicated in related human diseases.

"This study included data from more than 722 dogs and 144 modern breeds," says Dr. Ostrander, NIH Distinguished Investigator and senior author of the paper. "Through the results, we've learned some of the fascinating genetics behind the variability observed in the world's 450 dog breeds."

After humans initially selected for specific traits during dog breeding centuries ago, dogs have since formed traits and characteristics spontaneously over time. Jocelyn Plassais, a postdoctoral researcher in Dr. Ostrander's laboratory and lead author of the study explained that dogs naturally develop disorders that are common to humans, such as various forms cancers, infections and even diabetes. In addition, a vast number of regions within the dog genome remain similar to the human genome. Thus, dog genomes can provide insight into the biological mechanisms of human health and disease.

The researchers used whole genome sequencing and genome-wide association studies to identify genomic variants associated with sixteen observable characteristics. Most of the blood samples from dogs were taken via The Dog Genome Project, a citizen science initiative that relies on donations from motivated dog owners.

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Gene-Expression Profiling to Understand Cancers of Unknown Origins

Phase 2 Trial Examines Gene-Expression Profiling for Cancer of Unknown Primary Site

A randomized phase 2 trial examining the assignment of treatment based on gene-expression profiling compared with standard chemotherapy for patients with cancer of unknown primary site showed no improvement in the 1-year survival rate with the more tailored approach. However, several caveats may limit the relevance of the findings. A report of this study was published in the Journal of Clinical Oncology.1

Cancer of unknown primary site (CUP) refers to malignancies in which the originating tumor type cannot be identified. As a result, determining the best treatment for this cancer, diagnosed in approximately 31,000 people in the US each year, is extremely difficult.2 In recent years, oncologists have looked to genetic testing to identify the cancer type as a way to improve care.

In the current study, a molecular analysis of biopsied tissue predicted the originating cancer site for all of the 101 patients treated. The analysis identified a total of 16 sites; cancers of the pancreas (21% of participants), gastric system (21% of participants), and malignant lymphomas (20% of patients) were the 3 most common sites to be predicted as the primary site of malignancy. The Japan-based researchers then randomized the patients to receive therapy appropriate to the predicted site of origin (50 patients) or the standard, empiric treatment of paclitaxel plus carboplatin (51 patients).

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PacBio sequencing improves some transplant outcomes

HLA typing with PacBio Shown to Improve Transplant Outcomes

By Bio-IT World Staff

April 5, 2019 | Scientists at the Anthony Nolan Research Institute in the UK have demonstrated that ultra-high-resolution HLA typing performed with PacBio sequencing identified stronger matches associated with improved survival rates among patients who received hematopoietic stem cell transplants. The retrospective study was published this week in the Journal of Biology of Blood and Marrow Transplantation.

HLA typing involves analysis of the genes found in the human leukocyte antigen region of the human genome. For stem cell transplants, HLA typing is used to find the best donor/recipient match for the strongest chance of a positive outcome for transplant patients. The HLA genes are highly polymorphic and complex, making them very difficult to resolve fully with conventional technologies. They are also known to be important in immune-related diseases and drug hypersensitivity.

The Anthony Nolan Research Institute, which is funded by Anthony Nolan, a registered UK charity that maintains the world's oldest stem cell registry, has implemented Single Molecule, Real-Time (SMRT) Sequencing from PacBio to fully phase and characterize HLA genes with high accuracy. In this retrospective study, the scientists aimed to determine whether high-resolution HLA typing enabled by SMRT Sequencing would have made a difference for previously matched donors and recipients.

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Consumer Genomics Breast Cancer Test FAIL

23andMe DTC Breast and Ovarian Cancer Risk Test Misses Almost 90 Percent of BRCA Mutation Carriers

Julia Karow, GenomeWeb

SEATTLE (GenomeWeb) – A study led by researchers at Invitae has found that 23andMe's direct-to-consumer BRCA test, which tests for three common variants in the BRCA1 and BRCA2 genes and is authorized by the US Food and Drug Administration, misses almost 90 percent of BRCA mutation carriers, both in those with and those without a personal or family history of cancer. 

In addition, it misses almost 20 percent of BRCA mutations in those of self-reported Ashkenazi Jewish descent because it doesn't test for them.

The results of the study, which looked at data from almost 125,000 de-identified individuals who had been referred to Invitae for diagnostic testing with one of the firm's cancer risk tests, was presented yesterday at the American College of Medical Genetics and Genomics annual meeting by Edward Esplin,Dian a clinical geneticist at Invitae.

Esplin told GenomeWeb that the study, which did not mention 23andMe by name, was meant to criticize a screening strategy with an FDA-authorized DTC test that appears to have limited clinical utility rather than to criticize 23andMe for offering the test.

In his presentation, he pointed out that the FDA's authorization for the test last year "sounds more like a warning than an approval." FDA cautioned that the test, which examines three founder mutations in the BRCA genes that are common in the Ashkenazi Jewish population, does not assess more than 1,000 other known BRCA mutations, so a negative result does not rule out someone is a mutation carrier. It also advises that positive test results should not be used to determine any treatments without confirmatory testing and genetic counseling. 

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