Understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical labs could use to identify people with the mutated gene
New research from the University of California San Francisco (UCSF) may explain why some people could get COVID-19 but never test positive on a clinical laboratory test or develop symptoms despite exposure to the SARS-CoV-2 coronavirus.
According to the UCSF study, variations in a specific gene in a system of genes responsible for regulating the human immune system appears to be the factor in why about 10% of those who become infected with the virus are asymptomatic.
These scientific insights did not receive widespread news coverage but will be of interest to clinical laboratory managers and pathologists who oversee SARS-CoV-2 testing in their labs.
“Some people just don’t have symptoms at all,” Jill Hollenbach, PhD (above), Professor of Neurology atUCSF’s Weill Institute for Neurosciences and lead researcher in the study, told NBC News. “There’s something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection.” Identifying a genetic reason why some people are asymptomatic could lead to new precision medicine clinical laboratory diagnostics for COVID-19. (Photo copyright: Elena Zhukova /University of California San Francisco.)
Fortunate Gene Mutation
According to the Centers for Disease Control and Prevention’s (CDC) COVID Data Tracker, as of April 5, 2023, a total of 104,242,889 COVID-19 cases have been reported in the United States. However, according to a CDC Morbidity and Mortality Weekly Report (MMWR), “Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, [knowing the true] proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19.”
She also participates in the COVID-19 HLA and Immunogenetics Consortium, a group of academic researchers, clinical laboratory directors, journal editors, and others who examine the role of HLA variations in determining COVID-19 risk.
Hollenbach’s research identified an HLA variant—known as HLA-B*15:01—that causes the human immune system to react quickly to SARS-CoV-2 and “basically nuke the infection before you even start to have symptoms,” she told NPR.
“It’s definitely luck,” she added. “But, you know, this [gene] mutation is quite common. We estimate that maybe one in 10 people have it. And in people who are asymptomatic, that rises to one in five.”
“HLA variants are among the strongest reported associations with viral infections,” the UCSF study notes. So, the researchers theorized that HLA variations play a role in asymptomatic SARS-CoV-2 infections as well.
To conduct their study, shortly after the SARS-CoV-2 outbreak in 2020, the researchers recruited approximately 30,000 volunteer bone marrow donors from the National Marrow Donor Program to respond to periodic questions via a smartphone app or website. Because HLA variations can determine appropriate matches between donors and recipients, the database includes information about their HLA types.
Each week, respondents were asked to report if they had been tested for SARS-CoV-2. Each day, they were asked to report whether they had symptoms associated with COVID-19. “We were pretty stringent in our definition of asymptomatic,” Hollenbach told NBC News. “[The respondents couldn’t] even have a scratchy throat.”
The researchers eventually identified a cohort of 1,428 people who had tested positive for SARS-CoV-2 between February 2020 and April 30, 2021, before vaccines were widely available. Among these individuals, 136 reported no symptoms for two weeks before or two weeks after a positive test.
“Overall, one in five individuals (20%) who remained asymptomatic after infection carried HLA-B*15:01, compared to 9% among patients reporting symptoms,” the researchers wrote in their medRxiv preprint. Study participants with two copies of the gene were more than eight times more likely to be asymptomatic.
The UCSF researchers also looked at four other HLA variants and found none to be “significantly associated” with lack of symptoms. They confirmed their findings by reproducing the HLA-B association in two additional independent cohorts, one from an earlier study in the UK and the other consisting of San Francisco-area residents.
Individuals in the latter group had either tested positive for SARS-CoV-2 or reported COVID symptoms, and their DNA was analyzed to determine their HLA types.
Pre-existing T-Cell Immunity May Reduce Severity of COVID-19 Infection
The UCSF researchers also attempted to determine how HLA-B*15:01 plays a role in knocking out SARS-CoV-2 infections. They noted previous research that indicated previous exposure to seasonal coronaviruses, such as common cold viruses, could limit the severity of COVID-19. The scientists hypothesized that pre-existing T-cell immunity in HLA-B carriers may be the key.
The COVID-19 HLA and Immunogenetics Consortium website describes how HLA and T-cells work together to ward off disease. HLA “proteins are found on the surface of all cells except red-blood cells.” They’re “like windows into the inner workings of a cell,” and T-cells use the molecules to determine the presence of foreign proteins that are likely signs of infection. “Activated T-cells can kill infected cells, or activate B-cells, which produce antibodies in response to an infection,” the website explains.
Hollenbach’s research team analyzed T-cells from pre-pandemic individuals and observed that in more than half of HLA-B carriers, the T-cells were reactive to a SARS-CoV-2 peptide. The scientists corroborated the hypothesis by examining crystal structures of the HLA-B*15:01 molecule in the presence of coronavirus spike peptides from SARS-CoV-2 and two other human coronaviruses: OC43-CoV and HKU1-CoV.
“Altogether, our results strongly support the hypothesis that HLA-B*15:01 mediates asymptomatic COVID-19 disease via pre-existing T-cell immunity due to previous exposure to HKU1-CoV and OC43-CoV,” the researchers wrote.
Can Genes Prevent COVID-19 Infections?
Meanwhile, researchers at The Rockefeller University in New York City are attempting to go further and see if there are mutations that prevent people from getting infected in the first place. NPR reported that they were seeking participants for a study seeking to identify so-called “superdodger” genes.
Study participants identified as possibly having superdodger genes receive a kit designed to collect saliva samples, after which the researchers sequence the respondents’ genomes. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection,” Casanova told NPR.
All this genetic research is in very early stages. But results are promising and may lead to new precision medicine clinical laboratory tests for identifying people who are predisposed to having an asymptomatic response to COVID-19 infection. That in turn could help scientists learn how to moderate or even eliminate symptoms in those unfortunate people who suffer the typical symptoms of the disease.
Pathologists can be paid for their role in identifying and recruiting patients for basket studies and reporting results of medical laboratory tests
Anatomic
pathologists who biopsy, report, and diagnosis cancer will benefit from a
better understanding of basket
studies and their application in developing cancer treatment therapies. Such
studies can lead to more documentation of the effectiveness of various therapies
for cancers with specific gene
signatures.
The US
National Library of Clinical Medicine defines basket studies as “a new sort
of clinical studies to identify patients with the same kind of mutations and
treat them with the same drug, irrespective of their specific cancer type. In
basket studies, depending on the mutation types, patients are classified into ‘baskets.’
Targeted therapies that block that mutation are then identified and assigned to
baskets where patients are treated accordingly.”
“Historically, cancer clinical trials have been centered on the treatment of cancer based on the anatomic location in the body, like breast cancer or brain cancer or lung cancer. A basket study is a novel trial design that includes patients with a certain molecular aberration regardless of location or tissue of origin of cancer in the body. The genomic revolution in oncology has fueled these studies,” Vivek Subbiah, MD, Associate Professor and Medical Director, Clinical Center for Targeted Therapy ( Phase 1 trials program), at the University of Texas MD Anderson Cancer Center in Houston, told Cancer Therapy Advisor. (Photo copyright: MD Anderson Cancer Center.)
Basket Studies Get Results
During a basket study, researchers may find that a drug’s
effectiveness at targeting “a genetic mutation at one site can also treat the
same genetic mutation in cancer in another area of the body,” noted Pharmacy
Times, which also pointed out basket studies are often starting points for
larger oncology trials about drugs.
For example, it was a basket study which found that vemurafenib (marketed as
Zelboraf), intended for treatment of V600E, a mutation of the BRAF gene, may also treat Erdheim-Chester
disease (a rare blood disorder) in patients who have the BRAF V600 gene
mutation, Pharmacy Times reported.
Additionally, the US Food and Drug Administration’s approval
of the cancer drug Vitrakvi (larotrectinib), an oral TRK
inhibitor, marked the first treatment to receive a “tumor-agnostic
indication at time of initial FDA approval,” a Bayer
news release stated. The drug’s efficacy, Pharmacy Times noted, was
found in a “pivotal” basket study.
Basket Studies, a Master Protocol Trial Design
The basket study technique is an example of a master protocol trial design. The FDA defines a master protocol as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. A master protocol may be used to conduct the trial(s) for exploratory purposes or to support a marketing application and can be structured to evaluate, in parallel, different drugs compared to their respective controls or to a single common control.”
Other master protocols include umbrella studies and platform
studies, according to Cancer Therapy Advisor, which noted that each
master protocol trial design has its own unique objectives:
Umbrella studies look at the effectiveness of
multiple drugs on one type of cancer;
Platform trials investigate the effectiveness of
multiple therapies on one disease on an ongoing basis; and
Basket studies focus on the effectiveness of one
therapy on patients with different cancers based on a biomarker.
“In contrast to traditional trials designs, where a single
drug is tested in a single disease population in one clinical trial, master
protocols use a single infrastructure, trial design, and protocol to
simultaneously evaluate multiple drugs and or disease populations in multiple
substudies, allowing for efficient and accelerated drug development,” states
the FDA draft guidance, “Master
Protocols: Efficient Clinical Trial Design Strategies to Expedite Development
of Oncology Drugs and Biologics.”
Final FDA guidance on master protocols design is expected early in 2020, an FDA spokesperson told Cancer Therapy Advisor.
While master protocol studies show promise, they generally
have small sample sizes, noted researchers of a study published in the journal Trials.
And some researchers have ethical concerns about basket studies.
Nevertheless, basket studies appear to hold promise for precision medicine.
Anatomic pathologists may want to follow some of them or find a way to get
involved through identifying clinical laboratory tests and reporting the results.
In the same way that BRCA1 and BRCA2 mutations helped pathologists identify women with increased breast cancer risks in the late 1990s, this new study isolates an additional 72 mutations medical laboratories may soon use to diagnose breast cancer and assess risk factors
For 20 years genetic scientists, anatomic pathologists, and medical laboratories have employed the BRCA1/BRCA2 genes to identify women at higher risk for breast cancer. And, because pathologists receive a high number of breast biopsies to diagnose, physicians and clinical laboratories already have collaborative experience working with genetic mutations supported by ample published evidence outlining their relationship with cancer.
Now, a global research study is adding 72 more mutations to the list of mutations already known to be associated with breast cancer.
In coming years, physicians and anatomic pathologists can expect to use the knowledge of these 72 genetic mutations when diagnosing breast cancer and possibly other types of cancers in which these mutations may be involved.
New Precision Medicine Tools to Improve Breast Cancer Survival
Combining the efforts of more than 550 researchers across 300 institutions and six continents, the OncoArray Consortium analyzed the DNA of nearly 300,000 blood samples. The analysis included samples of both estrogen receptor (ER-positive and ER-negative) cases.
Taken from a study published in the British Journal of Cancer, the graph above illustrates “proportions of familial risk of breast cancer explained by hereditary variants.” It is expected that anatomic pathologists will eventually incorporate these genetic variants into diagnostic test for breast and other cancers. (Graphic copyright: British Journal of Cancer.)
The results of their research were published in two separate studies: one in the scientific journal Nature and the other in Nature Genetics. The studies outlined 72 newly isolated genetic mutations that might help quantify the risk of a woman developing breast cancer in her lifetime.
Among the 72 mutations, seven genes were specifically associated with ER-negative cases. ER-negative breast cancer often fails to respond to hormone therapy. Thus, this discovery could be crucial to developing and administering precision medicine therapies tailored to specific patients’ physiologies and conditions. Treatments that improve patient outcomes and overall survival rates in ER-negative and ER-positive breast cancers.
Genetics Could Help Clinical Laboratories Wage War on All Cancers
According to data published by the Centers for Disease Control and Prevention (CDC), breast cancer is the most common form of cancer among women of all races. It’s the second-leading cause of all cancer deaths among most races and first among Hispanic women.
In the past, it was estimated that 5-10% of breast cancers were inherited through the passing of abnormal genes. However, Lisa Schlager, Vice President of community affairs and public policy for FORCE (Facing Our Risk of Cancer Empowered), told CNN, “This new information may mean that that estimate is low.” FORCE is a national nonprofit organization dedicated to fighting hereditary breast, ovarian, and related cancers.
Schlager calls upon health systems to “embrace the ability to use genetic information to tailor healthcare by providing affordable access to the needed screening and preventive interventions.” As precision therapy and genetic analysis continue to shape the way patients are treated, medical laboratories will play a significant role in providing the information powering these innovative approaches.
Identifying Women at Increased Risk for Breast Cancer
Peter Kraft, PhD, Professor of Epidemiology at Harvard’s T.H. Chan School of Public Health, and a study author, told CNN, “Taken together, these risk variants may identify a small proportion of women who are at three-times increased risk of breast cancer.”
Kraft notes that samples were sourced from women of primarily European ancestry. Further study of other ethnic populations could lead to yet more mutations and indicators for cancers more common outside of the European region.
Research authors also highlight the importance of continued standard screening, such as mammograms. However, they suggest that genetic mutations, such as those found in the OncoArray study, might be used to highlight high-risk individuals and screen sooner, or conduct more in-depth genetic analyses, to catch potential cancer cases earlier and improve outcomes.
“Many women are offered mammogram screening when they are middle-aged,” Georgia Chenevix-Trench, PhD, co-author of the Nature Genetics study and researcher at the QIMR Berghofer Medical Research Institute in Australia, told LabRoots. “But if we know a woman has genetic markers that place her at higher risk of breast cancer, we can recommend more intensive screening at a younger age.”
Anatomic pathologists and clinical laboratories can use these new insights to offer increased options for oncologists and physicians on the front lines of the battle against cancer. While the list of genetic mutations related to cancer is far from complete, each added mutation holds the potential to power a new treatment, improve early detection rates, and improve survival rates of this global killer.
Sequencing this new DNA standard reference material enables medical laboratories to verify if their DNA test results are accurate
To reduce the variability in genetic test results that has been observed across different clinical laboratories and pathology groups, the National Institute for Standards and Technology (NIST) has introduced a new standard DNA reference. This is another step forward to improve transparency in the quality and accuracy of genetic test results produced by medical laboratories in the United States and abroad.
Even as scientists continue to identify genetic mutations that could cause various cancers and other diseases, such as Alzheimer’s and cystic fibrous, studies have demonstrated that DNA test results from the same specimen can vary depending on which medical laboratory performs the whole-genome sequencing analysis. This is partly due to variances in the technology, chemicals and processes used for the testing. Therefore, ensuring consistently reliable test results has been difficult, which could lead to inaccurate or missed diagnoses.
That is why a new standard DNA reference material developed by the National Institute for Standards and Technology has the potential to help DNA sequencing facilities to verify if their DNA test results are accurate. The new reference material, NIST RM 8398, was designed to improve the accuracy of diagnostic laboratories that analyze DNA using “next-generation sequencing” (NGS) technology. (more…)
Researchers sequenced the entire genomes of 2,636 Icelanders and gained useful insights into how human genes evolve and mutate
Over the past 15 years, Iceland has managed to be at the forefront of genetic research tied to personalized medicine and new biomarkers for diagnostics and therapeutics. This is true because, as most pathologists know, Iceland has a small population that has seen little immigration over the past 1,000 years, along with a progressive government and business community.
The relatively closed society of Iceland makes it much easier to identify genetic sequences that contribute to different diseases. The latest example of such research findings comes after the genomes of 2,636 Icelanders were sequenced. In addition to this being the world’s largest-ever study of the genetic makeup of a single population, the findings suggest a strategy for analyzing the full-spectrum of genetic variation in a single population.
