Nearly 100,000 patients submitted saliva samples to a genetic testing laboratory, providing insights into their disease risk
Researchers at Mayo Clinic have employed next-generation sequencing technology to produce a massive collection of exome data from more than 100,000 patients, offering a detailed look at genetic variants that predispose people to certain diseases. The study, known as Tapestry, was administered by doctors and scientists from the clinic’s Center for Individualized Medicine and produced the “largest-ever collection of exome data, which include genes that code for proteins—key to understanding health and disease,” according to a Mayo Clinic news release.
For our clinical laboratory professionals, this shows the keen interest that a substantial portion of the population has in using their personal genetic data to help physicians identify their risk for many diseases and types of cancer. This support by healthcare consumers is a sign that labs should be devoting attention and resources to providing these types of gene sequencing services.
As Mayo explained in the news release, the exome includes nearly 20,000 genes that code for proteins. The researchers used the dataset to analyze genes associated with higher risk of heart disease and stroke along with several types of cancer. They noted that the data, which is now available to other researchers, will likely provide insights into other diseases as well, the news release notes.
“What we’ve accomplished with the Tapestry study is a blueprint for future endeavors in medical science,” said gastroenterologist and lead researcher Konstantinos Lazaridis, MD (above), in the news story. “It demonstrates that through innovation, determination and collaboration, we can deeply advance our understanding of DNA function and eventually other bio-molecules like RNA, proteins and metabolites, turning them into novel diagnostic tools to improve health, prevent illness, and even treat disease.” Some of these newly identified genetic markers may be incorporated into new clinical laboratory assays. (Photo copyright: Mayo Clinic.)
How Mayo Conducted the Tapestry Study
One notable aspect of the study was its methodology. The study launched in July 2020 during the COVID-19 pandemic. Since many patients were quarantined, researchers conducted the study remotely, without the need for the patients to visit a Mayo facility. It ran for five years through May 31, 2024. The news release notes that it’s the largest decentralized clinical trial ever conducted by the Mayo Clinic.
The researchers identified 1.3 million patients from the main Mayo Clinic campuses in Minnesota, Arizona, and Florida who met the following eligibility criteria:
Participants had to be 18 or older,
they had to have internet and email access, and
be sufficiently proficient in speaking and reading English.
More than 114,000 patients consented to participate, but some later withdrew, resulting in a final sample of 98,222 individuals. Approximately two-thirds were women. Mean age was 57 (61.9 for men and 54.3 for women).
“It was a tremendous effort,” said Mayo Clinic gastroenterologist and lead researcher Konstantinos Lazaridis, MD, in the news release. “The engagement of such a number of participants in a relatively short time and during a pandemic showcased the trust and the dedication not only of our team but also of our patients.”
He added that the researchers “learned valuable lessons about some patients’ decisions not to participate in Tapestry, which will be the focus of future publications.”
Three Specific Genes
Enrolled patients were invited to visit a website, where they could view a video and submit an eligibility form. Once approved, they completed a digital consent agreement and received a saliva collection kit. Participants were also invited to provide information about their family history.
Helix, a clinical laboratory company headquartered in San Mateo, Calif., performed the exome sequencing.
Though Helix performed whole exome sequencing, the researchers were most interested in three specific sets of genes:
Patients received clinical results directly from Helix along with information about their ancestry. Clinical results were also transmitted to Mayo Clinic for inclusion in patients’ electronic health records (EHRs).
Among the participants, approximately 1,800 (1.9%) had what the researchers described as “actionable pathogenic or likely pathogenic variants.” About half of these were BRCA1/2.
These patients were invited to speak with a genetic counselor and encouraged to undergo additional testing to confirm the variants.
Tapestry Genomic Registry
In addition to the impact on the participants, Mayo Clinic’s now has an enormous amount of raw sequencing data stored in the Tapestry Genomic Registry, where it will be available for future research.
The database “has become a valuable resource for Mayo’s scientific community, with 118 research requests submitted,” the researchers wrote in the news release. Mayo has distribution more than a million exome datasets to other genetic researchers.
“What we’ve accomplished with the Tapestry study is a blueprint for future endeavors in medical science,” Lazaridis noted. “It demonstrates that through innovation, determination, and collaboration, we can deeply advance our understanding of DNA function and eventually other bio-molecules like RNA, proteins and metabolites, turning them into novel diagnostic tools to improve health, prevent illness, and even treat disease.”
Everything about this project is consistent with precision medicine, and the number of individuals discovered to have risk of cancers is relevant. Clinical laboratory professionals understand these ratios and the importance of early detection and early intervention.
Study findings could lead to new clinical laboratory screening tests that determine risk for cancer
New disease biomarkers generally lead to new clinical laboratory tests. Such may be the case in an investigational study conducted at the University of Oxford in the United Kingdom (UK). Researchers in the university’s Cancer Epidemiology Unit (CEU) have discovered certain proteins that appear to indicate the presence of cancer years before the disease is diagnosed.
The Oxford scientists “investigated associations between 1,463 plasma proteins and 19 cancers, using observational and genetic approaches in participants of the UK Biobank. They found 618 protein-cancer associations and 317 cancer biomarkers, which included 107 cases detected over seven years before the diagnosis of cancer,” News Medical reported.
To conduct their study, the scientists turned to “new multiplex proteomics techniques” that “allow for simultaneous assessment of proteins at a high-scale, especially those that remain unexplored in the cancer risk context,” News Medical added.
Many of these proteins were in “blood samples of people who developed cancer more than seven years before they received a diagnosis,” an Oxford Population Health news release notes.
“To be able to prevent cancer, we need to understand the factors driving the earliest stages of its development. These studies are important because they provide many new clues about the causes and biology of multiple cancers, including insights into what’s happening years before a cancer is diagnosed,” said Ruth Travis, BA, MSc, DPhil, senior molecular epidemiologist at Oxford Population Health and senior study author, in the news release.
“We now have technology that can look at thousands of proteins across thousands of cancer cases, identifying which proteins have a role in the development of specific cancers and which may have effects that are common to multiple cancer types,” said Ruth Travis, BA, MSc, DPhil (above), senior molecular epidemiologist, Oxford Population Health, in a news release. The study findings could lead to new clinical laboratory screening tests for cancer. (Photo copyright: University of Oxford.)
Proteomics to Address Multiple Cancers Analysis
In their published paper, the Oxford scientists acknowledged other research that identified links between blood proteins and risk for various cancers, including breast, colorectal, and prostate cancers. They saw an opportunity to use multiplex proteomics methods for the simultaneous measurement of proteins “many of which have not previously been assessed for their associations with risk across multiple cancer sites,” the researchers noted.
The researchers described “an integrated multi-omics approach” and the use of the Olink Proximity Extension Assay (PEA) to quantify 1,463 proteins in blood samples from 44,645 participants in the UK Biobank, a large biomedical database and resource to scientists.
Olink, a part of Thermo Fisher Scientific in Waltham, Mass., explains on its website that PEA technology “uniquely combines specificity and scalability to enable high-throughput, multiplex protein biomarker analysis.”
The researchers also compared proteins of people “who did and did not go on to be diagnosed with cancer” to determine differences and identify proteins that suggest cancer risk, News Medical reported.
Proteins Could Assist in Cancer Prevention
“To save more lives from cancer, we need to better understand what happens at the earliest stages of the disease. Data from thousands of people with cancer has revealed really exciting insights into how the proteins in our blood can affect our risk of cancer. Now we need to study these proteins in depth to see which ones could be reliably used for cancer prevention,” Keren Papier, PhD, senior nutritional epidemiologist at Oxford Population Health and joint lead author of the study, told News Medical.
While further studies and regulatory clearance are needed before the Oxford researchers’ approach to identifying cancer in its early stages can be used in patient care, their study highlights scientists’ growing interest in finding biomarker combinations that can predict or diagnose cancer even when it is presymptomatic. By focusing on proteins rather than DNA and RNA, researchers are turning to a source of information other than human genes.
For anatomic pathologists and clinical laboratory leaders, the Oxford study demonstrates how scientific teams are rapidly developing new knowledge about human biology and proteins that are likely to benefit patient care and diagnostics.
List also includes precision oncology, liquid biopsies, and early diagnosis of pancreatic cancer
Pathologists and clinical laboratory managers will be interested to learn that in a recently updated article the World Economic Forum (WEF) identified a dozen important recent breakthroughs in the ongoing fight to defeat cancer, including some related to pathology and clinical laboratory diagnostics.
The article noted that approximately 10 million people die each year from cancer. “Death rates from cancer were falling before the pandemic,” the authors wrote. “But COVID-19 caused a big backlog in diagnosis and treatment.”
The Swiss-based non-profit is best known for its annual meeting of corporate and government leaders in Davos, Switzerland. Healthcare is one of 10 WEF “centers” focusing on specific global issues.
Here are four advances identified by WEF that should be of particular interest to clinical laboratory leaders. The remaining advances will be covered in part two of this ebrief on Wednesday.
“Our study represents a major leap in cancer screening, combining the precision of protein-based biomarkers with the efficiency of sex-specific analysis,” said Novelna founder and CEO Ashkan Afshin, MD, ScD (above), in a company press release. “We’re not only looking at a more effective way of detecting cancer early but also at a cost-effective solution that can be implemented on a large scale.” The 12 breakthroughs listed in the World Economic Forum’s updated article will likely lead to new clinical laboratory screening tests for multiple types of cancer. (Photo copyright: Novelna.)
Novelna’s Early-Stage Cancer Test
Novelna, a biotech startup in Palo Alto, Calif., says it has developed a clinical laboratory blood test that can detect 18 early-stage cancers, including brain, breast, cervical, colorectal, lung, pancreatic, and uterine cancers, according to a press release.
In a small “proof of concept” study, scientists at the company reported that the test identified 93% of stage 1 cancers among men with 99% specificity and 90% sensitivity. Among women, the test identified 84% of stage 1 cancers with 85% sensitivity and 99% specificity.
The researchers collected plasma samples from 440 individuals diagnosed with cancers and measured more than 3,000 proteins. They identified 10 proteins in men and 10 in women that correlated highly with early-stage cancers.
“By themselves, each individual protein was only moderately accurate at picking up early stage disease, but when combined with the other proteins in a panel they were highly accurate,” states a BMJ Oncology press release.
The company says the test can be manufactured for less than $100.
“While further validation in larger population cohorts is necessary, we anticipate that our test will pave the way for more efficient, accurate, and accessible cancer screening,” said Novelna founder and CEO Ashkan Afshin, MD, ScD, in the company press release.
Precision Oncology
According to the National Institutes of Health’s “Promise of Precision Medicine” web page, “Researchers are now identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that develop in totally different parts of the body can sometimes, on a molecular level, have a lot in common. From this new perspective emerges an exciting era in cancer research called precision oncology, in which doctors are choosing treatments based on the DNA signature of an individual patient’s tumor.”
“These advanced sequencing technologies not only extend lifespans and improve cure rates for cancer patients through application to early screening; in the field of cancer diagnosis and monitoring they can also assist in the formulation of personalized clinical diagnostics and treatment plans, as well as allow doctors to accurately relocate the follow-up development of cancer patients after the primary treatment,” Wang wrote.
Based in China, Genetron Health describes itself as a “leading precision oncology platform company” with products and services related to cancer screening, diagnosis, and monitoring.
Liquid and Synthetic Biopsies
Liquid biopsies, in which blood or urine samples are analyzed for presence of biomarkers, provide an “easier and less invasive” alternative to conventional surgical biopsies for cancer diagnosis, the WEF article notes.
These tests allow clinicians to “pin down the disease subtype, identify the appropriate treatment and closely track patient response, adjusting course, if necessary, as each case requires—precision medicine in action,” wrote Merck Group CEO Belén Garijo, MD, in an earlier WEF commentary.
The WEF article also highlighted “synthetic biopsy” technology developed by Earli, Inc., a company based in Redwood City, Calif.
As explained in a Wired story, “Earli’s approach essentially forces the cancer to reveal itself. Bioengineered DNA is injected into the body. When it enters cancer cells, it forces them to produce a synthetic biomarker not normally found in humans.”
The biomarker can be detected in blood or breath tests, Wired noted. A radioactive tracer is used to determine the cancer’s location in the body.
“Pancreatic cancer is one of the deadliest cancers,” the WEF article notes. “It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years.”
The test is based on a technology known as high-conductance dielectrophoresis (DEP), according to a UC San Diego press release. “It detects extracellular vesicles (EVs), which contain tumor proteins that are released into circulation by cancer cells as part of a poorly understood intercellular communication network,” the press release states. “Artificial intelligence-enabled protein marker analysis is then used to predict the likelihood of malignancy.”
The test detected 95.5% of stage 1 pancreatic cancers, 74.4% of stage 1 ovarian cancers, and 73.1% of pathologic stage 1A lethally aggressive serous ovarian adenocarcinomas, they wrote.
“These results are five times more accurate in detecting early-stage cancer than current liquid biopsy multi-cancer detection tests,” said co-senior author Scott M. Lippman, MD.
Look to Dark Daily’s ebrief on Wednesday for the remainder of breakthroughs the World Economic Forum identifies as top advancements in the fight to defeat cancer.
Findings could lead to new therapies and clinical laboratory biomarkers for detecting and defeating antibiotic-resistant bacteria
Once again, new research shows that human gut bacteria (microbiota) may be useful in fighting antibiotic-resistant bacterial infections. The study findings could provide new therapeutics and clinical laboratory biomarkers for diagnosing and treating severe gastrointestinal disorders.
Antibiotic-resistant bacterial infections often appear in patients with chronic intestinal conditions and in those with long-term antibiotic use. Enterobacteriaceae is a large family of gram-negative bacteria that includes more than 30 genera and over 100 species.
“Despite two decades of microbiome research, we are just beginning to understand how to define health-promoting features of the gut microbiome,” said Marie-Madlen Pust, PhD, a computational postdoctoral researcher at the Broad Institute and co-first author of the paper, in the news release.
“Part of the challenge is that each person’s microbiome is unique. This collaborative effort allowed us to functionally characterize the different mechanisms of action these bacteria use to reduce pathogen load and gut inflammation,” she added.
The researchers identified a way to treat patients infected by antibiotic-resistant strains of bacteria that does not involve antibiotics. Should further research validate these early findings, this could be a viable approach to treating patients with this condition.
“Microbiome studies can often consist of analyzing collections of genetic sequences, without understanding what each gene does or why certain microbes are beneficial,” said Ramnik Xavier, MD (above), director of Broad Institute’s immunology program, co-director of the infectious disease and microbiome program, and co-senior author on the study, in a news release. “Trying to uncover that function is the next frontier, and this is a nice first step towards figuring out how microbial metabolites influence health and inflammation.” Clinical laboratories that test for intestinal conditions caused by antibiotic resistance will want to follow the Broad Institute’s research. (Photo copyright: Broad Institute.)
Suppressing Growth of Antibiotic-resistant Bacteria
To perform their research, the scientists isolated about 40 strains of bacteria from the stools of five healthy fecal donors. They then used those stool samples in fecal microbiota transplants to treat mice that had been infected with either Escherichia coli (E. coli) or Klebsiella, both forms of Enterobacteriaceae. The scientists tested different combinations of the 40 strains and identified 18 that suppressed the growth of Enterobacteriaceae.
“Antibiotic-resistant Enterobacteriaceae such as E. coli and Klebsiella bacteria are common in hospitals, where they can proliferate in the gut of patients and cause dangerous systemic infections that are difficult to treat. Some research suggests that Enterobacteriaceae also perpetuates inflammation in the intestine and infection by other microbes,” the Broad Institute news release notes.
The researchers discovered that Klebsiella changed the gene expression in carbohydrate uptake and metabolism in the Klebsiella-infected mice that were treated with the 18 beneficial strains. The gene expression included the downregulating of gluconate kinase and transporter genes, which revealed there is increased competition among gut bacteria for nutrients.
When combined, these 18 strains alleviated inflammation in the guts of the treated mice by depriving the harmful gut bacteria of carbohydrates. This non-antibiotic approach also prevented harmful bacteria from colonizing in the gut.
“In partnership with the Broad’s Metabolomics Platform, led by senior director and study co-author Clary Clish, PhD, they analyzed samples from pediatric patients with ulcerative colitis, looking for the presence of alternate gluconate pathway genes of gut microbes and fecal gluconate levels. They found higher levels of gluconate linked to more gluconate-consuming Enterobacteriaceae in samples from pediatric patients with ongoing inflammation, indicated by high levels of the protein calprotectin,” the study authors wrote in Nature.
“Together, the findings suggest that Enterobacteriaceae processes gluconate as a key nutrient and contributes to inflammation in patients. But when a gut microbiome includes the 18 helpful strains, they likely compete with Enterobacteriaceae for gluconate and other nutrient sources, limiting the proliferation of the harmful bacteria,” the scientists concluded.
Promising New Bacterial Therapies
This research could ultimately lead to the development of fecal microbiota transplants for individuals to eradicate antibiotic-resistant bacteria in a more objective and specific manner, with fewer side effects than current treatments.
“Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection,” the scientists wrote in Nature.
According to the news release, they plan to continue research to “uncover the identity and function of unknown metabolites that contribute to gut health and inflammation.” The team hopes to discover how different bacteria compete with each other, and to develop microbial therapeutics that improve gut microbiome and curb bacterial infections.
More studies are needed to prove the efficacy of this type of fecal bacterial treatment. However, this research demonstrates how using nano processes enabled by new technologies to identify the actual work of proteins, RNA, and DNA in the body cheaply, faster, and with greater precision, will open doors to both therapeutic and diagnostic clinical laboratory biomarkers.
Proof-of-concept study may eventually lead to new clinical laboratory urine tests for fast, non-invasive detection of cancer
Here is the latest example of researchers finding useful biomarkers in urine for diagnosing certain cancers. The discovery comes from the University of Michigan Health Rogel Cancer Center, where, in a proof-of-concept study, scientists developed a urine-based test that screens for circulating free DNA (cfDNA) fragments (aka, cell-free DNA) released by tumors in the head and neck. If they confirm these findings, it’s possible the technology could be adapted into a non-invasive clinical laboratory test for selected cancers.
One such cancer is human papillomavirus (HPV) which, though “widely recognized for causing cervical cancer” is “increasingly found to cause cancers in the mouth, throat, and other head and neck regions,” according to a U-M Medical School press release.
The U-M study findings could lead to an early, non-invasive test for the detection of cancer, as compared to traditional urine or blood-based liquid biopsy testing.
“In this study, we provide evidence to support the hypothesis that conventional assays do not detect ultrashort fragments found in urine since they are designed to support longer DNA fragments. Our team used an unconventional approach to develop a urine test for HPV-positive head and neck cancer ctDNA detection,” said Chandan Bhambhani, PhD (above), Research Lab Specialist Intermediate at University of Michigan and co-first author of the study, in a news release. Clinical laboratories may soon have a new urine-based test for detecting cancer. (Photo copyright: LinkedIn.)
According to the researchers, benefits of urine testing include:
Testing with urine is convenient for people who may be unable to access healthcare and phlebotomy services.
Urine has low biohazard risk and may be easily collected in large amounts, compared with blood.
Ongoing collection of urine could make way for TR-ctDNA “kinetics to be used as a high time-resolution biomarker” to monitor patients’ response to treatment.
However, urine, the researchers cautioned, must be analyzed in a different manner if it is to be comparable in efficiency to blood-based ctDNA testing.
“There have been mixed reports on the efficiency of TR-ctDNA detection compared with that of blood ctDNA. A potentially crucial factor for the analysis of TR-ctDNA is knowing the length of TR-ctDNA fragments present in urine, because this affects assay design for optimal sensitivity in TR-ctDNA detection,” the researchers explained.
New Assay Detects Ultrashort DNA Fragments
To complete their study, the U-M researchers developed an ultrashort HPV droplet digital PCR (polymerase chain reaction) assay that enabled detection of TR-ctDNA from HPV-associated oropharyngeal squamous cell carcinoma (HPV OPSCC), BioTechniques reported.
The assay was made to target the HPV16 E6 (Human papillomavirus 16) gene and to measure TR-ctDNA in patients with HPV OPSCC, the JCI Insight paper noted.
“The HPV16 E6 gene represents a highly recurrent ctDNA target in the population of patients with HPV OPSCC,” the researchers wrote in JCI Insight, adding:
Targeting ultrashort fragments was essential “for robust TR-ctDNA detection.”
Results in urine with patients with HPV OPSCC was consistent with results from plasma ctDNA.
The test, still in the discovery phase, was mailed to patients who were being treated for the disease and who reside within 100 miles of Ann Arbor, Mich. They returned urine samples for testing at the U-M lab and to get insights into possible post-treatment needs.
“Using longitudinal urine samples from a small case series, we showed proof of concept for early detection of cancer recurrence. Thus, our results indicate that by targeting ultrashort DNA fragments, TR-ctDNA becomes a viable approach for HPV OPSCC detection and potentially for cancer recurrence monitoring after treatment,” the authors wrote.
Further Studies, Possible Test Expansion
HPV infection—and especially HPV type 16—is a growing risk factor for oropharyngeal cancers, according to the National Cancer Institute.
The U-M Rogel Cancer Center scientists plan more studies to leverage the information urine may carry about an individual’s health. The researchers intend to expand the scope of their new test to other cancers including breast cancer and acute myeloid leukemia.
“The test that has been developed has detected cancer far earlier than would typically happen based on clinical imaging. As such, these promising results have given us the confidence to broaden the scope of this study, seeking to expanding distribution even further,” said J. Chad Brenner, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery, U-M Medicine, and co-senior author of the study, in the news release.
The University of Michigan Health study exemplifies scientists’ commitment to new categories of biomarkers that can be used for medical laboratory tests and prescription drugs. And by focusing on urine, the researchers made it possible for patients to collect specimens themselves and send them to the medical laboratory for analysis and reporting.
