UCSF Genomics Diagnostics Team Uses Next-Gen Sequencing as a ‘Laboratory-Developed Test’ to Reveal an Elusive Pathogen’s DNA and Save a Teen’s Life
It took UCSF physicians just 48 hours to identify the bacteria in cerebrospinal fluid that was causing fourteen-year-old Joshua Osborn’s hydrocephalus and status epilepticus
There’s rich irony in the FDA’s recent announcement that it would move forward with plans to regulate “laboratory-developed tests ” (LDTs) just weeks after the national media published stories about how innovative use of an LDT helped physicians make an accurate diagnosis that saved the life of seriously-ill 14-year old boy.
Pathologists and clinical laboratory managers may be aware of the case of Joshua Osborn. It was a laboratory-developed test that used next-generation gene sequencing in a unique approach that gave his care team the diagnostic information they needed to select the right therapies for his condition.
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Sequencing Developers’ Unprecedented Success Drives More Ambitious Goals For Genomics X Prize
New Genomic X PRIZE goals/subjects accelerate the drive toward personalized medicine
Swift improvements to the accuracy, speed, and lower cost of rapid gene sequencing have caused the sponsors of the globally-known X PRIZE to revamp their offer of a $10 million award to a team that is first to achieve a defined milestone in whole human genome sequencing.
Pathologists and clinical laboratory managers will be interested to learn how, last month, the X PRIZE Foundation announced a number of major changes to the formerly-named Archon Genomics X PRIZE. Most significantly, competition sponsors changed the subject from 100 genomes from unspecified donors, to genomes from 100 healthy centenarians.
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Mayo Clinic Researchers Uses Exome Sequencing to Identify Individuals at Risk of Hereditary Cancer
Half of the people tested were unaware of their genetic risk for contracting the disease
Existing clinical laboratory genetic screening guidelines may be inadequate when it comes to finding people at risk of hereditary breast-ovarian cancer syndromes and Lynch syndrome (aka, hereditary nonpolyposis colorectal cancer). That’s according to a study conducted at the Mayo Clinic in Rochester, Minn., which found that about half of the study participants were unaware of their genetic predisposition to the diseases.
Mayo found that 550 people who participated in the study (1.24%) were “carriers of the hereditary mutations.” The researchers also determined that half of those people were unaware they had a genetic risk of cancer, and 40% did not meet genetic testing guidelines, according to a Mayo Clinic news story.
The discoveries were made following exome sequencing, which the Mayo Clinic news story described as the “protein-coding regions of genes” and the sites for most disease-causing mutations.
“Early detection of genetic markers for these conditions can lead to proactive screenings and targeted therapies, potentially saving lives of people and their family members,” said lead author Niloy Jewel Samadder, MD, gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center.
The Mayo researchers published their findings in the journal JCO Precision Oncology titled, “Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.”
“This study is a wake-up call, showing us that current national guidelines for genetic screenings are missing too many people at high risk of cancer,” said lead author Niloy Jewel Samadder, MD (above), gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center. New screening guidelines may increase the role of clinical laboratories in helping physicians identify patients at risk of certain hereditary cancers. (Photo copyright: Mayo Clinic.)
Advancing Personalized Medicine
“The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC (hereditary breast and ovarian cancer) and LS (Lynch syndrome),” the authors wrote in JCO Precision Oncology.
Their work was a project of the Mayo Clinic Center for Individualized Medicine Tapestry study, which aims at advancing personalized medicine and developing a dataset for genetic research.
For the current study, Helix, a San Mateo, Calif. population genomics company, collaborated with Mayo Clinic to perform exome sequencing on the following genes:
- BRCA1 and BRCA2 genes (hereditary breast and ovarian cancer).
- MLH1, MHSH2, MSH6, PMS2, and EPCAM genes (Lynch syndrome).
According to the Mayo Clinic:
- BRCA1 can lead to a 50% chance of breast cancer, and a 40% chance of ovarian cancer, respectively, as well as other cancers.
- BRCA2 mutations suggest risk of breast cancer and ovarian cancer is 50% and 20%, respectively.
- Lynch syndrome relates to an 80% lifetime risk of developing colorectal cancer and 50% risk of uterine and endometrial cancer.
Mayo/Helix researchers performed genetic screenings on more than 44,000 study participants. According to their published study, of the 550 people who were found to have hereditary breast cancer or Lynch syndrome:
- 387 had hereditary breast and ovarian cancer (27.2% BRCA1, 42.8% BRCA2).
- 163 had lynch syndrome (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM).
- 52.1% were newly diagnosed carriers.
- 39.2% of the 550 carriers did not meet genetic evaluation criteria set by the National Comprehensive Cancer Network (NCCN).
- Participants recruited by researchers hailed from Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla.
- Minorities were less likely to meet the NCCN criteria than those who reported as White (51.5% as compared to 37.5%).
“Our results emphasize the importance of expanding genetic screening to identify people at risk for these cancer predisposition syndromes,” Samadder said.
Exome Data in EHRs
Exomes of more than 100,000 Mayo Clinic patients have been sequenced and the results are being included in the patients’ electronic health records (EHR) as part of the Tapestry project. This gives clinicians access to patient information in the EHRs so that the right tests can be ordered at the right time, Mayo Clinic noted in its article.
“Embedding genomic data into the patient’s chart in a way that is easy to locate and access will assist doctors in making important decisions and advance the future of genomically informed medicine.” said Cherisse Marcou, PhD, co-director and vice chair of information technology and bioinformatics in Mayo’s Clinical Genomics laboratory.
While more research is needed, Mayo Clinic’s accomplishments suggest advancements in gene sequencing and technologies are making way for data-driven tools to aid physicians.
As the cost of gene sequencing continue to fall due to improvement in the technologies, more screenings for health risk factors in individuals will likely become economically feasible. This may increase the role medical laboratories play in helping doctors use exomes and whole genome sequencing to screen patients for risk of specific cancers and health conditions.
—Donna Marie Pocius
Related Information:
Mayo Clinic Uncovers Genetic Cancer Risk in 550 Patients
Mayo Clinic’s Data-Driven Quest to Advance Individualized Medicine
Mount Sinai Researchers Create a “Smart Tweezer” That Can Isolate a Single Bacterium from a Microbiome Sample Prior to Genetic Sequencing
New technology could enable genetic scientists to identify antibiotic resistant genes and help physicians choose better treatments for genetic diseases
Genomic scientists at the Icahn School of Medicine at Mount Sinai Medical Center in New York City have developed what they call a “smart tweezer” that enables researchers to isolate a single bacterium from a patient’s microbiome in preparation for genetic sequencing. Though primarily intended for research purposes, the new technology could someday be used by clinical laboratories and microbiologists to help physicians diagnose chronic disease and choose appropriate genetic therapies.
The researchers designed their new technology—called mEnrich-seq—to improve the effectiveness of research into the complex communities of microorganisms that reside in the microbiomes within the human body. The discovery “ushers in a new era of precision in microbiome research,” according to a Mount Sinai Hospital press release.
“Metagenomics has enabled the comprehensive study of microbiomes. However, many applications would benefit from a method that sequences specific bacterial taxa of interest, but not most background taxa. We developed mEnrich-seq (in which ‘m’ stands for methylation and seq for sequencing) for enriching taxa of interest from metagenomic DNA before sequencing,” the scientists wrote in a paper they published in Nature Methods titled, “mEnrich-seq: Methylation-Guided Enrichment Sequencing of Bacterial Taxa of Interest from Microbiome.”
“Imagine you’re a scientist who needs to study one particular type of bacteria in a complex environment. It’s like trying to find a needle in a large haystack,” said the study’s senior author Gang Fang, PhD (above), Professor of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai Medical Center, in a press release. “mEnrich-seq essentially gives researchers a ‘smart tweezer’ to pick up the needle they’re interested in,” he added. Might smart tweezers one day be used to help physicians and clinical laboratories diagnose and treat genetic diseases? (Photo copyright: Icahn School of Medicine.)
Addressing a Technology Gap in Genetic Research
Any imbalance or decrease in the variety of the body’s microorganisms can lead to an increased risk of illness and disease.
“Imbalance of the normal gut microbiota, for example, have been linked with conditions including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), obesity, type 2 diabetes, and allergies. Meanwhile, the vaginal microbiome seems to impact sexual and reproductive health,” Inside Precision Medicine noted.
In researching the microbiome, many scientists “focus on studying specific types of bacteria within a sample, rather than looking at each type of bacteria present,” the press release states. The limitation of this method is that a specific bacterium is just one part of a complicated environment that includes other bacteria, viruses, fungi and host cells, each with their own unique DNA.
“mEnrich-seq effectively distinguishes bacteria of interest from the vast background by exploiting the ‘secret codes’ written on bacterial DNA that bacteria use naturally to differentiate among each other as part of their native immune systems,” the press release notes. “This new strategy addresses a critical technology gap, as previously researchers would need to isolate specific bacterial strains from a given sample using culture media that selectively grow the specific bacterium—a time-consuming process that works for some bacteria, but not others. mEnrich-seq, in contrast, can directly recover the genome(s) of bacteria of interest from the microbiome sample without culturing.”
Isolating Hard to Culture Bacteria
To conduct their study, the Icahn researchers used mEnrich-seq to analyze urine samples taken from three patients with urinary tract infections (UTIs) to reconstruct Escherichia coli (E. Coli) genomes. They discovered their “smart tweezer” covered more than 99.97% of the genomes across all samples. This facilitated a comprehensive examination of antibiotic-resistant genes in each genome. They found mEnrich-seq had better sensitivity than standard study methods of the urine microbiome.
They also used mEnrich-seq to selectively examine the genomes of Akkermansia muciniphila (A. muciniphila), a bacterium that colonizes the intestinal tract and has been shown to have benefits for obesity and Type 2 diabetes as well as a response to cancer immunotherapies.
“Akkermansia is very hard to culture,” Fang told GenomeWeb. “It would take weeks for you to culture it, and you need special equipment, special expertise. It’s very tedious.”
mEnrich-seq was able to quickly segregate it from more than 99.7% of A. muciniphila genomes in the samples.
Combatting Antibiotic Resistance Worldwide
According to the press release, mEnrich-seq could potentially be beneficial to future microbiome research due to:
- Cost-Effectiveness: It offers a more economical approach to microbiome research, particularly beneficial in large-scale studies where resources may be limited.
- Broad Applicability: The method can focus on a wide range of bacteria, making it a versatile tool for both research and clinical applications.
- Medical Breakthroughs: By enabling more targeted research, mEnrich-seq could accelerate the development of new diagnostic tools and treatments.
“One of the most exciting aspects of mEnrich-seq is its potential to uncover previously missed details, like antibiotic resistance genes that traditional sequencing methods couldn’t detect due to a lack of sensitivity,” Fang said in the news release. “This could be a significant step forward in combating the global issue of antibiotic resistance.”
More research and clinical trials are needed before mEnrich-seq can be used in the medical field. The Icahn researchers plan to refine their novel genetic tool to improve its efficiency and broaden its range of applications. They also intend to collaborate with physicians and other healthcare professionals to validate how it could be used in clinical environments.
Should all this come to pass, hospital infection control teams, clinical laboratories, and microbiology labs would welcome a technology that would improve their ability to detect details—such as antibiotic resistant genes—that enable a faster and more accurate diagnosis of a patient’s infection. In turn, that could contribute to better patient outcomes.
—JP Schlingman
Related Information:
‘Smart Tweezer’ Can Pluck Out Single Bacterium Target from Microbiome
mEnrich-seq: Methylation-guided Enrichment Sequencing of Bacterial Taxa of Interest from Microbiome
Genomic ‘Tweezer’ Ushers in a New Era of Precision in Microbiome Research
Molecular Tweezers Can Precisely Select Microbiome Bacteria
Identification of DNA Motifs that Regulate DNA Methylation
New Bacterial Epigenetic Sequencing Method Could Be Boon for Complex Microbiome Analyses
