Why should this matter to pathologists and clinical laboratories? Because a broader knowledge of how DNA evolves may help researchers and healthcare providers better understand how a modern family’s DNA can change over generations. In turn, these insights may lead to precision medicine tools for personalized diagnosis and treatment.
“We find that a low fraction, 1.5 to 7%, of the human genome is uniquely human, with the remainder comprising lineages shared with archaic hominins from either ILS [incomplete lineage sorting] or [genetic] admixture,” wrote the paper’s authors.
To complete their study, the researchers used DNA extracted from fossils of Neanderthals and Denisovans, as well as genetic information from 279 people from various locations around the world.
One goal was to determine what part of a modern human’s genome is truly unique. Though only a small percentage of our entire genome, those portions are important.
“We can tell those regions of the genome are highly enriched for genes that have to do with neural development and brain function,” Richard Green, PhD, Associate Professor of Biomolecular Engineering at the University of California Santa Cruz and co-author of the paper, told the Associated Press (AP).
In addition to highlighting what makes modern humans unique as a species, the study also suggests, “That we’re actually a very young species. Not that long ago, we shared the planet with other human lineages,” said Joshua Akey, PhD, Professor of Ecology and Evolutionary Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Akey co-authored the Science Advances research paper.
Human/Neanderthal Genetic Overlap
The genetic research being conducted at the University of California Santa Cruz is just the most recent in a flurry of studies over the past decade investigating the Neanderthal genome. Most of these studies point to the vast similarities between humans and Neanderthals, but also to how similar humans are to each other.
Practically Everyone Has Neanderthal DNA
Understanding that humans and Neanderthals are 93-98.5% similar genetically may—or may not—come as a surprise. In delving into those similarities and differences researchers are making interesting and potentially important discoveries.
For example, researchers have studied a gene that occurs in both modern humans and Neanderthal fossils that has to do with how the body responds to carcinogenic hydrocarbons, such as smoke from burning wood. Neanderthals were far more sensitive to the carcinogens, but also had more genetic variants, such as single-nucleotide polymorphisms, that could neutralize their effects.
Most modern humans carry some Neanderthal DNA. For some time, scientists thought that Africans likely did not carry Neanderthal DNA, since ancient people tended to migrate out of Africa and met Neanderthals in Europe. More recent research, however, shows that migration patterns were more complex than previously thought, and that the ancient people migrated back to Africa bringing Neanderthal DNA with them.
“Our results show this history was much more interesting and there were many waves of dispersal out of Africa, some of which led to admixture between modern humans and Neanderthals that we see in the genomes of all living individuals today,” Akey told CNN.
Neanderthal DNA and COVID-19
Researchers have found that having Neanderthal DNA may affect the health of modern people who carry it. Perception of pain, immune system function, and even hair color and sleeping patterns have been associated with having Neanderthal DNA.
Scientists have even found a potential link between severe COVID-19 infection and Neanderthal DNA, CNN reported.
The researchers added, “It turns out that this gene variant was inherited by modern humans from the Neanderthals when they interbred some 60,000 years ago. Today, the people who inherited this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus SARS-CoV-2.”
Of course, these links and associations are preliminary science. John Capra, PhD, Research Associate Professor of Biological Sciences and Associate Professor of Biomedical Informatics at the University of California, San Francisco says, “We can’t blame Neanderthals for COVID. That’s a damaging response, and that’s why I want to emphasize so much [that] the social and environmental factors are the real things that people should be worrying about,” he told CNN.
“That said,” he continued, “as a geneticist, I think it is important to know the evolutionary history of the genetic variants we find that do have effects on traits. The effects of Neanderthal DNA traits are detectable, but they’re modest.”
Nevertheless, genetic scientists agree that understanding the genetic roots of disorders could lead to breakthroughs that result in new types of clinical laboratory tests designed to guide precision medicine treatments.
Such a test, if proved safe and accurate for clinical use, could be a useful diagnostic tool for anatomic pathologists
What would it mean to anatomic pathology if breast cancer could be diagnosed in an hour from a fine needle aspiration (FNA) rather than a core biopsy? A new test created by researchers affiliated with Massachusetts General Hospital in Boston may be just such a game changer. Especially in remote locations where clinical laboratory resources are in short supply.
Regardless of how the next round of research and clinical studies turn out, one reason this development is significant is that it demonstrates how newer technologies and analytical software are being combined to create a faster diagnostic test for different types of cancer.
Another benefit to this research is that it may utilize simpler, less expensive instruments. In fact, the researchers said this test can be performed for about $5. For these reasons, pathologists may want to follow the progress of these researchers as they work to improve this test so it can be used in clinical care.
Affordable Image Cytometry of FNA Specimens
Though still in development, the new image cytometry system, dubbed CytoPAN, has demonstrated the ability to diagnose breast cancer within a one-hour time frame, and, according to the study published in Science Translational Medicine, “is devoid of moving parts for stable operations, harnesses optimized antibody kits for multiplexed analysis, and offers a user-friendly interface with automated analysis for rapid diagnoses.”
The international researcher team included scientists from:
“Here, we report the development and validation of an affordable image cytometry system that allows automated and same-day molecular analyses of fine needle aspiration (FNA) specimens. Termed CytoPAN, for portable fluorescence-based image cytometry analyzer, the system performs multichannel imaging for cancer diagnosis and subtyping,” the researchers wrote.
The CytoPAN technique is minimally invasive, they note, and only requires a few cellular specimens to determine if breast cancer cells are present, with results available in one hour.
“Unfortunately, in many low- and middle-income countries, [breast cancer] diagnosis often takes an extraordinarily long time—up to a few months—due to a lack of specialists and limited laboratory infrastructure,” Hyungsoon Im, PhD, Assistant Professor at Harvard Medical School and one of the researchers involved in the project, told United Press International (UPI).
“From a public health aspect, it is critically important to develop new diagnostic methods that overcome these barriers,” he added.
Because FNA testing is less invasive than surgical biopsy collection, it has fewer complications and is generally considered safe. Thus, it is “feasible to be performed even in resource-limiting settings at much lower costs,” Im told UPI. “This could lead to earlier treatment and accelerate new drug testing in clinical trials.”
CytoPAN Testing and Additional Trials
The researchers tested CytoPAN on 68 breast cancer patients in South Korea.
“To determine the clinical utility of the approach,” they wrote in the published study, “we next conducted a prospective clinical study in which the FNA could be directly compared to conventional pathology results. We enrolled treatment-native patients at the Kyungpook National University Chilgok Hospital (Daegu, South Korea) and who were referred for primary surgery. All patients consented to have a preoperative breast FNA before clinically indicated surgery. The breast masses were visualized by ultrasound or computed tomography, and a coaxial needle was introduced through which FNA samples (CytoPAN) and core biopsies were obtained. Surgical specimens and/or core biopsies were processed by routine pathology and served as the gold standard.”
The CytoPAN platform detected the presence of breast cancer cells with a 100% accuracy, using as few as 50 harvested cells per collected specimen.
The test also successfully identified two key breast cancer biomarkers:
“We are also preparing additional trials in the US and other countries,” Im told UPI. “The success in those trials will (hopefully) accelerate … widespread adoption of the technology.”
The researchers are currently testing CytoPAN on a larger number of patients in Botswana, with funding from the US federal National Institutes of Health (NIH).
According to the American Cancer Society (ACS), approximately 300,000 individuals are diagnosed with breast cancer annually in the US. The Union for International Cancer Control (UICC) states on their website that, globally, there are more than two million new cases of breast cancer diagnosed each year. And more than 600,000 people died from breast cancer worldwide in 2018. A disproportionate number of those deaths occurred in developing countries that have limited resources to diagnose and treat the disease.
Additional Research for Other Applications in Cancer Testing and Pathology
The new CytoPAN technology requires minimal training, according to the researchers, and only costs about $5 per test kit. This is substantially less expensive than the price associated with other tests available on the market, UPI noted.
Though additional research and clinical trials are needed before CytoPAN will be available for widespread clinical use, a cost-effective, relatively non-invasive test that can accurately diagnose cancer within an hour would be transformational for anatomic pathology and, potentially, could save many lives.
Number of patients eligible for genome-driven oncology therapy is increasing, but the percentage who reportedly benefit from the therapy remains at less than 5%
Advances in precision medicine in oncology (precision oncology) are fueling the need for clinical laboratory companion diagnostic tests that help physicians choose the best treatment protocols. In fact, this is a fast-growing area of clinical diagnostics for the nation’s anatomic pathologists. However, some experts in the field of genome-based cancer treatments disagree over whether such treatments offer more hype than hope.
Prasad and his colleagues evaluated 31 US Food and Drug
Administration (FDA) approved drugs, which were “genome-targeted” or
“genome-informed” for 38 indications between 2006 and 2018. The researchers
sought to answer the question, “How many US patients with cancer are eligible
for and benefit annually from genome-targeted therapies approved by the US Food
and Drug Administration?”
They found that in 2018 only 8.33% of 609,640 patients with
metastatic cancer were eligible for genome-targeted therapy—though this was an
increase from 5.09% in 2006.
Even more telling from Prasad’s view, his research team concluded
that only 4.9% had benefited from such treatments. Prasad’s study found the
percentage of patients estimated to have benefited from genome-informed therapy
rose from 1.3% in 2006 to 6.62% in 2018.
“Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer,” the researchers concluded. “To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued.”
A Value versus Volume Argument?
Hyman, who leads a team of oncologists that conduct dozens
of clinical trials and molecularly selected “basket studies” each year,
countered Prasad’s assertions by noting the increase in the number of patients
who qualify for precision oncology treatments.
As reported in Science, Hyman said during his AACR
presentation that Sloan Kettering matched 15% of the 25,000 patients’ tumors it
tested with FDA-approved drugs and 10% with drugs in clinical trials.
“I think this is certainly not hype,” he said during the
Hyman added that another 10% to 15% of patient tumors have a
DNA change that matches a potential drug tested in animals. He expects “basket”
trials to further increase the patient pool by identifying drugs that can work
for multiple tumor types.
The US National Institute of Health (NIH) describes “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.”
Are Expectations of Precision Medicine Exaggerated?
A profile in MIT Technology Review, titled, “The Skeptic: What Precision Medicine Revolution?,” describes Prasad’s reputation as a “professional scold” noting the 36-year-old professor’s “sharp critiques of contemporary biomedical research, including personalized medicine.” Nevertheless, Prasad is not alone in arguing that precision oncology’s promise is often exaggerated.
“Like most ‘moonshot’ medical research initiatives,
precision medicine is likely to fall short of expectations,” Joyner wrote.
“Medical problems and their underlying biology are not linear engineering
exercises and solving them is more than a matter of vision, money, and will.”
“Although some niche applications have been found for
precision medicine—and gene therapy is now becoming a reality for a few rare
diseases—the effects on public health are miniscule while the costs are astronomical,”
Hope for Precision Medicine Remains High
However, optimism over precision oncology among some industry leaders has not waned. Cindy Perettie, CEO of molecular information company Foundation Medicine of Cambridge, Mass., argues genome-directed treatments have reached an “inflection point.”
“Personalized cancer treatment is a possibility for more patients than ever thanks to the advent of targeted therapies,” she told Genetic Engineering and Biotechnology News. “With a growing number of new treatments—including two pan-tumor approvals—the need for broad molecular diagnostic tools to match patients with these therapies has never been greater. We continue to advance our understanding of cancer as a disease of the genome—one in which treatment decisions can be informed by insight into the genomic changes that contribute to each patient’s unique cancer.”
Prasad acknowledges genome-driven therapies are beneficial for some cancers. However, he told MIT Technology Review the data doesn’t support the “rhetoric that we’re reaching exponential growth, or that is taking off, or there’s an inflection point” signaling rapid new advancements.
“Right now, we are investing heavily in immunotherapy and heavily in genomic therapy, but in other categories of drugs, such as cytotoxic drugs, we have stopped investigating in them,” he told Medscape Medical News. “But it’s foolish to do this—we need to have the vision to look beyond the fads we live by in cancer medicine and do things in a broader way,” he added.
“So, I support broader funding because you have to sustain
efforts even when things are not in vogue if you want to make progress,” Prasad
Time will tell if precision oncology can fulfill its
promise. If it does, anatomic pathologists will play an important role in
pinpointing patients most likely to benefit from genome-driven treatments.
One thing that the debate between proponents of precision
medicine in oncology and their critics makes clear is that more and better
clinical studies are needed to document the true effectiveness of target
therapies for oncology patients. Such evidence will only reinforce the
essential role that anatomic pathologists play in diagnosis, guiding
therapeutic decisions, and monitoring the progress of cancer patients.
Innovative technological advances could potentially provide clinical laboratories, pathology groups, and medical researchers with improved methodologies for designing, performing, and analyzing lab tests that use genetic information
The enzyme enables the reproduction of large quantities of Ribonucleic acid (RNA) to be accurately duplicated. It also can perform reverse transcription and scrutinize itself while copying genetic information, which will enable both researchers and clinical laboratories to improve the accuracy of gene sequencing where RNA is involved.
It is also one more example of how mass spectrometry is being used by researchers to develop new types of diagnostic assays that perform as well as traditional clinical laboratory testing methods, such as chemistry and immunoassay.