Expanded ‘Cancer Gene Census’ is expected to accelerate development of new therapeutics and biomarker-based personalized medicine diagnostic tests for disease; could be useful for anatomic pathologists
Oncology is one of the fastest-developing fields in precision medicine and use of DNA-based diagnostics. Surgical pathologists are helping many cancer patients benefit from the use of a companion genetic test that shows their tumors are likely to respond to a specific drug or therapy. Consistent with that work, researchers in the United Kingdom (UK) have now produced the first comprehensive summary of all genes known to be strongly associated with cancer in humans.
The expansion of the “Cancer Gene Census” is noteworthy for anatomic pathologists who should expect to see the information increase the understanding of cancer causes and accelerate the development of new therapeutics and biomarker-based molecular diagnostics.
In this latest Cancer Gene Census, researchers from the Wellcome Sanger Institute (WSI) used CRISPR gene editing systems to produce an expanded catalog of 719 cancer-driving genes in humans.
According to a review article on the project published in Nature Reviews Cancer, “The recent expansion includes functional and mechanistic descriptions of how each gene contributes to disease generation in terms of the key cancer hallmarks and the impact of mutations on gene and protein function.”
The 2018 Cancer Gene Census from the Wellcome Sanger Institute in the United Kingdom summarizes 719 genes suspected of causing cancer in humans and describes how they function across all forms of the disease. (Photo copyright: Wellcome Sanger Institute.)
The Catalogue of Somatic Mutations in Cancer (COSMIC) provided the foundation for the WSI’s research. It involved manually condensing almost 2,000 research papers to develop evidence for a gene’s role in cancer.
While the COSMIC database characterizes more than 1,500
forms of human cancer and types of mutations, the U.K.’s Cancer Gene Census
goes further and “describes which genes are fundamentally involved and
describes how these genes cause disease,” a Wellcome Sanger Institute news
release states.
“For the first time ever, functional changes to these genes
are summarized in terms of the 10 cancer hallmarks—biological processes that
drive cancer,” the statement explains. “Mutations in some genes lead to errors
in repairing DNA, whereas mutations in other genes can suppress the immune
system or promote tumor invasion or spreading. Across the 700 genes in the
Cancer Gene Census, many have two or more different ways of causing cancer.”
Zbyslaw Sondka,
PhD, lead author on the WSI project, believes their study has provided
scientists with much needed new insights. “Scientific literature is very compartmentalized.
With the Cancer Gene Census, we’re breaking down all those compartments and
putting everything together to reveal the full complexity of cancer genetics,” he
noted in a WSI
article.
“This is the broadest and most detailed review of human
cancer genes and their functions ever created and will be continually updated
and expanded to keep it at the forefront of cancer genetics research,” Sondka
added.
Making Precision
Medicine More Precise
An understanding of the roles played by different genes in
various cancers is key to enabling researchers to develop drugs that will be
effective against individual cancers.
“The combination of the Cancer Gene Census with COSMIC will
enable researchers to investigate individual mutations and try to find good
targets for anti-cancer drugs based on the actual processes involved,” Simon Forbes, PhD,
Senior Author of the Cancer Gene Census paper and Director of COSMIC at the
Wellcome Sanger Institute, stated in the WSI news release.
Simon Forbes, PhD (above), Director of COSMIC at the Wellcome Sanger Institute and Senior Author of the Cancer Gene Census paper, believes the institute’s latest Cancer Gene Census, which catalogs 719 cancer-causing genes, will “help make precision medicine even more precise” by allowing “biologists and pharmaceutical scientists to see patterns and target particular pathways with anti-cancer drugs, not solely single genes.” (Photo copyright: Wellcome Sanger Institute.)
The path to precision medicine cancer treatments was further boosted this month when Wellcome Sanger Institute researchers, in partnership with the Open Targets Platform, announced a new system to prioritize and rank 600 drug targets that show the most promise for development into cancer treatments, noted a WSI statement.
The WSI/Open Targets team published its research in the international science journal Nature.
CRISPR-Cas9 and
Personalized Medicine
This latest research springboards off one of the largest CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 screens of cancer genes to date. Researchers used CRISPR gene-editing systems to disrupt every gene within 30 different types of cancers and locate several thousand key genes essential for cancer’s survival. They then identified 600 genes that potentially could be used in personalized medicine treatments.
“The results bring researchers one step closer to producing
the Cancer
Dependency Map, a detailed rulebook of precision cancer treatments to help
more patients receive effective therapies,” the Wellcome Sanger Institute statement
notes.
Anatomic pathologists and clinical laboratories should note
the speed at which development of useful biomarkers for diagnosing cancer is
progressing. All labs will want to be prepared to capitalize on those
advancements through the lab testing services they offer in their medical laboratories.
Human microbiota is linked to many diseases but could hold the key for advanced clinical laboratory tests and targeted precision medicine therapies Study of the human microbiome continues to provide understanding and knowledge regarding gut bacteria and its many benefits, and incites development into new clinical laboratory tests. However, a new study reveals that our bodies might also put gut bacteria under stress leading to better health. Traditionally, scientists believe the human gut is a...
According to the researchers, the finding could reveal athletes who removed their blood, took out the red blood cells, and transfused the cells into their bodies before competition. When conducted by medical laboratory professionals, such autologous blood therapies can enhance oxygen intake and increase performance during sports. However, these “self-transfusions” have been difficult to detect using current methods and that highlights the importance of ensuring these procedures are carried out by authorized healthcare facilities.
The World Anti-Doping Agency (WADA), an international organization aimed at research and education for doping-free sport, funded the Duke University research. WADA currently uses the Athlete Biological Passport to assess, over time, competitors’ body chemistries.
As the Duke researchers explored nucleic acids in red blood cells, they found that the cells actually do have a nucleus, contrary to popular belief. From there, they honed in on RNA.
Short RNA pieces, called microRNA (miRNA), control production of proteins in a cell, according to the researchers.
“While once thought to lack nucleic acids, red blood cells actually contain diverse and abundant RNA species,” the scientists noted in their paper. “In addition, proteomic analyses of red blood cells have identified the presence of Argonaute 2 (AGO2), supporting the regulatory function of miRNAs.”
The methodology Duke researchers followed involved these steps, among others:
Three units of blood were drawn from volunteers;
The researchers removed the white blood cells and about 80% of the plasma;
The remaining red blood cells were pure, just as they would need to be by someone doing autologous transfusion;
The researchers analyzed cell RNA samples at specific daily intervals: 1, 3, 7, 10, 14, 28, 36, and, 42 days;
They then compared samples to day 1 and recorded changes in RNA due to storage.
The researchers found:
Two types of miRNA increased during storage and two declined; and,
miR-720 had the most dramatic and consistent changes.
They concluded that finding increased miR-720 in athletes’ blood could be used as a biomarker for detecting stored red blood cells, which could indicate blood doping had taken place.
“The difficulty has been that the tests [WADA] have couldn’t tell the difference between a young blood cell and an old one,” Jen-Tsan Ashley Chi, MD, PhD, lead researcher on the study and Duke’s Associate Professor in Molecular Genetics and Microbiology, noted in the news release. “This increase in miR-720 is significant enough and consistent enough that it could be used as a biomarker for detecting stored red blood cells.” Chi is affiliated with Duke’s Center for Genomic and Computational Biology. (Photo copyright: Duke University.)
Implications for Detecting Blood Doping
How does this help clinical laboratories detect blood doping in athletes?
The researchers explained that RNA changes were, indeed, tell-tale signs of old blood cells circulating with normal cells. Those old blood cells could identify an athlete who did a self-transfusion of their blood before a competition.
However, before the test is used in sports more research is needed. Activity by the enzyme angiogenin in stored cells also is worthy of more exploration, as is its role in breaking apart larger RNA, the researchers noted.
“While autologous blood transfusions in athletes is very difficult to identify using conventional tests, it may be detectable based on the presence of red blood cells with levels of miR-720 significantly higher than the normal circulating cells. Further investigations will be necessary to identify the signals during red blood cell storage that stimulate angiogenin activation,” the study paper concluded.
Clinical Laboratories Involved in Sports Testing
In its 2017 Anti-Doping Testing Figures Report, WADA reported 322,050 samples were analyzed, a 7.1% increase from 300,565 samples in 2016. WADA accredits medical laboratories worldwide for conducting such analyses according to the organization’s code. This presents opportunities in sports medicine for medical laboratories to increase revenue through a new line of diagnostic tests.
The Duke study exemplifies how clinical laboratories can extend their services beyond patient care and enter a new realm of leveling playing fields worldwide.
UK study shows how LDTs may one day enable physicians to identify patients genetically predisposed to chronic disease and prescribe lifestyle changes before medical treatment becomes necessary
Could genetic predisposition lead to clinical laboratory-developed tests (LDTs) that enable physicians to assess patients’ risk for specific diseases years ahead of onset of symptoms? Could these LDTs inform treatment/lifestyle changes to help reduce the chance of contracting the disease?
A UK study into the genetics of one million people with high blood pressure reveals such tests could one day exist.
They also confirmed 274 loci (gene locations) and replicated 92 loci for the first time.
“This is the most major advance in blood pressure genetics to date. We now know that there are over 1,000 genetic signals which influence our blood pressure. This provides us with many new insights into how our bodies regulate blood pressure and has revealed several new opportunities for future drug development,” said Mark Caulfield, MD,
The researchers believe “this means almost a third of the estimated heritability for blood pressure is now explained,” the news release noted.
Clinical Laboratories May Eventually Get a Genetic Test Panel for Hypertension
Of course, more research is needed. But the study suggests a genetic test panel for hypertension may be in the future for anatomic pathologists and medical laboratories. Physicians might one day be able to determine their patients’ risks for high blood pressure years in advance and advise treatment and lifestyle changes to avert medical problems.
By involving more than one million people, the study also demonstrates how ever-growing pools of data will be used in research to develop new diagnostic assays.
The video above summarizes research led by Queen Mary University of London and Imperial College London, which found over 500 new gene regions that influence people’s blood pressure, in the largest global genetic study of blood pressure to date. Click here to view the video. (Photo and caption copyright: Queen Mary University of London.)
Genetics Influence Blood Pressure More Than Previously Thought
In addition to identifying hundreds of new genetic regions influencing blood pressure, the researchers compared people with the highest genetic risk of high blood pressure to those in the low risk group. Based on this comparison, the researchers determined that all genetic variants were associated with:
“having around a 13 mm Hg higher blood pressure;
“having 3.34 times the odds for increased risk of hypertension; and,
“1.52 times the odds for increased risk of poor cardiovascular outcomes.”
“We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation, but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future,” the researchers wrote in Nature Genetics.
Other Findings Link Known Genes and Drugs to Hypertension
The UK researchers also revealed the Apolipoprotein E (ApoE) gene’s relation to hypertension. This gene has been associated with both Alzheimer’s and coronary artery diseases, noted LabRoots. The study also found that Canagliflozin, a drug used in type 2 diabetes treatment, could be repurposed to also address hypertension.
“Identifying genetic signals will increasingly help us to split patients into groups based on their risk of disease,” Paul Elliott, PhD, Professor, Imperial College London Faculty of Medicine, School of Public Health, and co-lead author, stated in the news release. “By identifying those patients who have the greatest underlying risk, we may be able to help them to change lifestyle factors which make them more likely to develop disease, as well as enabling doctors to provide them with targeted treatments earlier.”
Working to Advance Precision Medicine
The study shares new and important information about how genetics may influence blood pressure. By acquiring data from more than one million people, the UK researchers also may be setting a new expectation for research about diagnostic tests that could become part of the test menu at clinical laboratories throughout the world. The work could help physicians and patients understand risk of high blood pressure and how precision medicine and lifestyle changes can possibly work to prevent heart attacks and strokes among people worldwide.
Pathologists around the world will be interested to learn that, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four
Early detection of prostate cancer, and the ability to identify its more aggressive forms, are important goals for every nation’s health system. However, a new study in the United Kingdom (UK) will be of interest to all anatomic pathologists handling prostate biopsies. Researchers determined that late diagnosis of prostate cancer is an issue that should be addressed by healthcare policymakers in the UK.
In 2015, deaths due to prostate cancer surpassed those of breast cancer in the UK. According to data from Cancer Research UK, this trend continued into 2016 with 11,631 deaths from prostate cancer and 11,538 deaths from breast cancer. The trend continued even though breast cancer saw roughly 8,000 more new cases in 2015, according to the same data.
Now, a report from Orchid—a UK male cancer charity—highlights a trend that should interest medical laboratories and histopathology (anatomic pathology in the US) groups that analyze prostate cancer samples. They found that 37% of UK prostate cancer cases involved diagnoses in stages three or four.
Late-Stage Diagnosis of Prostate Cancer: The US and UK Compared
“With prostate cancer due to be the most prevalent cancer in the UK within the next 12 years, we are facing a potential crisis in terms of diagnostics, treatment, and patient care,” stated Rebecca Porta, Chief Executive of Orchid, in a press release. “Urgent action needs to be taken now if we are to be in a position to deliver world class outcomes for prostate cancer patients and their families in the future.”
Orchid Chief Executive Rebecca Porta (far right) and her team are shown above receiving a check from the Industrial Agents Society (AIS) to help fund the charity’s research into male specific cancers, such as prostate cancer. (Photo copyright: AIS.)
The latest data from the Centers for Disease Control and Prevention (CDC) on prostate cancer and mortality rates in the US shows an interesting picture. In 2014, 172,258 men received a prostate cancer diagnosis. However, deaths from prostate cancer were at 28,343.
According to Statista, an international statistics portal, the UK is home to more than 32.3-million males. And, Statista’s data shows the US is home to 159.1-million males. This implies that despite the US having nearly five times the number of males, the number of prostate cancer deaths/year in the UK is significantly higher in relation to population size.
Cancer Research UK notes that despite decreasing by 13% in the last decade, prostate cancer mortality rates are still 21% higher than in the 1970s.
Awareness and Early Detection Key Components in the Fight Against Cancer
A study published in BMC Public Health offers one possible explanation for this disparity.
“Poorer outcomes in the UK are at least in part attributable to later stage diagnoses,” she explained. “Older adults should be vigilant about cancer. Yet, this is not reflected in the news media coverage of cancer risk. Taken together, invisibility, inaccuracy, and information overload build a skewed picture that cancer is a disease which affects younger people.”
While treatment options have improved in the past decade, early detection is a key part of successful treatment—especially as prostate cancer has both aggressive and slow variants. Effective timely health screening also is of critical concern.
Faster diagnosis and the ability to detect whether a prostate cancer is slow or aggressive could help to shift these numbers around the world.
According to BBC News, the NHS hopes to reduce diagnosis times and make the screening process less invasive by using magnetic resonance imaging (MRI). Hashim Ahmed, PhD, Chairman of Urology, Imperial College London, told BBC News, “Fast access to high-quality prostate MRI allows many men to avoid invasive biopsies as well as allowing precision biopsy in those men requiring it to find high-risk tumors much earlier.”
A team from the University of Dundee is trialing a shear wave elastography imaging (SWEI) process to detect prostate tumors as well. Speaking with The Guardian, team leader and Chair of the School of Medicine at The University of Dundee, Dr. Ghulam Nabi, noted, “We have been able to show a stark difference in results between our technology and existing techniques such as MRI. The technique has picked up cancers which MRI did not reveal. We can now see with much greater accuracy what tissue is cancerous, where it is, and what level of treatment it needs. This is a significant step forward.”
Should these tools prove successful, they might help to reverse current trends in the UK and offer greater insight and options for the histopathology groups there, as well as the medical laboratories, oncologists, and other medical specialists helping to treat cancer.
Until then, raising awareness and streamlining both detection and treatment protocols will remain a critical concern, not just in the UK, but around the world as the human population continues to age.
