A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynaecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause of maternal and infant death worldwide, a discovery that could lead to the development of new therapeutic treatments.
“Preeclampsia is a leading cause of maternal and foetal morbidity and mortality worldwide, yet its pathogenesis is still poorly understood,” Dr. Nayak said. “Many studies have suggested that elevated circulating levels of sFlt1 (a tyrosine kinase protein that disables proteins essential to blood vessel growth) contribute to the maternal symptoms of vascular dysfunction that characterize preeclampsia, but the molecular underpinnings of sFlt1 upregulation in preeclampsia have so far been elusive. Our manuscript describes the novel, field-changing finding that vascular endothelial growth factor, or VEGF, of maternal origin can stimulate soluble sFlt1 production by the placenta and that this signalling is involved in the cause of preeclampsia.”
Preeclampsia is a sudden increase in blood pressure after the 20th week of pregnancy. Indicated by a sudden increase in blood pressure and protein in the urine, preeclampsia warning signs, in addition to elevated blood pressure, can include headaches, swelling in the face and hands, blurred vision, chest pain and shortness of breath. While the condition can manifest within a few hours, some women report few or no symptoms.
The condition is responsible for 76,000 maternal deaths and more than 500,000 infant deaths every year, according to estimates from the Preeclampsia Foundation. It can affect the liver, kidney and brain. Some mothers develop seizures (eclampsia) and suffer intracranial haemorrhage, the main cause of death in those who develop the disorder. Some women develop blindness. The babies of preeclamptic mothers are affected by the condition and may develop intrauterine growth restriction or die in utero.
While VEGF is essential for normal embryonic development, Dr. Nayak said, his team’s research has demonstrated that even mild elevation of VEGF levels during early pregnancy can cause severe placental vascular damage and embryonic lethality. The results show that modest increases in VEGF could also be a primary trigger for elevation of placental sFlt1 expression, leading to preeclampsia.
Furthermore, the findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta in later stages of pregnancy and suggest that overproduction of sFlt1 in preeclampsia, although damaging to the mother, serves a critical protective function for the placenta and foetus by “sequestering” excess maternal VEGF.
According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 percent to 8 percent of pregnancies. Left untreated or undetected, preeclampsia can rapidly lead to eclampsia, one of the top five causes of maternal death and infant illness and death. Approximately 13 percent of all maternal deaths worldwide – the death of a mother every 12 minutes – have been attributed to eclampsia. The foundation reports that preeclampsia is responsible for nearly 18 percent of all maternal deaths in the United States.
Wayne State University School of Medicine
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Scientists have identified a genetic mutation in about 20 percent of colorectal and endometrial cancers that had been overlooked in recent large, comprehensive gene searches. With this discovery, the altered gene, called RNF43, now ranks as one of the most common mutations in the two cancer types.
The investigators from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard said the mutated gene helps control an important cell-signalling pathway, Wnt, that has been implicated in many forms of cancer. They suggest that having a mutation in RNF43 may serve as a biomarker that identifies patients with colorectal and endometrial cancer who could benefit from precision cancer drugs that target the Wnt pathway, although no such drugs have yet been approved.
“Tumours that have this mutation may be telling us that they are dependent on the Wnt signalling pathway, and they will be uniquely sensitive to drugs that inhibit this pathway,” said Charles Fuchs, MD, MPH, an author of the paper and director of the Center for Gastrointestinal Cancer at Dana-Farber. He is also affiliated with Brigham and Women’s Hospital and the Harvard School of Public Health.
In pre-clinical cancer models, tumours with RNF43 mutations have been found to be sensitive to new Wnt pathway inhibitors that are now in clinical trials in humans, according to Marios Giannakis, MD, PhD, who is an attending physician at Dana-Farber and is also a conducting research at the Broad Institute.
The researchers were surprised to find RNF43 mutations in such a significant proportion of colorectal and endometrial cancers because they had not been detected in recent comprehensive searches of tumor DNA conducted by scientists of The Cancer Genome Atlas (TGCA) project.
Authors of the new study believe computer algorithms used by TCGA to parse data from DNA sequencing of tumors may have interpreted the “signal” of the RNF45 mutation as an artifact, and discarded it, much as a legitimate email will sometimes be trapped in a junk filter.
“These mutations occur in repetitive regions of the genome where you often have errors in DNA sequencing, so past algorithms may have been more likely to assume that the RNF43 mutation was an artifact of the sequencing process,” explained Eran Hodis, an MD/PhD student at Harvard Medical School and MIT and also affiliated with the Broad and Dana-Farber. Giannakis and Hodis are co-first authors on the new report.
Other frequently mutated genes in colorectal cancer include APC (75 percent), P53 (50 percent), and KRAS (40 percent).
The new evidence for RNF43 mutations first came from analysis of tumour samples of colorectal cancer that were obtained from two large cohort studies – the Nurses’ Health Study, which has been following 121,000 healthy women since 1976, and the Health Professionals Follow-up Study, which includes 52,000 men enrolled in 1986. About 10 years ago, Fuchs, along with Dana-Farber pathologist Shuji Ogino, MD, PhD, MS, began collecting and studying gastrointestinal tumour samples that had been taken from men and women in the studies who developed cancer. Because these specimens are accompanied by a wealth of data about the patients’ lifestyle, medical history, and other factors, Fuchs calls this collection of tumour samples “a gold mine.”
For the new study, 185 colorectal cancer specimens from this collection were analyzed by whole-exome DNA sequencing at the Broad Institute under the leadership of Levi Garraway, MD, PhD, who is affiliated with Dana-Farber, the Broad, and Brigham and Women’s Hospital, and is corresponding author of the report. The RNF43 mutation was identified in 18.9 percent of the colorectal tumors.
This surprising result prompted the investigators to re-analyse 222 colorectal cancer samples from TCGA project and found the RNF43 mutation in 17.6 percent. The researchers, noting that endometrial cancer is dependent on abnormal Wnt signalling, then re-analysed 248 DNA samples from endometrial cancer that had been previously published by TCGA scientists. They found a strikingly similar proportion – 18.1 percent – of RNF43 mutations in those cancers.
The study authors noted that the discovery of such a significant cancer mutation that hadn’t been picked up in the previous gene hunts shows that carrying out these comprehensive genomic searches continues to have value.
Dana-Farber Cancer Institute
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Scientists from UCL and Queen Mary University of London have identified what they believe could be a cause of pre-term premature rupture of the foetal membrane (PPROM) which accounts for 40 per cent of pre-term births, the main reason for infant death world-wide.
The researchers used bioengineering techniques to test the effect of repetitive stretch on tissues of the amniotic membrane which surrounds and protects the baby prior to birth.
They found that stretching of the amniotic membrane leads to the overproduction of prostaglandin E2 (PGE2) which is damaging to both the cells and mechanical structure of the tissue. This overproduction activates the stretch-sensitive protein connexin 43 (Cx43) and reduces the mechanical properties of the membrane potentially, leading to rupture and pre-term birth.
The research is the first to look at the role of Cx43 in causing PPROM.
The team are now researching possible treatments that would allow the amniotic membrane to be repaired.
Co-author of the research, Dr Tina Chowdhury from the School of Engineering and Material Sciences at Queen Mary University of London, said, “To have potentially found a way to reduce pre-term births and prevent early deaths of young babies worldwide is incredibly exciting. The unique bioengineering tools at QMUL have allowed us to test the tissue in a way that has never been done before. This gives us an understanding of both the mechanical as well as biological mechanisms involved and will help us to develop therapies that will reduce the number of pre-term births.”
Dr Anna David, a consultant in obstetrics and pre-term birth from the UCL Institute for Women’s Health and a co-author of the paper, said,“Our findings have provided a new understanding of why pregnant women who have pre-term contractions go on to rupture their membranes early. The new project funded by the Rosetrees Trust could lead to a therapy that will heal the amniotic membrane and reduce preterm births. This has the potential to save many lives worldwide and improve the health and well-being of women during pregnancy and their families after birth.”
University College London
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Ways to simplify treatments for tuberculosis (TB) to reduce drug resistance and make it easier for patients to complete their course of treatment have been trialled by two international groups involving UCL scientists.
The results from both trials found that novel drug combinations including the antibiotic moxifloxacin in TB treatment plans can approximately halve the number of pills that patients need to take but cannot shorten treatment time.
Most TB cases are curable after a six-month treatment regimen, providing patients stick to the treatment plan. Problems can arise if patients do not take their medication regularly, as the disease can recur or develop drug resistance.
Standard treatment plans require patients to take a cocktail of drugs every day for six months, which can be challenging and burdensome for patients to keep up with. The researchers found that with a new drug combination including moxifloxacin, taking daily medication for the first two months and then weekly high-dose medication for the last four months was equally effective at curing TB.
These results were from the RIFAQUIN phase III trial of 827 new cases of tuberculosis, led by researchers at UCL and St George’s, University of London, working with colleagues in Botswana, South Africa, Zambia and Zimbabwe. The trial found that drug combinations with moxifloxacin could help to reduce the number of pills needed but treatment could not be effectively shortened to four months.
The REMoxTB trial, a phase III trial of 1,931 patients at 50 sites in nine countries, also found that treatments could not be shortened from six to four months by using novel combinations including moxifloxacin.
Both trials involved researchers from the UCL Centre for Clinical Microbiology and Medical Research Council Clinical Trials Unit (MRC CTU) at UCL.
Professor Andrew Nunn, Scientific Programme Leader at the Medical Research Council Clinical Trials Unit, said: “New treatment strategies are urgently needed to battle the growing problem of drug resistance in TB. Resistant strains can develop when patients stop taking medication or take their treatment erratically because they start to feel better, allowing resistant TB bacteria to multiply. For example, an increasing number of TB strains are now resistant to the drug isoniazid, which has been a mainstay of treatment for over half a century. Strategies that make it easier for patients to complete treatments, such as the weekly treatments in RIFAQUIN, will help us to not only fight resistance but also to improve the quality of patients’ lives.”
University College London
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The scientific community has made significant strides in recent years in identifying important genetic contributors to malignancy and developing therapeutic agents that target altered genes and proteins. A recent approach to treat cancer called synthetic lethality takes advantage of genetic alterations in cancer cells that make them more susceptible to certain drugs. Alan F. List, MD, president and CEO of Moffitt Cancer Center, co-authored an article on synthetic lethality.
“Genetic alterations in cancer in humans may involve gene inactivation, amplification or inactivation,” said List. These changes are not present in non-malignant cells. Common chemotherapeutic agents aggressively kill tumour cells irrespective of genetic alterations. They also have a negative impact on normal cells and can cause significant side effects. Synthetic lethality harnesses the genetic differences between tumour cells and normal cells to minimize the effects on normal cells, and maximize a drug’s effects on cancer cells.
Synthetic lethality can target a variety of cellular defects, including alterations in DNA repair, cell-cycle control and metabolism. This approach can also be used to target interactions between tumour cells and surrounding normal cells that promote tumour survival and oncogenes that drive tumorigenesis that are difficult to target directly. Many of the synthetic lethal drugs and targets have been identified in large-scale drug screens of the entire human genome.
An example of synthetic lethality is the recent approach being investigated to treat breast cancer patients with BRCA1 and BRCA2 mutations. BRCA1 plays an important role is repairing damaged DNA. Women who have mutations in BRCA1 or BRCA2 have an increased risk of developing breast and ovarian cancer because their cells cannot properly repair DNA. This suggests that BRCA mutated breast cancer cells may be more susceptible to drugs that target DNA. Laboratory studies have confirmed this hypothesis by showing that agents that target another DNA repair protein called PARP significantly kill BRCA mutated cells. Several PARP inhibitors are now being investigated in clinical trials in breast cancer patients, and early results are promising.
“The goal of current anticancer approaches is to offer individualized and highly selective therapy. The treatment model for many anticancer approaches has been expanded, with movement away from dose-intensive, non-targeted cytotoxic agents to combination chemoimmunotherapy, new therapeutic combinations and targeted agents,” said List. Synthetic lethality approaches may provide an additional avenue for individualized patient treatment.
Moffitt Cancer Center
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New research points to malfunctioning tau, not amyloid-beta (Abeta) plaque, as the seminal event that spurs neuron death in disorders such as Alzheimer’s disease. The finding, which dramatically alters the prevailing theory of Alzheimer’s development, also explains why some people with plaque build-up in their brains don’t have dementia.
Neuronal death happens when tau, found inside neurons, fails to function. Tau’s role is to provide a structure — like a train track —inside brain neurons that allows the cells to clear accumulation of unwanted and toxic proteins.
“When tau is abnormal, these proteins, which include Abeta, accumulate inside the neurons,” explains the study’s senior investigator, Charbel E-H Moussa, MB, PhD, assistant professor of neuroscience at Georgetown University Medical Center. “The cells start to spit the proteins out, as best they can, into the extracellular space so that they cannot exert their toxic effects inside the cell. Because Abeta is ‘sticky,’ it clumps together into plaque,” Moussa says.
He says his study suggests the remaining Abeta inside the neuron (that isn’t pushed out) destroys the cells, not the plaques that build up outside. “When tau does not function, the cell cannot remove the garbage, which at that point includes Abeta as well as tangles of non-functioning tau, and the cell dies. The Abeta released from the dead neuron then sticks to the plaque that had been forming.”
Moussa’s experiments in animal models also show less plaques accumulate outside the cell when tau is functioning; when tau was reintroduced into neurons that did not have it, plaques did not grow.
Malfunctioning tau can occur due to errant genes or through aging. As individuals grow older, some tau can malfunction while enough normal tau remains to help clear the garbage. In these cases, the neurons don’t die, he says. “That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa says.
Moussa has long sought a way to force neurons to clean up their garbage. In this study, he shows that nilotinib, a drug approved to treat cancer, can aid in that process. Nilotinib helps the neuron clear garbage, but requires some functional tau, he says.
“This drug can work if there is a higher percentage of good to bad tau in the cell,” Moussa says. “There are many diseases of dementia that have malfunctioning tau and no plaque accumulation, such as frontal temporal dementia linked to Parkinsonism,” Moussa says. “The common culprit is tau, so a drug that helps tau do its job may help protect against progression of these diseases.”
Georgetown University Medical Center
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Analysis of 607 small cell lung cancer (SCLC) lung tumours and neuroendocrine tumours (NET) identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research.
This study examined the clinical specimens of 607 total cases of SCLC tumours (375) and lung NET (232), which included carcinoid, atypical carcinoid and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (Next-Generation Sequencing (NGS) or Sanger-based); immunohistochemistry (IHC) to identify which proteins are present; and in situ hybridization (ISH) testing, a form of gene amplification, to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present.
Sequencing data were obtained from 201 total specimens (SCLC=115, NET=86). The 115 SCLC tumors harboured a wide spectrum of gene markers. Sequencing revealed mutations in p53 (57 percent), RB1 (11 percent), ATM, cMET (6 percent), PTEN (6 percent), BRAF (3 percent), SMAD4, KRAS (3 percent), ABL1, APB, CTNNB1, EGFR, FBXW7, FGFR2 (2 percent), HNF1A, HRAS, JAK3 (2 percent), MLH1 and PIK3CA (1 percent).
Multiple genes of interest were found in the NET group of 86 tumours, including 66 pulmonary neuroendocrine carcinomas and 20 carcinoid tumours. Among the neuroendocrine tumours, mutations were seen in p53 (44 percent), FGFR2 (9percent), ATM (9 percent), KRAS (6 percent) and PIK3CA (4 percent) as well as EGFR (2 percent) and BRAF (4 percent). Analysis of the carcinoid tumours revealed fewer markers, with notable mutations in p53 (11 percent), HRAS (11 percent), and BRAF (6 percent).
EGFR amplification was verified for 11 percent (5) of the 46 SCLC tumours tested. No SCLC tumours displayed amplification of cMET or HER2. The neuroendocrine tumours exhibited amplification of EGFR (13 percent), cMET (3 percent), and HER2 (4 percent) amplification, while the carcinoid tumours only showed amplification in EGFR (8 percent).
The overexpression of cKIT (64 percent vs. 37 percent), RRM1 (54 percent vs. 28 percent), TOP2A (91 percent vs. 48 percent), TOP01 (63 percent vs. 43 percent), and TS (46 percent vs. 25 percent) was found more frequently in SCLC tumours compared to lung NET, respectively (p=0.0001 for all). Low expression of PTEN was more often identified in SCLC tumours compared to lung NET (56 percent vs. 36 percent; p=0.001).
Molecular profiling of these lung cancer subtypes is not routinely performed, however, numerous mutations were found to be in common with non-small cell lung cancer tumours. Specifically, an EGFR mutation was noted in one small cell lung cancer specimen and one neuroendocrine specimen, an ALK rearrangement was detected in a neuroendocrine tumor, and HER2 amplification was seen in a neuroendocrine specimen.
“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” said Stephen V. Liu, MD, senior study author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. “We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumours and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed.”
ASTRO
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Developed for the first time, the Hemoglobins Atlas is dedicated to helping Sebia’s capillary electrophoresis users orientate their diagnosis of hemoglobinopathies. Hemoglobin electrophoresis is an established technique routinely used in clinical laboratories for screening samples for hemoglobinopathies (hemoglobin variants and thalassemia). The assay is based on the principle of capillary electrophoresis in free solution. Sebia’s capillary electrophoresis technology allows fast and efficient separation of hemoglobin fractions and detection of the major hemoglobin variants and thalassemia patterns. The high sensitivity and specificity offered by capillary electrophoresis makes it a reliable first line screening method. To mark the tenth year of this technology, the company has developed the CDRom Hemoglobin Atlas as a reference compendium that will help laboratories increase their diagnostic knowledge of hemoglobinopathies. The Atlas is dedicated to the Sebia customers who use the Capillarys and Minicap instruments. The instruments perform sequences automatically, from sampling to final clear-cut profile, with precise quantification, exceptionally sharp separation and presumptive identification of the most common hemoglobins. Professor Piero Giordano, Emeritus associated professor and clinical biochemical molecular geneticist at Leiden University medical centre in the Netherlands, has collaborated as scientific counsellor on all of the research data. He also helped to develop the content. “As an interactive educational aid, the Atlas will cover as many variants as possible, from common to rare and in variable genotype combinations,” said Professor Giordano. “Presumed risk information is also included. If a lab result ends up in the files without any preventive follow up, the diagnostic efforts of the lab will have been wasted. For this reason we are now sharing all of the relevant confirmed and frequent patterns that are associated with severe diseases.” “Our customers will find the new Atlas a valuable companion in deciding how and when to confirm their provisional findings, either with a simple sickle test or with molecular diagnosis,” said Benoit Adelus, Sebia president and CEO. “We aim to keep this Atlas interactive by offering constant updates. Soon we will also provide extranet access for Sebia customers.” The Sebia Hemoglobins Atlas will be updated with new cases on a regular basis. All Sebia users are invited to contribute to the enrichment of the Atlas database by sharing their collection of capillary electrophoresis profiles displaying rare hemoglobin variants with their Sebia representative. The company enjoys an ongoing collaboration with Professor Giordano. Plans for the next version of the Atlas are already underway. The second edition will provide more case studies and additional user-friendly features.
www.sebia.com
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By combing through the DNA of more than 100,000 people, researchers at Broad Institute, Massachusetts General Hospital, and elsewhere have identified rare, protective genetic mutations that lower the levels of LDL cholesterol — the so-called “bad” cholesterol — in the blood. The researchers’ findings reveal that these naturally occurring mutations also reduce a person’s risk of coronary heart disease by about 50 percent. Remarkably, the mutations disrupt a gene called Niemann-Pick C1-Like 1 (NPC1L1) — the molecular target of the FDA-approved drug ezetimibe, often used as a treatment for high LDL.
“Protective mutations like the one we’ve just identified for heart disease are a treasure trove for understanding human biology,” said Sekar Kathiresan, a senior author of the study, Broad associate member, and director of preventive cardiology at Massachusetts General Hospital. “They can teach us about the underlying causes of disease and point to important drug targets.”
Over the past several years, evidence has been mounting that certain loss-of-function mutations — mutations that reduce or completely eliminate a gene’s ability to work — can, at the same time, protect against disease. With this latest discovery, the list now stands at four genes that have been found to offer protective effects against either heart or metabolic disease. (The genes PCSK9, AP0C3, and now NPC1L1 have been found to protect against heart disease, and SLC30A8 has been shown to protect against type 2 diabetes.)
The scientific community is interested in these protective mutations not only because of what they can reveal about the biological basis of disease, but also for their ability to suggest potential paths toward new therapeutics. From a pharmaceutical perspective, it is much more feasible to develop a drug that disables, rather than activates, a gene.
Kathiresan’s long-standing interest in the genetics of blood cholesterol and heart disease first led him to uncover rare mutations in the NPC1L1 gene in just a handful of patients. He wondered if other patients carried similar mutations, so he set off on a massive hunt.
With the combined expertise of Broad Institute’s Genomics Platform, led by Stacey Gabriel, and major support from the National Human Genome Research Institute, Kathiresan and his colleagues sequenced the exomes (the protein-coding portions of the genome) of over 20,000 people of European, African, or South Asian ancestry. They discovered 15 distinct mutations in NPC1L1, all of which serve to inactivate or dampen gene activity. Roughly 1 in 650 people carries one of these inactivating NPC1L1 mutations.
“When it comes to rare variant studies, there is simply no substitute for extremely large sample sizes,” said co-author Gabriel, director of Broad Institute’s Genomics Platform. “This has become crystal clear through our work on NPC1L1 as well as several other similar projects here at the Broad. We now know the right path to get statistically robust results, and that’s the path we are on.”
After defining the mutational landscape of NPC1L1 in the initial study group of 20,000 people, Kathiresan and his colleagues correlated those mutations with LDL levels. The researchers examined the genomes of another 91,000 people and found that those with inactivating mutations in NPC1L1 tended to have lower LDL levels than those without such mutations. The reductions averaged about 12mg/dL, a 10 percent drop that is similar to what is seen in patients receiving ezetimibe therapy.
Individuals who carry inactivating NPC1L1 mutations also have a lower risk of coronary heart disease — roughly half the risk compared to those individuals without those mutations.
Broad Institute
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A new comprehensive analysis of thyroid cancer from The Cancer Genome Atlas Research Network has identified markers of aggressive tumours, which could allow for better targeting of appropriate treatments to individual patients.
The finding suggests the potential to reclassify the disease based on genetic markers and moves thyroid cancer into a position to benefit more from precision medicine.
“This understanding of the genomic landscape of thyroid cancer will refine how it’s classified and improve molecular diagnosis. This will help us separate those patients who need aggressive treatment from those whose tumour is never likely to grow or spread,” says Thomas J. Giordano, M.D., Ph.D., professor of pathology at the University of Michigan Medical School.
Giordano is the project co-lead for TCGA thyroid cancer analysis along with Gad Getz, Ph.D., director of Cancer Genome Computational Analysis at the Broad Institute of MIT and Harvard.
Thyroid cancer incidence has increased three-fold over the last 30 years and is the most rapidly increasing cancer in the United States. While the tumours are often slow-growing and easily treated with a combination of surgery, thyroid hormone and radioactive iodine, some patients will develop more aggressive and deadly thyroid cancers.
In this TCGA study the researchers analysed nearly 500 thyroid cancer samples to identify all genetic mutations that play a role. They found several new cancer genes as well as new variations of existing genes.
Overall, the thyroid cancer genome is relatively quiet, with fewer genetic mutations involved than in other common cancers, the researchers found. This may explain why the disease is often slow-growing.
Fewer mutations meant the researchers were able to look at the signalling pathways involved and understand what drives thyroid tumours. This approach helped them understand the genetic drivers of more of these cancers, reducing the percentage of “dark matter” cases – those with unknown genetic drivers – from 25 percent to 3.5 percent.
Those drivers can be broken down into two primary oncogenic groups: BRAF plus similar mutations and RAS plus similar mutations. But within these two primary groups, especially the BRAF group, several different subtypes of thyroid cancer exist. Currently, all thyroid cancers associated with BRAF, for example, had been considered essentially the same. That’s not the case.
“This study integrated a wide variety of genomic data to not only identify cancer drivers, but to compare how these different drivers behave,” said Getz, who is also director of the Bioinformatics Program at the Massachusetts General Hospital Cancer Center and an associate professor of pathology at Harvard Medical School. “Interestingly, we found that subsets of BRAF-mutated thyroid cancers are driving cancer through distinct mechanisms, and that some of these subsets are associated with higher risk and less differentiated cancers.”
The researchers used this understanding to create measures or scores that can determine how a tumour signals and how aggressive a thyroid tumour is. These scores are being tested in a clinical trial to assess if it can lead to more targeted treatment recommendations.
“These findings are a major step forward in how doctors and patients will address thyroid cancer diagnosis and treatment. Researchers around the world will be using this data, coming back to it and asking other scientific questions,” says Carolyn Hutter, Ph.D., M.S., program director in the division of genomic medicine at the National Human Genome Research Institute.
An initial recommendation is for the pathology and scientific communities to consider reclassifying thyroid cancer based on molecular subtypes to better reflect their underlying molecular properties. This would allow doctors to identify the slow-growing tumours from the aggressive tumours and recommend appropriate treatments.
Broad Institute
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Key signalling pathway in cause of preeclampsia
, /in E-News /by 3wmediaA team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynaecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause of maternal and infant death worldwide, a discovery that could lead to the development of new therapeutic treatments.
“Preeclampsia is a leading cause of maternal and foetal morbidity and mortality worldwide, yet its pathogenesis is still poorly understood,” Dr. Nayak said. “Many studies have suggested that elevated circulating levels of sFlt1 (a tyrosine kinase protein that disables proteins essential to blood vessel growth) contribute to the maternal symptoms of vascular dysfunction that characterize preeclampsia, but the molecular underpinnings of sFlt1 upregulation in preeclampsia have so far been elusive. Our manuscript describes the novel, field-changing finding that vascular endothelial growth factor, or VEGF, of maternal origin can stimulate soluble sFlt1 production by the placenta and that this signalling is involved in the cause of preeclampsia.”
Preeclampsia is a sudden increase in blood pressure after the 20th week of pregnancy. Indicated by a sudden increase in blood pressure and protein in the urine, preeclampsia warning signs, in addition to elevated blood pressure, can include headaches, swelling in the face and hands, blurred vision, chest pain and shortness of breath. While the condition can manifest within a few hours, some women report few or no symptoms.
The condition is responsible for 76,000 maternal deaths and more than 500,000 infant deaths every year, according to estimates from the Preeclampsia Foundation. It can affect the liver, kidney and brain. Some mothers develop seizures (eclampsia) and suffer intracranial haemorrhage, the main cause of death in those who develop the disorder. Some women develop blindness. The babies of preeclamptic mothers are affected by the condition and may develop intrauterine growth restriction or die in utero.
While VEGF is essential for normal embryonic development, Dr. Nayak said, his team’s research has demonstrated that even mild elevation of VEGF levels during early pregnancy can cause severe placental vascular damage and embryonic lethality. The results show that modest increases in VEGF could also be a primary trigger for elevation of placental sFlt1 expression, leading to preeclampsia.
Furthermore, the findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta in later stages of pregnancy and suggest that overproduction of sFlt1 in preeclampsia, although damaging to the mother, serves a critical protective function for the placenta and foetus by “sequestering” excess maternal VEGF.
According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 percent to 8 percent of pregnancies. Left untreated or undetected, preeclampsia can rapidly lead to eclampsia, one of the top five causes of maternal death and infant illness and death. Approximately 13 percent of all maternal deaths worldwide – the death of a mother every 12 minutes – have been attributed to eclampsia. The foundation reports that preeclampsia is responsible for nearly 18 percent of all maternal deaths in the United States. Wayne State University School of Medicine
Unsuspected gene found frequently mutated in colorectal, endometrial cancers
, /in E-News /by 3wmediaScientists have identified a genetic mutation in about 20 percent of colorectal and endometrial cancers that had been overlooked in recent large, comprehensive gene searches. With this discovery, the altered gene, called RNF43, now ranks as one of the most common mutations in the two cancer types.
The investigators from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard said the mutated gene helps control an important cell-signalling pathway, Wnt, that has been implicated in many forms of cancer. They suggest that having a mutation in RNF43 may serve as a biomarker that identifies patients with colorectal and endometrial cancer who could benefit from precision cancer drugs that target the Wnt pathway, although no such drugs have yet been approved.
“Tumours that have this mutation may be telling us that they are dependent on the Wnt signalling pathway, and they will be uniquely sensitive to drugs that inhibit this pathway,” said Charles Fuchs, MD, MPH, an author of the paper and director of the Center for Gastrointestinal Cancer at Dana-Farber. He is also affiliated with Brigham and Women’s Hospital and the Harvard School of Public Health.
In pre-clinical cancer models, tumours with RNF43 mutations have been found to be sensitive to new Wnt pathway inhibitors that are now in clinical trials in humans, according to Marios Giannakis, MD, PhD, who is an attending physician at Dana-Farber and is also a conducting research at the Broad Institute.
The researchers were surprised to find RNF43 mutations in such a significant proportion of colorectal and endometrial cancers because they had not been detected in recent comprehensive searches of tumor DNA conducted by scientists of The Cancer Genome Atlas (TGCA) project.
Authors of the new study believe computer algorithms used by TCGA to parse data from DNA sequencing of tumors may have interpreted the “signal” of the RNF45 mutation as an artifact, and discarded it, much as a legitimate email will sometimes be trapped in a junk filter.
“These mutations occur in repetitive regions of the genome where you often have errors in DNA sequencing, so past algorithms may have been more likely to assume that the RNF43 mutation was an artifact of the sequencing process,” explained Eran Hodis, an MD/PhD student at Harvard Medical School and MIT and also affiliated with the Broad and Dana-Farber. Giannakis and Hodis are co-first authors on the new report.
Other frequently mutated genes in colorectal cancer include APC (75 percent), P53 (50 percent), and KRAS (40 percent).
The new evidence for RNF43 mutations first came from analysis of tumour samples of colorectal cancer that were obtained from two large cohort studies – the Nurses’ Health Study, which has been following 121,000 healthy women since 1976, and the Health Professionals Follow-up Study, which includes 52,000 men enrolled in 1986. About 10 years ago, Fuchs, along with Dana-Farber pathologist Shuji Ogino, MD, PhD, MS, began collecting and studying gastrointestinal tumour samples that had been taken from men and women in the studies who developed cancer. Because these specimens are accompanied by a wealth of data about the patients’ lifestyle, medical history, and other factors, Fuchs calls this collection of tumour samples “a gold mine.”
For the new study, 185 colorectal cancer specimens from this collection were analyzed by whole-exome DNA sequencing at the Broad Institute under the leadership of Levi Garraway, MD, PhD, who is affiliated with Dana-Farber, the Broad, and Brigham and Women’s Hospital, and is corresponding author of the report. The RNF43 mutation was identified in 18.9 percent of the colorectal tumors.
This surprising result prompted the investigators to re-analyse 222 colorectal cancer samples from TCGA project and found the RNF43 mutation in 17.6 percent. The researchers, noting that endometrial cancer is dependent on abnormal Wnt signalling, then re-analysed 248 DNA samples from endometrial cancer that had been previously published by TCGA scientists. They found a strikingly similar proportion – 18.1 percent – of RNF43 mutations in those cancers.
The study authors noted that the discovery of such a significant cancer mutation that hadn’t been picked up in the previous gene hunts shows that carrying out these comprehensive genomic searches continues to have value. Dana-Farber Cancer Institute
Scientists identify potential cause for 40% of pre-term births
, /in E-News /by 3wmediaScientists from UCL and Queen Mary University of London have identified what they believe could be a cause of pre-term premature rupture of the foetal membrane (PPROM) which accounts for 40 per cent of pre-term births, the main reason for infant death world-wide.
The researchers used bioengineering techniques to test the effect of repetitive stretch on tissues of the amniotic membrane which surrounds and protects the baby prior to birth.
They found that stretching of the amniotic membrane leads to the overproduction of prostaglandin E2 (PGE2) which is damaging to both the cells and mechanical structure of the tissue. This overproduction activates the stretch-sensitive protein connexin 43 (Cx43) and reduces the mechanical properties of the membrane potentially, leading to rupture and pre-term birth.
The research is the first to look at the role of Cx43 in causing PPROM.
The team are now researching possible treatments that would allow the amniotic membrane to be repaired.
Co-author of the research, Dr Tina Chowdhury from the School of Engineering and Material Sciences at Queen Mary University of London, said, “To have potentially found a way to reduce pre-term births and prevent early deaths of young babies worldwide is incredibly exciting. The unique bioengineering tools at QMUL have allowed us to test the tissue in a way that has never been done before. This gives us an understanding of both the mechanical as well as biological mechanisms involved and will help us to develop therapies that will reduce the number of pre-term births.”
Dr Anna David, a consultant in obstetrics and pre-term birth from the UCL Institute for Women’s Health and a co-author of the paper, said,“Our findings have provided a new understanding of why pregnant women who have pre-term contractions go on to rupture their membranes early. The new project funded by the Rosetrees Trust could lead to a therapy that will heal the amniotic membrane and reduce preterm births. This has the potential to save many lives worldwide and improve the health and well-being of women during pregnancy and their families after birth.” University College London
Simplifying TB treatments to improve patients’ lives
, /in E-News /by 3wmediaWays to simplify treatments for tuberculosis (TB) to reduce drug resistance and make it easier for patients to complete their course of treatment have been trialled by two international groups involving UCL scientists.
The results from both trials found that novel drug combinations including the antibiotic moxifloxacin in TB treatment plans can approximately halve the number of pills that patients need to take but cannot shorten treatment time.
Most TB cases are curable after a six-month treatment regimen, providing patients stick to the treatment plan. Problems can arise if patients do not take their medication regularly, as the disease can recur or develop drug resistance.
Standard treatment plans require patients to take a cocktail of drugs every day for six months, which can be challenging and burdensome for patients to keep up with. The researchers found that with a new drug combination including moxifloxacin, taking daily medication for the first two months and then weekly high-dose medication for the last four months was equally effective at curing TB.
These results were from the RIFAQUIN phase III trial of 827 new cases of tuberculosis, led by researchers at UCL and St George’s, University of London, working with colleagues in Botswana, South Africa, Zambia and Zimbabwe. The trial found that drug combinations with moxifloxacin could help to reduce the number of pills needed but treatment could not be effectively shortened to four months.
The REMoxTB trial, a phase III trial of 1,931 patients at 50 sites in nine countries, also found that treatments could not be shortened from six to four months by using novel combinations including moxifloxacin.
Both trials involved researchers from the UCL Centre for Clinical Microbiology and Medical Research Council Clinical Trials Unit (MRC CTU) at UCL.
Professor Andrew Nunn, Scientific Programme Leader at the Medical Research Council Clinical Trials Unit, said: “New treatment strategies are urgently needed to battle the growing problem of drug resistance in TB. Resistant strains can develop when patients stop taking medication or take their treatment erratically because they start to feel better, allowing resistant TB bacteria to multiply. For example, an increasing number of TB strains are now resistant to the drug isoniazid, which has been a mainstay of treatment for over half a century. Strategies that make it easier for patients to complete treatments, such as the weekly treatments in RIFAQUIN, will help us to not only fight resistance but also to improve the quality of patients’ lives.” University College London
Synthetic lethality offers a new approach to kill tumour cells
, /in E-News /by 3wmediaThe scientific community has made significant strides in recent years in identifying important genetic contributors to malignancy and developing therapeutic agents that target altered genes and proteins. A recent approach to treat cancer called synthetic lethality takes advantage of genetic alterations in cancer cells that make them more susceptible to certain drugs. Alan F. List, MD, president and CEO of Moffitt Cancer Center, co-authored an article on synthetic lethality.
“Genetic alterations in cancer in humans may involve gene inactivation, amplification or inactivation,” said List. These changes are not present in non-malignant cells. Common chemotherapeutic agents aggressively kill tumour cells irrespective of genetic alterations. They also have a negative impact on normal cells and can cause significant side effects. Synthetic lethality harnesses the genetic differences between tumour cells and normal cells to minimize the effects on normal cells, and maximize a drug’s effects on cancer cells.
Synthetic lethality can target a variety of cellular defects, including alterations in DNA repair, cell-cycle control and metabolism. This approach can also be used to target interactions between tumour cells and surrounding normal cells that promote tumour survival and oncogenes that drive tumorigenesis that are difficult to target directly. Many of the synthetic lethal drugs and targets have been identified in large-scale drug screens of the entire human genome.
An example of synthetic lethality is the recent approach being investigated to treat breast cancer patients with BRCA1 and BRCA2 mutations. BRCA1 plays an important role is repairing damaged DNA. Women who have mutations in BRCA1 or BRCA2 have an increased risk of developing breast and ovarian cancer because their cells cannot properly repair DNA. This suggests that BRCA mutated breast cancer cells may be more susceptible to drugs that target DNA. Laboratory studies have confirmed this hypothesis by showing that agents that target another DNA repair protein called PARP significantly kill BRCA mutated cells. Several PARP inhibitors are now being investigated in clinical trials in breast cancer patients, and early results are promising.
“The goal of current anticancer approaches is to offer individualized and highly selective therapy. The treatment model for many anticancer approaches has been expanded, with movement away from dose-intensive, non-targeted cytotoxic agents to combination chemoimmunotherapy, new therapeutic combinations and targeted agents,” said List. Synthetic lethality approaches may provide an additional avenue for individualized patient treatment. Moffitt Cancer Center
Tau, not amyloid-beta, triggers neuronal death process in Alzheimer’s
, /in E-News /by 3wmediaNew research points to malfunctioning tau, not amyloid-beta (Abeta) plaque, as the seminal event that spurs neuron death in disorders such as Alzheimer’s disease. The finding, which dramatically alters the prevailing theory of Alzheimer’s development, also explains why some people with plaque build-up in their brains don’t have dementia.
Neuronal death happens when tau, found inside neurons, fails to function. Tau’s role is to provide a structure — like a train track —inside brain neurons that allows the cells to clear accumulation of unwanted and toxic proteins.
“When tau is abnormal, these proteins, which include Abeta, accumulate inside the neurons,” explains the study’s senior investigator, Charbel E-H Moussa, MB, PhD, assistant professor of neuroscience at Georgetown University Medical Center. “The cells start to spit the proteins out, as best they can, into the extracellular space so that they cannot exert their toxic effects inside the cell. Because Abeta is ‘sticky,’ it clumps together into plaque,” Moussa says.
He says his study suggests the remaining Abeta inside the neuron (that isn’t pushed out) destroys the cells, not the plaques that build up outside. “When tau does not function, the cell cannot remove the garbage, which at that point includes Abeta as well as tangles of non-functioning tau, and the cell dies. The Abeta released from the dead neuron then sticks to the plaque that had been forming.”
Moussa’s experiments in animal models also show less plaques accumulate outside the cell when tau is functioning; when tau was reintroduced into neurons that did not have it, plaques did not grow.
Malfunctioning tau can occur due to errant genes or through aging. As individuals grow older, some tau can malfunction while enough normal tau remains to help clear the garbage. In these cases, the neurons don’t die, he says. “That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa says.
Moussa has long sought a way to force neurons to clean up their garbage. In this study, he shows that nilotinib, a drug approved to treat cancer, can aid in that process. Nilotinib helps the neuron clear garbage, but requires some functional tau, he says.
“This drug can work if there is a higher percentage of good to bad tau in the cell,” Moussa says. “There are many diseases of dementia that have malfunctioning tau and no plaque accumulation, such as frontal temporal dementia linked to Parkinsonism,” Moussa says. “The common culprit is tau, so a drug that helps tau do its job may help protect against progression of these diseases.” Georgetown University Medical Center
Molecular tumour markers could reveal new therapeutic targets for lung cancer treatment
, /in E-News /by 3wmediaAnalysis of 607 small cell lung cancer (SCLC) lung tumours and neuroendocrine tumours (NET) identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research.
This study examined the clinical specimens of 607 total cases of SCLC tumours (375) and lung NET (232), which included carcinoid, atypical carcinoid and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (Next-Generation Sequencing (NGS) or Sanger-based); immunohistochemistry (IHC) to identify which proteins are present; and in situ hybridization (ISH) testing, a form of gene amplification, to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present.
Sequencing data were obtained from 201 total specimens (SCLC=115, NET=86). The 115 SCLC tumors harboured a wide spectrum of gene markers. Sequencing revealed mutations in p53 (57 percent), RB1 (11 percent), ATM, cMET (6 percent), PTEN (6 percent), BRAF (3 percent), SMAD4, KRAS (3 percent), ABL1, APB, CTNNB1, EGFR, FBXW7, FGFR2 (2 percent), HNF1A, HRAS, JAK3 (2 percent), MLH1 and PIK3CA (1 percent).
Multiple genes of interest were found in the NET group of 86 tumours, including 66 pulmonary neuroendocrine carcinomas and 20 carcinoid tumours. Among the neuroendocrine tumours, mutations were seen in p53 (44 percent), FGFR2 (9percent), ATM (9 percent), KRAS (6 percent) and PIK3CA (4 percent) as well as EGFR (2 percent) and BRAF (4 percent). Analysis of the carcinoid tumours revealed fewer markers, with notable mutations in p53 (11 percent), HRAS (11 percent), and BRAF (6 percent).
EGFR amplification was verified for 11 percent (5) of the 46 SCLC tumours tested. No SCLC tumours displayed amplification of cMET or HER2. The neuroendocrine tumours exhibited amplification of EGFR (13 percent), cMET (3 percent), and HER2 (4 percent) amplification, while the carcinoid tumours only showed amplification in EGFR (8 percent).
The overexpression of cKIT (64 percent vs. 37 percent), RRM1 (54 percent vs. 28 percent), TOP2A (91 percent vs. 48 percent), TOP01 (63 percent vs. 43 percent), and TS (46 percent vs. 25 percent) was found more frequently in SCLC tumours compared to lung NET, respectively (p=0.0001 for all). Low expression of PTEN was more often identified in SCLC tumours compared to lung NET (56 percent vs. 36 percent; p=0.001).
Molecular profiling of these lung cancer subtypes is not routinely performed, however, numerous mutations were found to be in common with non-small cell lung cancer tumours. Specifically, an EGFR mutation was noted in one small cell lung cancer specimen and one neuroendocrine specimen, an ALK rearrangement was detected in a neuroendocrine tumor, and HER2 amplification was seen in a neuroendocrine specimen.
“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” said Stephen V. Liu, MD, senior study author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. “We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumours and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed.” ASTRO
Sebia launches Hemoglobins Atlas as interactive educational aid
, /in E-News /by 3wmediaDeveloped for the first time, the Hemoglobins Atlas is dedicated to helping Sebia’s capillary electrophoresis users orientate their diagnosis of hemoglobinopathies. Hemoglobin electrophoresis is an established technique routinely used in clinical laboratories for screening samples for hemoglobinopathies (hemoglobin variants and thalassemia). The assay is based on the principle of capillary electrophoresis in free solution. Sebia’s capillary electrophoresis technology allows fast and efficient separation of hemoglobin fractions and detection of the major hemoglobin variants and thalassemia patterns. The high sensitivity and specificity offered by capillary electrophoresis makes it a reliable first line screening method. To mark the tenth year of this technology, the company has developed the CDRom Hemoglobin Atlas as a reference compendium that will help laboratories increase their diagnostic knowledge of hemoglobinopathies. The Atlas is dedicated to the Sebia customers who use the Capillarys and Minicap instruments. The instruments perform sequences automatically, from sampling to final clear-cut profile, with precise quantification, exceptionally sharp separation and presumptive identification of the most common hemoglobins. Professor Piero Giordano, Emeritus associated professor and clinical biochemical molecular geneticist at Leiden University medical centre in the Netherlands, has collaborated as scientific counsellor on all of the research data. He also helped to develop the content. “As an interactive educational aid, the Atlas will cover as many variants as possible, from common to rare and in variable genotype combinations,” said Professor Giordano. “Presumed risk information is also included. If a lab result ends up in the files without any preventive follow up, the diagnostic efforts of the lab will have been wasted. For this reason we are now sharing all of the relevant confirmed and frequent patterns that are associated with severe diseases.” “Our customers will find the new Atlas a valuable companion in deciding how and when to confirm their provisional findings, either with a simple sickle test or with molecular diagnosis,” said Benoit Adelus, Sebia president and CEO. “We aim to keep this Atlas interactive by offering constant updates. Soon we will also provide extranet access for Sebia customers.” The Sebia Hemoglobins Atlas will be updated with new cases on a regular basis. All Sebia users are invited to contribute to the enrichment of the Atlas database by sharing their collection of capillary electrophoresis profiles displaying rare hemoglobin variants with their Sebia representative. The company enjoys an ongoing collaboration with Professor Giordano. Plans for the next version of the Atlas are already underway. The second edition will provide more case studies and additional user-friendly features.
www.sebia.com
Defective NPC1L1 gene found to protect against heart disease
, /in E-News /by 3wmediaBy combing through the DNA of more than 100,000 people, researchers at Broad Institute, Massachusetts General Hospital, and elsewhere have identified rare, protective genetic mutations that lower the levels of LDL cholesterol — the so-called “bad” cholesterol — in the blood. The researchers’ findings reveal that these naturally occurring mutations also reduce a person’s risk of coronary heart disease by about 50 percent. Remarkably, the mutations disrupt a gene called Niemann-Pick C1-Like 1 (NPC1L1) — the molecular target of the FDA-approved drug ezetimibe, often used as a treatment for high LDL.
“Protective mutations like the one we’ve just identified for heart disease are a treasure trove for understanding human biology,” said Sekar Kathiresan, a senior author of the study, Broad associate member, and director of preventive cardiology at Massachusetts General Hospital. “They can teach us about the underlying causes of disease and point to important drug targets.”
Over the past several years, evidence has been mounting that certain loss-of-function mutations — mutations that reduce or completely eliminate a gene’s ability to work — can, at the same time, protect against disease. With this latest discovery, the list now stands at four genes that have been found to offer protective effects against either heart or metabolic disease. (The genes PCSK9, AP0C3, and now NPC1L1 have been found to protect against heart disease, and SLC30A8 has been shown to protect against type 2 diabetes.)
The scientific community is interested in these protective mutations not only because of what they can reveal about the biological basis of disease, but also for their ability to suggest potential paths toward new therapeutics. From a pharmaceutical perspective, it is much more feasible to develop a drug that disables, rather than activates, a gene.
Kathiresan’s long-standing interest in the genetics of blood cholesterol and heart disease first led him to uncover rare mutations in the NPC1L1 gene in just a handful of patients. He wondered if other patients carried similar mutations, so he set off on a massive hunt.
With the combined expertise of Broad Institute’s Genomics Platform, led by Stacey Gabriel, and major support from the National Human Genome Research Institute, Kathiresan and his colleagues sequenced the exomes (the protein-coding portions of the genome) of over 20,000 people of European, African, or South Asian ancestry. They discovered 15 distinct mutations in NPC1L1, all of which serve to inactivate or dampen gene activity. Roughly 1 in 650 people carries one of these inactivating NPC1L1 mutations.
“When it comes to rare variant studies, there is simply no substitute for extremely large sample sizes,” said co-author Gabriel, director of Broad Institute’s Genomics Platform. “This has become crystal clear through our work on NPC1L1 as well as several other similar projects here at the Broad. We now know the right path to get statistically robust results, and that’s the path we are on.”
After defining the mutational landscape of NPC1L1 in the initial study group of 20,000 people, Kathiresan and his colleagues correlated those mutations with LDL levels. The researchers examined the genomes of another 91,000 people and found that those with inactivating mutations in NPC1L1 tended to have lower LDL levels than those without such mutations. The reductions averaged about 12mg/dL, a 10 percent drop that is similar to what is seen in patients receiving ezetimibe therapy.
Individuals who carry inactivating NPC1L1 mutations also have a lower risk of coronary heart disease — roughly half the risk compared to those individuals without those mutations. Broad Institute
Thyroid cancer genome analysis finds markers of aggressive tumours
, /in E-News /by 3wmediaA new comprehensive analysis of thyroid cancer from The Cancer Genome Atlas Research Network has identified markers of aggressive tumours, which could allow for better targeting of appropriate treatments to individual patients.
The finding suggests the potential to reclassify the disease based on genetic markers and moves thyroid cancer into a position to benefit more from precision medicine.
“This understanding of the genomic landscape of thyroid cancer will refine how it’s classified and improve molecular diagnosis. This will help us separate those patients who need aggressive treatment from those whose tumour is never likely to grow or spread,” says Thomas J. Giordano, M.D., Ph.D., professor of pathology at the University of Michigan Medical School.
Giordano is the project co-lead for TCGA thyroid cancer analysis along with Gad Getz, Ph.D., director of Cancer Genome Computational Analysis at the Broad Institute of MIT and Harvard.
Thyroid cancer incidence has increased three-fold over the last 30 years and is the most rapidly increasing cancer in the United States. While the tumours are often slow-growing and easily treated with a combination of surgery, thyroid hormone and radioactive iodine, some patients will develop more aggressive and deadly thyroid cancers.
In this TCGA study the researchers analysed nearly 500 thyroid cancer samples to identify all genetic mutations that play a role. They found several new cancer genes as well as new variations of existing genes.
Overall, the thyroid cancer genome is relatively quiet, with fewer genetic mutations involved than in other common cancers, the researchers found. This may explain why the disease is often slow-growing.
Fewer mutations meant the researchers were able to look at the signalling pathways involved and understand what drives thyroid tumours. This approach helped them understand the genetic drivers of more of these cancers, reducing the percentage of “dark matter” cases – those with unknown genetic drivers – from 25 percent to 3.5 percent.
Those drivers can be broken down into two primary oncogenic groups: BRAF plus similar mutations and RAS plus similar mutations. But within these two primary groups, especially the BRAF group, several different subtypes of thyroid cancer exist. Currently, all thyroid cancers associated with BRAF, for example, had been considered essentially the same. That’s not the case.
“This study integrated a wide variety of genomic data to not only identify cancer drivers, but to compare how these different drivers behave,” said Getz, who is also director of the Bioinformatics Program at the Massachusetts General Hospital Cancer Center and an associate professor of pathology at Harvard Medical School. “Interestingly, we found that subsets of BRAF-mutated thyroid cancers are driving cancer through distinct mechanisms, and that some of these subsets are associated with higher risk and less differentiated cancers.”
The researchers used this understanding to create measures or scores that can determine how a tumour signals and how aggressive a thyroid tumour is. These scores are being tested in a clinical trial to assess if it can lead to more targeted treatment recommendations.
“These findings are a major step forward in how doctors and patients will address thyroid cancer diagnosis and treatment. Researchers around the world will be using this data, coming back to it and asking other scientific questions,” says Carolyn Hutter, Ph.D., M.S., program director in the division of genomic medicine at the National Human Genome Research Institute.
An initial recommendation is for the pathology and scientific communities to consider reclassifying thyroid cancer based on molecular subtypes to better reflect their underlying molecular properties. This would allow doctors to identify the slow-growing tumours from the aggressive tumours and recommend appropriate treatments. Broad Institute