Tuesday, 25 February 2014
If a driver is traveling to New York City, I-95 might be their route of choice. But they could also take I-78, I-87 or any number of alternate routes. Most cancers begin similarly, with many possible routes to the same disease. A new study found evidence that assessing the route to cancer on a case-by-case basis might make more sense than basing a patient's cancer treatment on commonly disrupted genes and pathways.
The study found little or no overlap in the most prominent genetic malfunction associated with each individual patient's disease compared to malfunctions shared among the group of cancer patients as a whole.
"This paper argues for the importance of personalized medicine, where we treat each person by looking for the etiology of the disease in patients individually," said John McDonald, a professor in the School of Biology at the Georgia Institute of Technology in Atlanta. "The findings have ramifications on how we might best optimize cancer treatments as we enter the era of targeted gene therapy."
The research was published February 11 online in the journal PANCREAS and was funded by the Georgia Tech Foundation and the St. Joseph's Mercy Foundation.
In the study, researchers collected cancer and normal tissue samples from four patients with pancreatic cancer and also analyzed data from eight other pancreatic cancer patients that had been previously reported in the scientific literature by a separate research group.
McDonald's team compiled a list of the most aberrantly expressed genes in the cancer tissues isolated from these patients relative to adjacent normal pancreatic tissue.
The study found that collectively 287 genes displayed significant differences in expression in the cancers vs normal tissues. Twenty-two cellular pathways were enriched in cancer samples, with more than half related to the body's immune response. The researchers ran statistical analyses to determine if the genes most significantly abnormally expressed on an individual patient basis were the same as those identified as most abnormally expressed across the entire group of patients. The researchers found that the molecular profile of each individual cancer patient was unique in terms of the most significantly disrupted genes and pathways. "If you're dealing with a disease like cancer that can be arrived at by multiple pathways, it makes sense that you're not going to find that each patient has taken the same path," McDonald said. Although the researchers found that some genes that were commonly disrupted in all or most of the patients examined, these genes were not among the most significantly disrupted in any individual patient. "By and large, there appears to be a lot of individuality in terms of the molecular basis of pancreatic cancer," said McDonald, who also serves as the director of the Integrated Cancer Research Center and as the chief scientific officer of the Ovarian Cancer Institute.
Though the study is small, it raises questions about the validity of pinpointing the most important gene or pathway underlying a disease by pooling data from multiple patients, McDonald said. He favors individual profiling as the preferred method for initiating treatment.
The cost of a molecular profiling analysis to transcribe the DNA sequences of exons -- the parts of the genome that carry instructions for proteins -- is about $2,000 (exons account for about two percent of a cell's total DNA). That's about half the cost of this analysis five years ago, McDonald said, and a $1,000 molecular profiling analysis might not be far off.
"As costs continue to come down, personalized molecular profiling will be carried out on more cancer patients," McDonald said.
Yet cost isn't the only limiting factor, McDonald said. Scientists and doctors have to shift their paradigm on how they use molecular profiling to treat cancer.
"Are you going to believe what you see for one patient or are you going to say, 'I can't interpret that data until I group it together with 100 other patients and find what's in common among them,'" McDonald said. "For any given individual patient there may be mutant genes or aberrant expression patterns that are vitally important for that person's cancer that aren't present in other patients' cancers."
Future work in McDonald's lab will see if this pattern of individuality is repeated in larger studies and in patients with different cancers. The group is currently working on a genomic profiling analysis of patients with ovarian and lung cancers.
"If there are multiple paths, then maybe individual patients are getting cancer from alternative routes," McDonald said. "If that's the case, we should do personalized profiling on each patient before we make judgments on the treatment for that patient."
1. Loukia N. Lili, Lilya V. Matyunina, L. DeEtte Walker, George W. Daneker, John F. McDonald. Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer. Pancreas, 2014; 43 (2): 198 DOI:10.1097/MPA.0000000000000020
Posted by: Indian Biosciences and Research Institute
Sunday, 9 February 2014
Seven new genetic regions associated with type 2 diabetes have been identified in the largest study to date of the genetic basis of the disease.
DNA data was brought together from more than 48,000 patients and 139,000 healthy controls from four different ethnic groups. The research was conducted by an international consortium of investigators from 20 countries on four continents, co-led by investigators from Oxford University's Wellcome Trust Centre for Human Genetics.
The majority of such 'genome-wide association studies' have been done in populations with European backgrounds. This research is notable for including DNA data from populations of Asian and Hispanic origin as well.
The researchers believe that, as more genetic data increasingly become available from populations of South Asian ancestry and, particularly, African descent, it will be possible to map genes implicated in type 2 diabetes ever more closely.
'One of the striking features of these data is how much of the genetic variation that influences diabetes is shared between major ethnic groups,' says Wellcome Trust Senior Investigator Professor Mark McCarthy from the University of Oxford. 'This has allowed us to combine data from more than 50 studies from across the globe to discover new genetic regions affecting risk of diabetes.'
He adds: 'The overlap in signals between populations of European, Asian and Hispanic origin argues that the risk regions we have found to date do not explain the clear differences in the patterns of diabetes between those groups.'
Among the regions identified by the international research team are two, near the genes ARL15 and RREB1, that also show strong links to elevated levels of insulin and glucose in the body -- two key characteristics of type 2 diabetes. This finding provides insights into the ways basic biochemical processes are involved in the risk of type 2 diabetes, the scientists say.
The genome-wide association study looked at more than 3 million DNA variants to identify those that have a measurable impact on risk of type 2 diabetes. By combining DNA data from many tens of thousands of individuals, the consortium was able to detect, for the first time, regions where the effects on diabetes susceptibility are rather subtle.
'Although the genetic effects may be small, each signal tells us something new about the biology of the disease,' says first author Dr Anubha Mahajan of Oxford University. 'These findings may lead us to new ways of thinking about the disease, with the aim ultimately of developing novel therapies to treat and prevent diabetes. There's every reason to expect that drugs acting on these biological processes would have a far larger impact on an individual's diabetes than the genetic effects we have discovered.'
Principal investigator Dr Andrew Morris, also of the Wellcome Trust Centre for Human Genetics at Oxford University, says: 'The findings of our study should also be relevant to other common human diseases. By combining genetic data from different ethnic groups, we would expect also to be able identify new DNA variants influencing risk of heart disease and some forms of cancer, for example, which are shared across ethnic groups. It has the potential to have a major impact on global public health.'
- Anubha Mahajan et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature Genetics, February 2014
Given its unique nature, the X chromosome has often been neglected when performing large-scale genetic studies. Because women have two copies of this chromosome and men only one, identifying genetic associations with X chromosomal genes can be particularly valuable in helping us to understand why some characteristics differ between sexes. Researchers from the University of Helsinki, Finland, have now identified novel X-chromosomal genetic variants that influence human height.
aim of the study was to find genetic factors that could explain individual differences in several traits, including BMI, height, blood pressure and lipid levels. In addition, the researchers also investigated whether the X chromosome would contribute to some of the well-known differences between men and women in certain traits, such as height. Hundreds of genetic variants having an effect on these traits have already been identified, but, given its unique nature, the X chromosome has been neglected in most of these previous studies.
The results were published in PLOS Genetics journal, February 6th.
"Studying the X chromosome has some particular challenges. The fact that women have two copies of this chromosome and men only one has to be taken into account in the analysis. We nevertheless wanted to take up the challenge since we had a strong belief that opening 'the X files' for research would reveal new, interesting biological insights," says Dr. Taru Tukiainen who is currently working at the Massachusetts General Hospital in Boston.
The study showed that a genetic variant close to ITM2A, a gene that has a role in cartilage development, is frequent among the people being shorter than average. The identified variant, which is present in more than a third of Europeans, was also shown to increase the expression of ITM2A, suggesting that the more the gene is expressed the shorter the person will be. Interestingly, the effect of this variant on height was shown to be much stronger in women.
"The double dose of X-chromosomal genes in women could cause problems during the development. To prevent this, there is a process by which one of the two copies of the X chromosome present in the cell is silenced. When we realized that the height associated variant we identified was nearby a gene that is able to escape the silencing we were particularly excited," explains Professor Samuli Ripatti, the principal investigator behind the study.
Because both copies of ITM2A remain active, the gene is expressed in higher levels in women. Identifying associations in regions like this where X-chromosomal gene doses are not balanced between men and women can be particularly valuable in helping us to understand why some characteristics differ between sexes, he continues.
"Based on our calculations, this variant accounts for a significant, though small proportion, 1-2% of the current difference in mean height between men and women in the Finnish population."
Also two other new X-chromosomal regions, one associating with fasting insulin levels and the other with height, were identified in this study. Neither of these showed any evidence of sex difference in the strength of the genetic effect.
- Taru Tukiainen, Matti Pirinen, Antti-Pekka Sarin, Claes Ladenvall, Johannes Kettunen, Terho Lehtimäki, Marja-Liisa Lokki, Markus Perola, Juha Sinisalo, Efthymia Vlachopoulou, Johan G. Eriksson, Leif Groop, Antti Jula, Marjo-Riitta Järvelin, Olli T. Raitakari, Veikko Salomaa, Samuli Ripatti. Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation. PLoS Genetics, 2014; 10 (2): e1004127 DOI: 10.1371/journal.pgen.1004127
Thursday, 30 January 2014
The biochemist Professor Volker A. Erdmann at Freie Universität Berlin succeeded for the first time in creating mirror-image enzymes -- so-called Spiegelzymes -- out of nucleic acids. The Spiegelzymes can be used in living cells for the targeted cutting of natural nucleic acids.
In an article published in PLOS ONE, Erdmann and his co-authors delineate how engineered Spiegelzymes have great potential for cutting up individual nucleic acids responsible for human diseases, and thus "deactivating" them. According to Erdmann Spiegelzymes, also called molecular scissors, have the advantage that they do not trigger side reactions of the immune system and they are extremely stable.
In the experiments Erdmann and his team were able to show that with specially constructed Spiegelzymes the production of a green glowing protein could be inhibited in the cells. The Spiegelzymes cut the messenger RNA, the molecule responsible for the production of the protein. Following similar procedures, it should be possible to prevent the synthesis of any one of the approximately 21,000 proteins anchored in the human genome, says Erdmann.
Volker A. Erdmann thinks it is plausible that in the future it will be possible to intervene in the processes of a cell to selectively cut RNA molecules that regulate the synthesis of proteins and other nucleic acids. Since RNA molecules are responsible for ensuring that a stem cell develops into a skin cell or muscle cell, or even a tumor cell, the targeted use of Spiegelzymes shows promise for completely new applications in basic research, biotechnology, and molecular medicine.
- Eliza Wyszko, Florian Mueller, Marta Gabryelska, Angelika Bondzio, Mariusz Popenda, Jan Barciszewski, Volker A. Erdmann. Spiegelzymes® Mirror-Image Hammerhead Ribozymes and Mirror-Image DNAzymes, an Alternative to siRNAs and microRNAs to Cleave mRNAs In Vivo? PLoS ONE, 2014; 9 (1): e86673 DOI: 10.1371/journal.pone.0086673
Posted by: Indian Biosciences and Research Institute
Scientists have discovered a potential cure for one of the most aggressive and least treatable forms of breast cancer called "triple negative breast cancer." In laboratory experiments involving human cancer cells, scientists used a virus similar to the one that helped eradicate smallpox to coax cancer cells to produce a protein which makes them susceptible to radioactive iodine.
"We hope that the recent advances in virology, genetic engineering and targeted radiotherapy will soon translate into an entire class of novel oncolytic, virotherapies for the treatment of deadly cancers," said Yuman Fong, M.D., a researcher involved in the work from the Department of Surgery at Memorial Sloan-Kettering Cancer Center in New York, NY.
To make this discovery, Fong and colleagues successfully infected and killed TNBC cells using a vaccinia virus. In addition, the researchers were also able to use the virus to cause infected cancer cells produce a cell surface protein called hNIS that normally is used to concentrate iodine in thyroid cells. The hNIS protein, expressed in thyroid cancer, is why most thyroid cancers can be cured or successfully treated with a small dose of radioactive iodine (which kills thyroid cancer cells expressing hNIS). Armed with the ability to force TNBC cells to produce this protein, researchers now have a way to deliver anticancer therapies to this deadly and resistant form of cancer.
"This is an important and significant discovery that basically combines proven cures for two other diseases," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Even more exciting is that the effects of this virus and radioactive iodine are well known in people, hopefully reducing the amount of time it will take for it to reach the clinic.
* The discovery was published in the February 2014 issue of The FASEB Journal.
* Posted by: Indian Biosciences and Research Institute
Indian Biosciences and Research Institute, located in the National Capital Territory, Noida, is a versatile research & training institute running under the Indian National Education and Research Society. Since its inception, IBRI has reflected growing impact of new biological technologies. Through innovative research, the organization deals with the challenges in the bioscience domain.
IBRI aims to motivate and promote students by providing subject learning and the excellent hands on practical experience to meet the rapidly evolving opportunities and challenges in the field of biotechnology, bioinformatics and applied pharmaceuticals.