Posts Tagged ‘rna’

New gene mutations for Wilms tumor found

Wilms tumor is the most common childhood genitourinary tract cancer and the third most common solid tumor of childhood.

“While most children with Wilms tumor are thankfully cured, those with more aggressive tumors do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumor patients. We wanted to know — what are the genetic causes of Wilms tumor in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.

The new findings appear in Nature Communications. Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.

Previous research has identified one or two mutant genes in Wilms tumors, but only about one-third of Wilms tumors had these mutations.

“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumors and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”

“Let-7 is an important microRNA that slows cell growth and in Wilms tumors in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.

These findings have implications for future treatment of Wilms tumor and several other childhood cancers, including neuroblastoma, germ cell tumor, and rhabdomyosarcoma.

“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumors. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumor looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. This study also is a gratifying example of great teamwork. As oncologists, Dr. Chen and I were able to make rapid progress by teaming up with Dr. Rakheja, an expert pathologist, and with Dr. Mendell, a leading expert on microRNA biology.”

According to the American Cancer Society, an estimated 510 cases of Wilms tumor will be diagnosed among children in 2014. Also called nephroblastoma, Wilms tumor is an embryonal tumor of the kidney that usually occurs in children under age 5, and 92 percent of kidney tumors in this age group are Wilms tumor. Survival rates for Wilms tumor have increased from 75 percent in 1975-1979 to 90 percent in 2003-2009.

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Predicting aggressive lymphoma

The new statistical method will be able to determine who will need a bone-marrow transplantation and who can be spared the extreme burden that this excruciating treatment entails.

The results have recently been published in Blood.

Many types of lymphoma

Lymphoma can be divided into approximately 60 subgroups. The prognoses are unpredictable. Some have no recurrence, while in others the disease recurs quickly. Some patients struggle with repeated recurrences.

Patient survival vary greatly. Some patients die within one or two years, while others survive for twenty to thirty years. Those who survive suffer from numerous symptoms. In addition, the treatment may have major adverse effects.

The two main groups of lymphoma are Hodgkin’s, which primarily affects young people — with approximately 130 cases annually — and non-Hodgkin’s, with a little less than 1000 cases annually.

In the group that develops non-Hodgkin’s, 15 per cent are afflicted by cancer of the T-cells and 85 per cent by cancer of the B-cells. T-cells and B-cells are both part of the adaptive immune defense system. B and T-cells eliminate intruders in different ways. T-cells attack bacteria and viruses in particular. B-cells produce antibodies that in turn attack intruders.

Therefore, it is extremely detrimental when cancer deactivates parts of the immune defense system.

Aggressive variant

Professors Erlend Smeland and Harald Holte at the Institute of Cancer Research, UiO, and the Department of Oncology at Oslo University Hospital are among the country’s foremost specialists in B-cell lymphoma. This is the largest group of lymphomas, which affects more than 800 Norwegians each year.

This form of cancer can be further subdivided into an aggressive and an indolent variant. The indolent form may develop very slowly without major discomfort for the patient, but it may gradually change in character and turn more aggressive. If so, the prognosis worsens. The change to the aggressive variant is called transformation. The question is: who will develop this transformation and who will be spared.

Three per cent develop this transformation in the course of a year. This means that after fifteen years, half of all those affected will have developed the transformation.

Predicting who will become ill

Together with Marianne Brodtkorb, a doctor at the Institute for Cancer Research and Ole Christian Lingjærde, professor and head of the research group for biomedical bioinformatics at the Institute of Informatics, the researchers have discovered a completely new method that can predict at an early stage of the disease who will have a recurrence and when the recurrence will appear.

“The point is to be able to tailor the treatment and nip the cancer in the bud, or delay or at best avoid the most burdensome treatment for those who are not at risk. Thus, many can have a milder form of treatment than they have today,” Harald Holte explains.

To succeed, the researchers needed to find the genetic imprint of the different cancer variants. This was a formidable task.

Historic material

The only way to do this was to examine all the fresh frozen tissue samples from the diagnostic biobank at the Norwegian Radium Hospital back to the 1970s. Norway is one of few countries in the world where tissue samples from all cancer patients have been stored. Since a part of the biopsy have been frozen, the genetic material remains intact.

The researchers compared the genetic imprint with the course of the disease in all patients, such as how the disease developed, when the aggressive variant occurred, i.e. the transformation, and for how long the patient survived.

“We found genetic markers that can predict in the early stage of disease how the patient will fare and how the course of the disease will develop,” Erlend Smeland emphasizes to the research magazine Apollon.

Found the most important genes

The researchers detected a total of 700 changes to both DNA and RNA. RNA is the active component of DNA.

Marianne Brodtkorb, who recently completed her PhD degree, investigated which of these 700 genes functioned in the same way. She found 14 genes which had the same function. Thereafter, she studied only these markers.

“This demonstrated for the first time that these 14 genes are associated with the transformation. These genes are known from other forms of lymphoma, but they have never before been linked to this type of lymphoma. With this new knowledge, we can now test known methods of treatment for this disease,” Brodtkorb explains.

In addition, they have identified the range of genes that fluctuate in unison with the 14 genes. These genes reinforce the effect of the disease.

“In fact, this involves a range of 30 to 50 genes for each of the 14 genes. These ranges of genes are unrelated to the 700 initial changes that were detected.”

New statistics

To compare the genetic imprints on the several thousand samples, Ole Christian Lingjærde has developed completely new statistical methods.

“We needed to use quite sophisticated statistical methods to detect the genetic signature that enables us to predict whether and when the cancer will enter an aggressive phase,” Lingjærde points out.

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Cellular biology of colorectal cancer: New Insight

Lead author Kristi Neufeld, associate professor in the Department of Molecular Biosciences and co-leader of the Cancer Biology program at the KU Cancer Center, has spent the better part of her career trying to understand the various activities of APC, a protein whose functional loss is thought to initiate roughly 80 percent of all colon polyps, a precursor to colon cancer. Neufeld, along with her postdoctoral fellow Maged Zeineldin, undergraduate student Mathew Miller and veterinary pathologist Ruth Sullivan, now reports that APC found in a particular subcellular compartment, the nucleus, protects from inflammation as well as tumor development associated with chronic colitis.

Whether APC reaches the nucleus may well affect the ability of intestinal stem cells to produce differentiated cells with specialized functions, Neufeld said.

“It’s not widely appreciated, but there is still plenty of cell growth going on in adults, with the colon being a good example,” she said. “On average, we shed and replace about 70 pounds of intestinal tissue annually, so you can imagine that this process requires exquisite control to prevent tumor formation.”

Regular renewal of the colon lining occurs through stem cells that are capable of constantly dividing. These cells produce descendants that take up specific roles: By secreting mucin, for instance, goblet cells generate a mucus layer that serves as the colon’s physical barrier against its many microbial tenants. But if APC can’t find its way to the nucleus, Neufeld and her team have noted far fewer goblet cells as one outcome.

“We introduced a specific APC mutation into mice that took away the nuclear zip code, so to speak, leaving APC stuck in the cytoplasm,” Neufeld said. The researchers studied this mouse model under conditions that induce ulcerative colitis, a form of inflammatory bowel disease that can be a prelude to colon cancer.

Observing significantly more colon tumors in these mice compared to those with normal APC in the same disease setting, they hypothesized that functional nuclear APC might somehow guard against inflammation and its downstream effects, including tumor development. Now, Neufeld thinks she and her team may have a clue as to how this happens.

“The drop in goblet cell numbers we observed was striking,” she said. “We then examined one of the proteins found in mucus, called Muc2, and found that its RNA levels were greatly decreased. If there are fewer goblet cells as a result of APC being unable to reach the nucleus, there will also be less mucus, which could increase the colon’s sensitivity to bacteria and other microorganisms in the gut that are capable of promoting inflammation.”

Neufeld said while there are still no quick fixes for mutant genes, perhaps tools could be developed to synthetically replace this less-than-ideally thick mucus layer in affected people.

One known function of APC is that it halts cell proliferation: by muzzling the canonical arm of the Wnt signaling pathway, which otherwise instructs cells to go forth and multiply. Neufeld and her group have already shown, using the same mouse model, that APC stationed in the nucleus is necessary to suppress Wnt and its signaling partners — particularly β-catenin, a key target of normal APC. With a role for nuclear APC in controlling goblet cell differentiation now supported, the researchers are probing possible mechanisms to learn if and how Wnt pathway members might be involved.

Comprising 2,843 amino acids, APC is a large protein.

“Rather than being a simple, single-function protein, APC is more like a complex set of moving parts, each doing something different and most still poorly understood,” Neufeld said. “I think if the sole purpose of this protein was to target β-catenin for destruction, it wouldn’t need to be this large. Our next job is to figure out exactly how goblet cell differentiation is controlled by one or more of APC’s many components.”

Beyond a slew of mechanistic details, the bigger picture that Neufeld and her group will keep exploring is that some colon cancers could arise from an inflammatory response to bacterial penetration of a thinner-than-normal mucus layer in the gut, resulting from defective APC. The possibilities of just what APC does and doesn’t do, and how to compensate for any intestinal glitches related to loss of APC function, present a challenging mystery but also a plentiful harvest for scientists like Neufeld to reap going forward.

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