Posts Tagged ‘biology’

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.

source : http://www.sciencedaily.com/releases/2014/09/140905113651.htm

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Breast conserving therapy shows survival benefit compared to mastectomy in early-stage patients with hormone receptor positive disease

The study findings defy the conventional belief that the two treatment interventions offer equal survival, and show the need to revisit some standards of breast cancer practice in the modern era.

The research was presented at the 2014 Breast Cancer Symposium by Catherine Parker, MD, formerly a fellow at MD Anderson, now at the University of Alabama Birmingham.

In the 1980s, both US-based and international randomized clinical studies found that BCT and mastectomy offered women with early stage breast cancer equal survival benefit. However, those findings come from a period in time when very little was understood about breast cancer biology, explains Isabelle Bedrosian, M.D., associate professor, surgical oncology at MD Anderson.

“Forty years ago, very little was known about breast cancer disease biology — such as subtypes, differences in radio-sensitivities, radio-resistances, local recurrence and in metastatic potential,” explains Bedrosian, the study’s senior author. “Since then, there’s been a whole body of biology that’s been learned — none of which has been incorporated into patient survival outcomes for women undergoing BCT or a mastectomy.

“We thought it was important to visit the issue of BCT versus mastectomy by tumor biology,” Bedrosian continues.

The researchers hypothesized that they would find that patients’ surgical choice would matter and impact survival with tumor biology considered.

For the retrospective, population-based study, the researchers used the National Cancer Database (NCDB), a nation-wide outcomes registry of the American College of Surgeons, the American Cancer Society and the Commission on Cancer that captures approximately 70 percent of newly-diagnosed cases of cancer in the country. They identified 16,646 women in 2004-2005 with Stage I disease that underwent mastectomy, breast conserving surgery followed by six weeks of radiation (BCT), or breast conserving surgery without radiation (BCS). Bedrosian notes that it was important that the study focused solely on women with Stage I disease in order to keep the study group homogenous and because in this cohort few would be ineligible for BCT.

Since estrogen receptor (ER) and progesterone receptor (PR) data were available and HER2 status was not, the researchers categorized the tumors as ER or PR positive (HR positive), or both ER and PR negative (HR negative). Patients were rigorously matched using propensity-score for a broad range of variables, including age, receiving hormone therapy and/or chemotherapy, as well as type of center where patients were treated and comorbidities.

Of the 16,646 women: 1,845 (11 percent) received BCS; 11,214 (67 percent) received BCT and 3,857 (22 percent) underwent a mastectomy. Women that had BCT had superior survival to those that had a mastectomy or BCS — the five-year overall survival was 96 percent, 90 percent and 87 percent, respectively. After adjusting for other risk factors, the researchers again found an overall survival benefit for BCT compared to BCS and mastectomy. In a matched cohort of 1,706 patients in each arm, the researchers still found an overall survival benefit with BCT over mastectomy in the HR positive subset but not in the HR negative subset.

While provocative, Bedrosian cautions that the findings are not practice changing, as the study is retrospective. Still, the research complements other recent studies that showed BCT was associated with a survival benefit compared to mastectomy. Also, she points to the delivery of radiation therapy as the possible driver of the overall survival benefit.

“We’ve historically considered surgery and radiation therapy as tools to improve local control,” says Bedrosian. Yet recent studies suggest that there are survival-related benefits to radiation in excess of local control benefits. Therefore, radiation may be doing something beyond just helping with local control. Also, we know hormone receptive positive tumors are much more sensitive to radiation, which could explain why we found the survival benefit in this group of patients.”

As follow up, Bedrosian and her team hope to mine the randomized controlled trial findings from the 1980s, matching those cohorts to current NCDB patients to see if a similar survival benefit could be observed.

“While retrospective, I think our findings should give the breast cancer community pause. In the future, we may need to reconsider the paradigm that BCT and mastectomy are equivalent,” she says. “When factoring in what we know about tumor biology, that paradigm may no longer hold true.”

source : http://www.sciencedaily.com/releases/2014/09/140904103336.htm

Better classification to improve treatments for breast cancer

Cancer arises due to genetic changes which cause normal cells to develop into tumors. As we learn more about breast cancer, we are seeing that it is not one single disease — the mutations in the genes that cause different cancers are not alike, and this is why tumors respond differently to treatment and grow at different rates. Currently, there are two key markers that clinicians use to predict response to treatments.

Spotting the trends in tumor genetics and creating a system to diagnose tumor types is a primary objective of cancer scientists. To this end, researchers at Cancer Research UK and the University of Cambridge have been developing the IntClust system, which uses genomic technology to create a classification system with enough detail to more accurately pinpoint which type of breast cancer a patient has, and therefore what treatment would be most appropriate.

To test the system, the scientists looked at the 997 tumor samples they had used to develop the system, and 7,544 samples from public databases, along with the genomic and clinical data including data from The Cancer Genome Atlas. They classified these using their IntClust system, and the two main systems in use today — PAM50, which groups cancers into five types, and SCMGENE, which classifies cancer into four.

They found that IntClust was at least as good at predicting patients’ prognosis and response to treatment as the existing system. But the system identified a previously unnoticed subgroup of tumors in just 3.1% of women with very poor survival rates, which appeared to be resistant to treatment. Identifying the genomic signatures for this group could flag up these high risk cancers early, and having the genomic data for these could aid in the investigation of new avenues for treatments for this type of cancer.

At present, using this system to classify tumors would be costly for most clinicians, and interpreting the results requires training that many clinical settings don’t have access to. But the detail and accuracy of this system could be of great use to breast cancer researchers, who will be able to investigate the reasons that certain groups of cancer respond better to certain treatments, in order to find clinical markers, or to identify new targets for breast cancer treatments.

Raza Ali, lead author from Cancer Research UK Cambridge Institute, says: “We have developed an expression-based method for classification of breast tumours into the IntClust subtypes. Our findings highlight the potential of this approach in the era of targeted therapies, and lay the foundation for the generation of a clinical test to assign tumors to IntClust subtypes.”

source : http://www.sciencedaily.com/releases/2014/08/140827203633.htm