Gene mutation identified for rhabdomyosarcoma

Researchers have identified a gene that may play a role in the growth and spread of a childhood cancer called rhabdomyosarcoma, which develops in the body’s soft tissues. The finding has revealed a potential new target for the treatment of this disease. The study, by scientists at the US National Cancer Institute (NCI) and the US National Heart, Lung and Blood Institute, components of the US National Institutes of Health, and colleagues at The Children’s Hospital in Westmead, Australia, and the Nationwide Children’s Hospital, Columbus, Ohio, was published online 5 October 2009, in the Journal of Clinical Investigation.

Rhabdomyosarcoma (RMS) is the most common type of sarcoma found in children. This aggressive cancer can occur in many places in the body, but it usually begins in cells that form muscle tissue. Although progress has been made in increasing the overall survival of patients treated for RMS, less than 30% of children whose cancer has spread, or metastasized, survive more than five years.

The newly implicated gene produces a substance called fibroblast growth factor receptor 4, also referred to as FGFR4 protein. This protein belongs to a family known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival, as well as the formation of new blood vessels. Mutations in receptor tyrosine kinase genes have been found previously in some other human cancers. Some of these mutations cause the tyrosine kinase to be active in the absence of an external signal that is normally required for activation, and this inappropriate activation may promote the development of cancer.

Researchers find new gene mutations for melanoma

Drawing on the power of DNA sequencing, United States National Institutes of Health researchers have identified a new group of genetic mutations involved in the deadliest form of skin cancer, melanoma. This discovery is particularly encouraging because some of the mutations, which were found in nearly one-fifth of melanoma cases, reside in a gene already targeted by a drug approved for certain types of breast cancer.

Melanoma is becoming increasingly more common around the world. A major cause of melanoma is thought to be sun exposure; the ultraviolet radiation in sunlight can damage DNA and lead to cancer-causing genetic changes within skin cells.

In work published in the September issue of Nature Genetics, a team led by Yardena Samuels, PhD, of the US National Human Genome Research Institute sequenced the protein tyrosine kinase (PTK) gene family in tumour and blood samples from people with metastatic melanoma. The samples were collected by the study’s co-author Steven Rosenberg, MD, PhD, a leading expert on melanoma and chief of surgery at the US National Cancer Institute.

The PTK family includes many genes that, when mutated, promote various types of cancer. However, relatively little had been known about roles played by PTK genes in human melanoma. The NIH study was among the first to use large-scale DNA sequencing to systematically analyse all 86 members of the PTK gene family in melanoma samples.

The team’s initial survey, which involved samples from 29 melanoma patients, identified mutations in functionally important regions of 19 PTK genes, only three of which had been previously implicated in melanoma. The researchers then conducted more detailed analyses of those 19 genes in samples from a total of 79 melanoma patients.

One of the newly implicated genes stood out from the rest. Researchers detected mutations in the ERBB4 gene (also known as HER4) in 19% of patients’ tumours, making it by far the most frequently mutated PTK gene in melanoma. In addition, researchers found that many ERBB4 mutations were located in functionally important areas similar to those seen in other PTK oncogenes involved in lung cancer, brain cancer and gastric cancer.

What’s more the researchers showed that the melanoma cells grew much more slowly when they were exposed to a chemotherapeutic drug known to inhibit ERBB4. The drug, called lapatinib (Tykerb), was approved by the US Food and Drug Administration in 2007 for combination use in breast cancer patients already taking the drug capecitabine (Xeloda).

MicroRNA may help liver cancer treatment

A small RNA molecule, known as a microRNA, may help physicians identify liver cancer patients who, in spite of their poor prognosis, could respond well to treatment with a biological agent called interferon. The finding, by scientists at the US National Cancer Institute (NCI), part of the US National Institutes of Health, and their partners at Fudan University, Shanghai, and the University of Hong Kong in China and at Ohio State University, Columbus, appeared in the 8 Oct, 2009, issue of The New England Journal of Medicine.

“Interferon is an experimental therapeutic agent that has been used for many years to treat cancer patients, but with modest benefit,” said study first author Junfang Ji, PhD, of the Liver Carcinogenesis Section at NCI’s Center for Cancer Research.

“Our findings are exciting because we are rediscovering a drug that may have great potential for patients with a particular genomic profile. Being able to treat patients with an existing drug based on a tumour’s genomic profile should improve its efficacy and reduce the cost of treatment,” added study senior author Xin Wei Wang, PhD, chief of the Liver Carcinogenesis Section.

Hepatocellular carcinoma, or HCC, is a common type of liver cancer. Surgery is currently the most effective therapy for this disease, but only about 10% to 20% of patients are eligible for this option, and even among eligible patients the relapse rate is high. Post-operative treatment with interferon often follows surgery in an attempt to prevent relapse in some patients, but this approach often fails as well.

How HCC develops is unclear. What is known is that it occurs more often in men than in women, and men tend to develop a more aggressive form of the disease. Differences in tumour biology and/or in the tumour microenvironment – the noncancerous tissue surrounding a tumour – may play a role.

Changes in microRNA levels have been noted in various human cancers, so a research team led by Wang looked at variation in the expression of microRNAs involved in HCC. The team measured levels of microRNAs associated with both cancerous and normal tissue in men and women. The researchers analysed microRNA expression profiles from 241 surgery patients. By first comparing the microRNA profiles of normal liver tissue, and then comparing microRNAs in men and women, the researchers identified several microRNAs that were expressed more abundantly in normal female liver tissue. One of these, miR- 26, was highly abundant and showed the greatest difference between the sexes, so it was chosen for further analysis.

Overall, whether male or female, patients who had low levels of miR-26 did not live as long as patients who had higher expression levels of this microRNA. There was about a four-year difference in survival between the patient groups. The researchers validated their findings in three independent groups of HCC patients, and again, those with lower tumour miR-26 levels had poorer survival.

In a separate analysis, the team investigated whether miR-26 status influenced sensitivity to interferon therapy and found that patients with low tumour levels of miR-26 (indicative of a poor prognosis) benefited from receiving adjuvant interferon therapy.

These findings indicate that miR-26 status in tumours may be useful information both to determine prognosis for patients with HCC and to inform the selection of patients who might benefit from treatment with interferon to prevent disease relapse.

● Reference: Wang XW, et al. MicroRNA expression, survival, and response to interferon in men and women with liver cancer. The New England Journal of Medicine. No. 361, Vol. 15.

Researchers find genetic cause of immune deficiency disorder

Researchers at the US National Institutes of Health (NIH) have identified a genetic mutation that accounts for a perplexing condition found in people with an inherited immunodeficiency. The disorder, called combined immunodeficiency, is characterised by a constellation of severe health problems, including persistent bacterial and viral skin infections, severe eczema, acute allergies and asthma, and cancer.

The team that made the discovery was led by Helen Su, MD, PhD, at the US National Institute of Allergy and Infectious Diseases (NIAID), and included collaborators from NIAID and the US National Cancer Institute (NCI). The research is reported in the 21 September issue of New England Journal of Medicine.

Combined immunodeficiency is a type of primary immune deficiency disease (PIDD) in which several parts of the immune system are affected. This inherited disorder is characterised by increased susceptibility to bacterial, viral and fungal infections of various organs of the body. In some cases, susceptibility to cancers also may be seen.

There are 150 known PIDDs. Approximately 500,000 people in the United States have been diagnosed with a PIDD, while many more remain undiagnosed.

The NIAID and NCI investigators recognized that certain patients with an undefined form of combined immunodeficiency shared enough clinical features to make it likely that the cause might be a common genetic mutation. Originally, these individuals were thought to have a variant form of hyperimmunoglobulinema E syndrome (HIES), a disorder characterised by increased levels of a class of antibodies known as immunoglobulin E, superficial and systemic bacterial and fungal infections, and atopic dermatitis, also known as eczema.

This newly described group, however, had far more severe eczema than is typical in people with variant HIES. They also had extensive and difficult-to-manage viral infections of the skin, such as warts, molluscum contagiosum – a type of poxvirus that only infects the skin – and herpes simplex. Some in this group also developed skin cancers, as well as lymphoma of the skin. “Even though these individuals were diagnosed with a more uncommon form of HIES, they were still considered to have a mystery disease, because they had severe allergies and had developed cancers,” says Dr Su.

New gene target may aid type 2 diabetes treatment

Scientists have identified a genetic variation in people with type 2 diabetes that affects how the body’s muscle cells respond to the hormone insulin, in a new study published 6 September in Nature Genetics. The researchers, from Imperial College London and other international institutions, say the findings highlight a new target for scientists developing treatments for diabetes.

Previous studies have identified several genetic variations in people with type 2 diabetes that affect how insulin is produced in the pancreas. This study shows for the first time a genetic variation that seems to impair the ability of the body’s muscle cells to use insulin to help them make energy. Until now, scientists had not been able to identify the genetic factors contributing to insulin resistance in type 2 diabetes.

In the new research, scientists from international institutions including Imperial College London, McGill University, Canada, CNRS, France, and the University of Copenhagen, Denmark, looked for genetic markers in over 14,000 people and identified four variations associated with type 2 diabetes. One of these was located near a gene called IRS1, which makes a protein that tells the cell to start taking in glucose from the blood when it is activated by insulin. The researchers believe that the variant they have identified interrupts this process, impairing the cells’ ability to make energy from glucose. The researchers hope that scientists will be able to target this process to produce new treatments for type 2 diabetes.

Professor Philippe Froguel, one of the corresponding authors of the study from the Department of Genomic Medicine at Imperial College London, said: “We are very excited about these results – this is the first genetic evidence that a defect in the way insulin works in muscles can contribute to diabetes. Muscle tissue needs to make more energy using glucose than other tissues. We think developing a treatment for diabetes that improves the way insulin works in the muscle could really help people with type 2 diabetes.

“It is now clear that several drugs should be used together to control this disease. Our new study provides scientists developing treatments with a straightforward target for a new drug to treat type 2 diabetes,” he said.

● Reference: A multistage genome-wide association study detects a new risk locus near IRS1 for type 2 diabetes, insulin resistance and hyperinsulinemia, P Froguel et al, Nature Genetics, 6 September 2009.

Natural Killer cell master gene identified

Researchers at the National Institute for Medical Research (NIMR) in London have identified the Natural Killer cell ‘master gene’ thus creating a mouse model that lacks this lineage of lymphoid cells. The research is published in Nature Immunology

. Natural Killer (NK) cells are lymphocytes but are less well characterised than T and B cells. NK cells can directly kill target cells ranging from microbialinfected cells to cancer cells. NK cells also produce pro-inflammatory cytokines such as Interferon- activate dendritic cells and even prime T and B cells. Altered NK cell function is thought to be central to the pathology of multiple disease states including cancer, autoimmune disorders, inflammatory conditions, persistent viral infections, female infertility and graft rejection. Harnessing the therapeutic potential of NK cells has therefore been a goal of medical research for some time. A major obstacle has been a lack of understanding of the regulation of NK cell production as well as a suitable mouse model in which to study the precise role of NK cells.

In collaboration with Dimitris Kioussis’ lab in NIMR’s Division of Molecular Immunology, Duncan Gascoyne and Hugh Brady have identified the gene E4bp4 as critical to NK cell lineage commitment. After generating mice lacking E4bp4 they found that these mice have no NK cells but that other related cell types such as memory T cells and NKT cells were unaffected.

Transducing blood stem cells with E4bp4 is sufficient to induce them to differentiate into NK cells. E4bp4 regulates a genetic pathway, also including Gata3 and Id2, which is specifically responsible for producing NK cells.

“Our findings provide a master key that will allow us to unlock the gene network that controls the formation of mature NK cells. This should let us identify molecular targets for drugs to manipulate NK cell numbers and activity. In addition, the mouse model is the only one available to specifically remove all functional NK cells. This will allow us to clear up once and for all the requirement for NK cells to prevent or promote various disease states,” Brady said.

● Reference: Duncan M. Gascoyne, et al, The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development, published online 13 September, Nature Immunology. doi:10.1038/ni.1787 

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