New breast cancer genes discovered

In a study published 16 May 2012 in Nature, researchers describe nine new genes that drive the development of breast cancer. This takes the tally of all genes associated with breast cancer development to 40.

The team examined all the genes in the genomes of 100 cases of breast cancer. The mutated cancer-causing genes were different in different cancer samples, indicating that breast cancer is genetically very diverse. Understanding the consequences of this diversity will be important in progressing towards more rational treatment.

Changes to DNA lie behind all cases of cancer. Cancer develops as a result of mutations – called somatic mutations – that are acquired during a person’s lifetime. Driver mutations, which occur in cancer genes, are a small subset of somatic mutations that drive the development of cancer.

“Breast cancer is the most common cancer in women,” explains Dr Patrick Tarpey, first author from the Wellcome Trust Sanger Institute. “To identify new cancer genes that lead to the development of breast cancer, we searched for driver mutations in over 21,000 genes, and found evidence for nine new cancer genes involved in the development of this cancer.”

These genome analyses provide a direct survey of the landscape of driver mutations in breast cancer. The team found driver mutations were present in at least 40 different cancer genes. Most individual cancers had different combinations of mutated cancer genes, demonstrating the substantial genetic diversity in breast cancer.

Professor Mike Stratton, lead author and director of the Wellcome Trust Sanger Institute, said: “In 28 cases we found only a single driver, but the maximum number of driver mutations in an individual cancer was six. We found that breast cancer can be caused by more than 70 different combinations of mutations. If we consider three breast cancers, each with four driver mutations: they might share none of those driver mutations – so each is a different genetic ‘animal’. They are different cancers driven by different genes. We need to classify them as carefully as we can. This study is a step towards that goal.”


New non-invasive genetic test for Down Syndrome and Edwards Syndrome

Current screening strategies for Down Syndrome and Edwards Syndrome have false positive rates of 2-3%, and false negative rates of 5% or higher. Positive screening results must be confirmed by amniocentesis or chorionic villus sampling, which carry a foetal loss rate of approximately 1 in 300 procedures. Now an international, multicentre cohort study finds that a genetic test to screen a maternal blood sample for both syndromes’ genetic markers is almost 100% accurate.

The trial evaluated a novel assay known as Digital Analysis of Selected Regions (DANSR) that analyses foetal cell-free DNA, small DNA fragments which circulate in maternal blood. Unlike similar tests that analyse DNA from the entire genome, DANSR analyses only the chromosomes under investigation for a more efficient and less expensive process. The results are evaluated with a novel analysis algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE), which considers age-related risks and the percentage of foetal DNA in the sample to provide an individualised risk score for trisomy detection.

A total of 4,002 pregnant women were enrolled in the NICE (Non-Invasive Chromosomal Evaluation) study. The mean maternal age was 34.3 years and the cohort was racially and ethnically diverse. The classification of samples as High Risk or Low Risk using the DANSR and FORTE method was compared with the results from amniocentesis and CVS.

doi: 10.1016/j.ajog.2012.05.021

US NHGRI awards grants for researching genome function

The US-based National Human Genome Research Institute (NHGRI), part of the US National Institutes of Health, has awarded 10 grants, totalling Dh38.6 million ($10.5 million), to develop revolutionary technologies that will help researchers identify millions of genomic elements that play a role in determining what genes are expressed and at what levels in different cells. These multi-year grants are part of the Encyclopedia of DNA Elements (ENCODE) project, whose aim is to provide the scientific community with a comprehensive catalogue of functional genomic elements that will ultimately help explain the role that the genome plays in health and disease.

“The ENCODE project is providing a Rosetta Stone to understand how the sequence of the human genome forms the words that tell our bodies how to work at the molecular level,” said Eric D. Green, MD, PhD, director of NHGRI, which directs and funds the ENCODE project. “By developing more revolutionary technologies for probing genome function, we expect to accelerate these efforts.”

The ENCODE Project

Stem-cell conversion causes less mutations than thought

A team of researchers from Johns Hopkins University and the US National Human Genome Research Institute has evaluated the whole genomic sequence of stem cells derived from human bone marrow cells – so-called induced pluripotent stem (iPS) cells – and found that relatively few genetic changes occur during stem cell conversion by an improved method. The findings were reported in the March 2012 issue of Cell Stem Cell, the official journal of the International Society for Stem Cell Research (ISSCR).

Linzhao Cheng PhD, professor of Medicine and Oncology, and a member of the Johns Hopkins Institute for Cell Engineering, said: “Our results show that human iPS cells accrue genetic changes at about the same rate as any replicating cells, which we don’t feel is a cause for concern.”

She explained that each time a cell divides, it has the chance to make errors and incorporate new genetic changes in its DNA. Some genetic changes can be harmless, but others can lead to changes in cell behaviour that may lead to disease and, in the worst case, to cancer.

In the new study, the researchers showed that iPS cells derived from adult bone marrow cells contain random genetic changes that do not specifically predispose the cells to form cancer.

Cheng said: “Little research was done previously to determine the number of DNA changes in stem cells, but because whole genome sequencing is getting faster and cheaper, we can now more easily assess the genetic stability of these cells derived by various methods and from different tissues.”

Geneticists discover a sixth nucleotide

Two modifications of cytosine, one of the four bases that make up DNA, look almost the same but mean different things. Now, a team of scientists from the University of Chicago, the Ludwig Institute for Cancer Research, the University of California, San Diego and Emory University has developed and tested a technique to accomplish this task. The team used the technique to map 5-methylcytosine (5- mC) and 5-hydroxymethylcytosine (5- hmC) in DNA from human and mouse embryonic stem cells, revealing new information about their patterns of distribution. These studies have revealed that these DNA modifications play major roles in fundamental life processes such as cell differentiation, cancer and brain function.

Scientists have been examining the patterns of 5-mC for decades, as part of the field of epigenetics: the study of the information that lies “on top” of the DNA sequence. However, researchers only recognised that 5-hmC was present at significant levels in our DNA a few years ago. 5-mC is generally found on genes that are turned off, and helps silence genes that aren’t supposed to be turned on. In contrast, 5-hmC appears to be enriched on active genes, especially in brain cells. Also, defects in the Tet enzymes that convert 5-mC into 5-hmC can drive leukemia formation, hinting that changes in 5-hmC are important in cancer.

A patent is pending on the new gene deciphering invention. UChicago is working with Chicago-based Wisegene to further develop the technology. Researchers in epigenetics expect TABSeq to have a major impact on their work.

Nottingham researchers lead world’s largest study into pre-eclampsia

Researchers from The University of Nottingham are leading the largest ever international research project into the genetics of the potentially fatal condition pre-eclampsia. The research will aim to provide new insights into the prevention, prediction and treatment of the disease, which kills up to 40,000 women and almost one million babies every year worldwide.

As part of the study, DNA collected from thousands of pregnant women will be studied in an attempt to find genetic clues which may predict which women are more at risk of developing the illness.

Dr Linda Morgan, associate professor in The University of Nottingham’s School of Molecular Medical Sciences, said: “We are studying the genes which lead women to develop pre-eclampsia. By understanding which genes cause the disease, it may be possible to prevent pre-eclampsia or improve treatment.”

Nottingham is co-ordinating the InterPregGen (International Pregnancy Genetics) study, which also involves obstetricians, midwives and geneticists from Finland, Iceland, Kazakhstan, Norway, Uzbekistan and the universities of Leeds and Glasgow, the London School of Hygiene and Tropical Medicine and the Wellcome Trust Sanger Institute in the UK.

With funding from the European Union, the project will run for four-and-a-half years and will aim to develop our understanding of the genetic link which scientists believe plays a major role in pre-eclampsia. The condition runs in families – a woman whose mother or sister has had pre-eclampsia is at least three times more likely to develop the disease. As babies inherit genes from both parents the study will be looking at the genetic makeup of mother, father and child.

Once the researchers find a gene that is connected with pre-eclampsia, they can identify in detail what that particular gene does and find out when it is active during pregnancy. The academics will then be able to decide whether it is at work in the mother, baby or the placenta. When they understand the genetic mechanisms influencing the condition, they will be in a better position to prevent and treat it.

It will also help to identify women who are at the highest risk of developing the condition during their pregnancy, so that additional ante-natal care can be provided for them.

As part of the international study, researchers will be undertaking whole genome sequencing of people from Central Asia for the first time, in a similar way to the 1,000 Genomes Project, which will also provide long-term biological information for future research in these populations.


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