̽��ֱ�� of Cambridge - mutation

Cause of rare growth disease discovered

bjb42 — Sun, 24 Jun 2012 18:00:54 +0000

A rare genetic disease which causes some parts of the body to grow excessively has been linked to a cancer-associated mutation that drives cell growth, potentially paving the way for new treatments. ̽��ֱ��research findings were published today, 24 June, in Nature Genetics.

An international collaboration among the ̽��ֱ�� of Cambridge, the Sanger Institute, and the Babraham Institute in the UK and the National Institute for Health in the US has discovered that unrestrained and sometimes massive fatty ‘overgrowth’ affecting only some body regions is caused by mutations in the phosphatidylinositol-3-kinase (PI3K)/AKT signalling pathway (which is critical for cellular growth and metabolism).

̽��ֱ��types of mutations which cause these overgrowths typically arise during embryonic development. Unlike conditions caused by genetic mutations which are transmitted from parents (in which every cell in the body is affected), in this condition only the ‘offspring’ of the cell where the mutation occurs carry the change. This accounts for why only some parts of the body are affected.

̽��ֱ��scientists from the ̽��ֱ�� of Cambridge and the Sanger Institute, who were funded mainly by the Wellcome Trust, first studied a patient who had severe overgrowth of her legs but a normal upper body. By conducting a genetic analysis of cells sampled from the affected and unaffected areas, they were able to identify a critical mutation which caused the overgrowth in her legs. Scientists at the Babraham Institute then made use of their unique lipidomics mass spectrometry capability to demonstrate abnormal activation of the signalling pathway in cells from the leg but not the arm. These studies were extended in collaboration with scientists at the US National Institute for Health in Maryland, leading to discovery of nine other patients with similar mutations, confirming the results and suggesting that activation of the PI3K pathway may be a common cause of this form of fatty overgrowth.

Dr Robert Semple, from the ̽��ֱ�� of Cambridge Metabolic Research Laboratories at the Institute of Metabolic Science, said: “ ̽��ֱ��mutations we have found are well known as ‘cancer mutations’. However, in cancers they are found with numerous other genetic changes, while here they are apparently in isolation.”

“Studying our patients will thus give new information about the specific role played by these mutations in cancer. Moreover, the major effort to make drugs targeting these mutations for cancer therapy should benefit people with this rare problem, and when drugs safe enough for long-term use are developed they may offer for the first time a targeted, and effective, non-surgical treatment for the excessive growth. We are testing currently available drugs in cells at present.”

Dr Inȇs Barroso, from the Wellcome Trust Sanger Institute, said “We wanted to understand the biology behind this rare and debilitating disorder and thought exome sequencing - sequencing the region of the genome where genetic material is translated into proteins - would be a powerful approach to facilitate the discovery of the underlying mutation. Using DNA sequencing we found that a mutation associated with cancer in the gene PIK3CA was found only in the affected cells of patients”.

Professor Michael Wakelam from the Babraham Institute said “This study exemplifies the importance of collaboration between basic and clinical scientists in translating methodologies and concepts from the research lab to bring about greater understanding and potentially treatment of human disease.”

Scientists hopeful discovery will provide a biological target for drug therapy.

̽��ֱ��mutations we have found are well known as ‘cancer mutations’. However, in cancers they are found with numerous other genetic changes, while here they are apparently in isolation.

Robert Semple

Nature Genetics.

Example of fatty overgrowth, affecting specific body regions, caused by mutations in the phosphatidylinositol 3 kinase PI3K (AKT) signalling pahtway.

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Finding the ‘genetic signposts’ of disease

ns480 — Sat, 01 Sep 2007 11:57:45 +0000

̽��ֱ��Wellcome Trust Case Control Consortium (WTCCC) brought together 50 research groups from dozens of institutions in the UK, including the Wellcome Trust Sanger Institute at Hinxton, Cambridge, and the ̽��ֱ�� of Cambridge. ̽��ֱ��success of the project depended both on capitalising on the knowledge built by the Human Genome Project and the HapMap Project, two consortia in which the Sanger Institute was a major partner, and also on the sheer size of the collaboration across the UK.

Dr Panos Deloukas, who led the team at the Sanger Institute, explains: ‘This was unprecedented in the UK. ̽��ֱ��sharing of samples and data on this scale has changed the ethos of the research community – through working with 50 laboratories across the country and conducting large-scale disease genetics at a level that has never been done before.’

̽��ֱ��collaborators contributed their large national collections of DNA samples collected from different patient groups – totalling an incredible 17,000 samples across the UK (2000 patients for each of the diseases studied plus 3000 healthy controls) – allowing over 10 billion pieces of genetic information to be analysed by genome scan using the Affymetrix GeneChip assay. Tiny genetic variations between individuals that predispose to type 1 and type 2 diabetes, Crohn’s disease, bipolar disorder, coronary heart disease, hypertension and rheumatoid arthritis were sought. By identifying these ‘genetic signposts’, scientists might understand which people are most at risk and why.

‘We have found 24 genomic regions with very strong evidence of harbouring variants that underlie six of the phenotypes we studied and we saw a spectrum of genetic architectures among these common diseases,’ explains Dr Deloukas. ‘Once we had these findings then the medical collaborators provided insight into the significance of the gene associations and tried to replicate them.’

Significant new breakthroughs have been made for Crohn’s disease and type 1 diabetes, and a link between the two diseases has been discovered. Dr Miles Parkes (Gastroenterology Unit, Addenbrooke’s Hospital, Cambridge) and Professor John Todd (Department of Medical Genetics, ̽��ֱ�� of Cambridge), both participants in the WTCCC, are now leading studies to follow up these findings. ‘It’s rewarding to see that the highly significant genetic associations are now being replicated in independent samples,’ says Dr Deloukas. ‘ ̽��ֱ��framework set up by the WTCCC clearly works.’

Dr Mark Walport, Director of the Wellcome Trust, views the WTCCC as a success: ‘It is an excellent illustration of the importance of knowing the human genome sequence and cataloguing its variations. Hopefully, with the insight gained into these diseases we will be able to make real progress in combating them.’

For more information on the Wellcome Trust Sanger Institute and the WTCCC (including a full list of participants), please go to www.sanger.ac.uk and www.wtccc.org.uk

One of the biggest projects ever undertaken to identify genetic variants that predispose some people to certain diseases was begun in 2005, thanks to £9 million funding from the Wellcome Trust. ̽��ֱ��ground-breaking results of this study were published in June this year.

It is an excellent illustration of the importance of knowing the human genome sequence and cataloguing its variations. Hopefully, with the insight gained into these diseases we will be able to make real progress in combating them.

Dr Mark Walport, Director of the Wellcome Trust

S.A.Mossman from Flickr

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̽��ֱ��Wellcome Trust

<div> <p> ̽��ֱ��Wellcome Trust is well known as the leading funder of biomedical research in the UK, spending many millions on major research projects that have tangible impacts on health and disease.</p> <p>This ethos is abundantly evident in the £9 million support given to the Wellcome Trust Case Control Consortium, a collaboration of leading human geneticists across the UK, to analyse thousands of DNA samples and identify genetic predispositions to common diseases. ̽��ֱ��Trust also embraces studies on how biomedical research affects people and society; the funding of a research project being undertaken in the ̽��ֱ�� of Cambridge’s Centre for Family Research is an example of this rounded view.</p> <p> ̽��ֱ��Wellcome Trust is the UK’s largest source of funds for biomedical research and the second largest medical research charity in the world. Spending around £500 million each year in the UK and internationally, the mission of the Trust is to support the brightest scientists with the best ideas, and to ‘respond flexibly to medical needs and scientific opportunities’. Through support of a broad portfolio of biomedical research from immunology and infectious diseases to physiological sciences, the Trust aims to make a difference by advancing understanding of the processes that underpin health and disease. And, as the leading funder of translation research in the UK, the Trust is also committed to translating research innovations into health benefits. Technology Transfer at the Trust can help bridge the gap between fundamental research and commercial application by funding research that is sometimes deemed ‘too early’ or ‘too high-risk’ to be pursued by the corporate healthcare or investment sectors.</p> <p>Perhaps less well known are the Trust’s funding streams across medical humanities and public engagement. Through these, the importance is recognised of engaging with society to foster an informed climate within which biomedical research can flourish. This understanding can inform many things, from the ethical conduct of research, to the development of public policy and regulatory environments, to the enlightened debate about biomedical science, its achievements, applications and implications.</p> </div>

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