25 June 2012

Cause of rare growth disease discovered

Scientists hopeful discovery will provide a biological target for drug therapy

Plain radiograph of the hand, showing distorting overgrowth of the second and third rays of the right hand.

Plain radiograph of the hand, showing distorting overgrowth of the second and third rays of the right hand. [doi:10.1038/ng.2332]

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. The research findings were published today, 24 June, in Nature Genetics.

An international collaboration among the University 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).

The 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.

The scientists from the University 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.

" Using DNA sequencing we found that a mutation associated with cancer in the gene PIK3CA was found only in the affected cells of patients. "

Dr Inês Barroso

Dr Robert Semple, from the University of Cambridge Metabolic Research Laboratories at the Institute of Metabolic Science, said: "The 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 Inês 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."

Notes to Editors

Publication details

  • Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

    Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG and Semple RK

    Nature genetics 2012;44;8;928-33

Funding

The work was funded by the Wellcome Trust, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, MRC Centre for Obesity and Related Metabolic Disease and the BBSRC

The National Institute for Health Research

The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government's strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world.

Website

The Institute of Metabolic Science

The Institute of Metabolic Science is a joint venture between the University of Cambridge, the Medical Research Council and Cambridge University Hospitals NHS Foundation Trust. The Institute of Metabolic Science is unique in the UK, being focussed on understanding the biological basis of diabetes, obesity and metabolic disorders, all of which are major and increasing threats to public health, and on translating these scientific discoveries into improved patient care and disease prevention.

Website

The Babraham Institute

The Babraham Institute, which receives strategic funding (£22.4M in 2010-11) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute's research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing.

Website

BBSRC

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, and with an annual budget of around £445M (2011-2012), we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see:

Website

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

Website

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

Website

More information

Thomas Kirk Office of Communications
University of Cambridge

Tel +44 (0)1223 332 300
Email Thomas.Kirk@admin.cam.ac.uk

Dr Robert Semple
University of Cambridge

Email rks16@cam.ac.uk

Contact the Press Office

Don Powell Media and Public Relations Manager
Wellcome Trust Sanger Institute, Hinxton, Cambs, CB10 1SA, UK

Tel +44 (0)1223 496 928
Mobile +44 (0)7753 775 397
Fax +44 (0)1223 494 919
Email press.office@sanger.ac.uk

* quick link - http://q.sanger.ac.uk/xv14eyjr