Pancreatic cancer - at least ten per cent of which is thought to be caused by inherited genetic mutations - is the fifth most common cause of cancer mortality in the UK. Yet the genes responsible for this largely fatal disease have so far remained elusive. Now the genetic cause of familial pancreatic cancer has been discovered by an Anglo-American team of researchers.
Dr Tatjana Crnogorac-Jurcevic, Senior Lecturer in Cancer Genomics at Queen Mary's School of Medicine and Dentistry, and her colleague Dr Sally Dowen, are among a group led by the University of Washington's Professor Teri Brentnall, to have discovered that the gene palladin, when mutated, causes familial pancreatic cancer. The research, published online today (December 12, 2006) in the peer-reviewed journal PLOS-Medicine, may help explain how the disease develops and why it is so deadly.
During the course of their research, the team focused upon a single family - family X - in which 18 members from 4 generations had either pancreatic cancer or precancerous lesions of the pancreas. Tracing the DNA segments that were shared by these patients but not present in the healthy family members, the researchers had previously mapped the gene to a distinct region of chromosome 4, which contains 243 known genes. They then made a gene chip that can measure expression levels of these candidate genes and compared normal pancreas tissue with cancerous pancreas tissue (both from a family X member and from unrelated pancreatic cancer patients). Palladin, one of the 243 genes, turned out to be abnormally highly expressed in both the family X tissue and the sporadic cancers.
Researchers then quantified the expression of palladin RNA in an independent set of normal and cancerous pancreatic samples, and in precancerous pancreatic tissue taken from family X members. This analysis indicated that palladin was overexpressed early in sporadic and inherited pancreatic cancer development. Sequencing of the palladin gene subsequently uncovered a mutation in palladin that was present in family X members with pancreatic cancer or precancerous lesions but not in unaffected members. Finally, the researchers showed that the introduction of mutated palladin into a human cell line growing in the laboratory increased its migration rate and disrupted its cytoskeleton (both features typical of cancer cells).
The results leave little doubt that mutated palladin is involved in the development of pancreatic cancer in family X. Moreover, they suggest that overexpression of palladin is also associated, and possibly responsible for a sizeable proportion of sporadic pancreatic cancers. The identification of palladin as a "pancreatic cancer gene" provides researchers with a molecular entry point into the cellular processes underlying this cancer and will hopefully help to improve diagnosis and development of new treatments for this deadly disease.
Dr Tatjana Crnogorac-Jurcevic said: "The finding that mutation in palladin in familial cases causes critical changes in cytoskeleton that results in increased motility of pancreatic cancer cells is hugely important. Ongoing studies of palladin and its interacting partners in sporadic cases will enable us to fully understand how the whole complex is regulated and how it causes pancreatic cancer cells to metastasize so readily. We are hoping to translate this knowledge into clinical practice soon, and finally make an impact on this major killer."
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The international team of scientists who made the discoveries was led by University of Washington researcher Teri Brentnall MD, an Associate Professor of Medicine. Most of the work was done by eight women from different academic centres: Ru Chen, PhD; Kara White; Terin Brentnall, MD, University of Washington. Kay Pogue-Geile, PhD, University Of Pittsburgh. Mary Bonner, MD Cleveland Clinic Foundation. Carol Otey, PhD, University of North Carolina, Chapel Hill. Tatjana Crnogorac-Jercevic, MD; Sally Dowen, PhD, Queen Mary, University Of London.
Queen Mary, University of London
Queen Mary is one of the leading colleges in the federal University of London, with over 11,000 undergraduate and postgraduate students, and an academic and support staff of around 2,600.
Queen Mary is a research university, with over 80 per cent of research staff working in departments where research is of international or national excellence (RAE 2001). It has a strong international reputation, with around 20 per cent of students coming from over 100 countries.
The College has 21 academic departments and institutes organised into three sectors: Science and Engineering; Humanities, Social Sciences and Laws; and the School of Medicine and Dentistry.
It has an annual turnover of £200 million, research income worth £43 million, and it generates employment and output worth nearly £500 million to the UK economy each year.
Queen Mary's roots lie in four historic colleges: Queen Mary College, Westfield College, St Bartholomew's Hospital Medical College and the London Hospital Medical College.