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Breakthrough Gene Discovery
Identifying The Gene That Causes Pancreatic Cancer

A Pancreatic Cancer Surveillance study on the leading-edge of familial pancreatic cancer research, led by Dr. Teresa Brentnall and her nationwide team of collaborators, has attracted its share of attention throughout more than a ten-year span. The product of this groundbreaking research, discovery of a genetic cause of familial pancreatic cancer, was published published the medical journal PLoS (Public Library of Science). The identification of the genes that are mutated in familial pancreatic cancer might provide insights into how both inherited and sporadic cancer develops in the pancreas. Such information could suggest ways to detect pancreatic cancers earlier than is currently possible and could identify new therapeutic targets for this deadly diseas.

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Discovering the Palladin Mutation

Dr. Brentnall has devoted herself to better understanding the risks and biological mechanisms involved in familial pancreatic cancer since the very day a 41-year old man presented to her office with grave concern about developing the disease due to an extensive family history. The family (known as ‘Family X’) served as the inspiration for Dr. Brentnall’s Pancreatic Cancer Surveillance Study, which has been tracking high-risk patients in an effort to improve early detection methods and working to identify gene(s) responsible for causing the familial disease.

For years, growing evidence has suggested that a genetic susceptibility may predispose people to pancreatic cancer. Currently, two or more family members are affected in at least 10% of all pancreatic cancer cases – and risk increases with each affected family member. Genetic susceptibility is also suspected in many “sporadic,” or non-familial, forms of the disease.

Dr. Brentnall and her team set out to discover the gene in ‘Family X’ that caused pancreatic cancer to be inherited in the family. The result was identification of an unknown gene located on a small region of Chromosome 4.

To discover exactly what the gene was, Dr. Brentnall and her team studied the expression of all the genes in the Chromosome 4 region in the pre-cancerous pancreas from ‘Family X’ and from 10 sporadic pancreatic cancer samples. The researchers assumed that the genetic information encoded in a gene is switched ‘on’ at certain times and ‘speaks out’ in pre-cancer and cancer. Using sophisticated DNA profiling techniques, the researchers compared gene expression among ‘Family X’ pre-cancerous tissue, normal pancreatic tissue, and diseased tissue from sporadic pancreatic cancers. The analysis revealed that a gene, Palladin, a cytoskeletal protein that helps control cell structure and mobility, was highly over-expressed in both ‘Family X’ tissue and all 10 of the sporadic pancreatic cancer tissues. They went on to show that abnormal Palladin expression occurs very early during stages of disease development.

The team found a mutation in Palladin was present only in ‘Family X’ members with pancreatic cancer or precancerous lesions – and not in unaffected family members. Although this specific mutation was not found in sporadic pancreatic cancers, most of the sporadic pancreas cancers studied illustrated abnormal expression of Palladin– suggesting that Palladin may also play a role in the development of sporadic pancreatic cancer. The researchers discovered that the abnormal expression of Palladin allows cells to become increasingly mobile, a key feature of cancer cells.

Although further investigation is necessary to examine Palladin mutations in other high-risk families and explain its abnormal expression in sporadic cases, Dr. Brentnall’s discovery is unlocking a key to our understanding of familial pancreatic cancer and blazing a path for future avenues of research into this disease.

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