31 July 2010

Living without a stomach

Most of us take our stomachs for granted, but for some families the risk of cancer of the stomach is exceptionally high, often occurring at a young age. This story from BBC News relates how two sisters with a mutation in the E-Cadherin (CDH1) gene have been coping after having prophylactic gastrectomy - the only treatment known to reduce the risk of developing gastric cancer.

CDH1 is a fascinating gene; I've been interested in the cadherins since my time in Birmingham when we published the first reports of CDH1 mutations in UK gastric cancer patients back in 1999, and also linked it to colorectal cancer (although the risks of this appear a good deal lower). If you carry a disruptive mutation in CDH1, you have a high risk of developing diffuse intestinal-type stomach cancer, and females are at increased risk of lobular breast cancer. Cadherins are proteins involved in cell to cell adhesion in many tissues, and there are quite a few of them. Their stickiness is based around their molecular structure and their ability to bind calcium ions.

More recently I was involved in some work which connected a very rare and intriguing form of epilepsy, EFMR, to a protocadhern gene PCDH19. EFMR - (Epilepsy affecting Females, with Mental Retardation) shows a very odd inheritance pattern; it is X-linked, but while it affects female carriers (who have one faulty PCDH19 gene and one normal gene), males (who only carry one copy of PCDH19) are left completely spared, although they can pass the disorder to their daughters. The phenomenon seems to be due to "scrambling" of the connections between cells, due to a process in females where one X chromosome is switched off in each cell, resulting in some cells running off one of the Xs, while the rest run off the other.

These are fascinating molecules, involved in a wide variety of disease processes, and make exciting targets for therapy. It shows that the common claim that the Genome Project has had minimal impact of human disease is a load of bunk. Our ability to get down and dirty with the genes is already yielding major benefits, and these are being rolled out to patients every day. Is it easy? No. Does it offer a panacea? No. But we are making a heck of a lot of progress, and genetics remains the most exciting and active field in medicine today.

[Click the image for more info from Breast Cancer Research]

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