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MRC News - July 2005

Colon cancer: untangling its genetics

South African researchers have made great strides in understanding the genetic basis for colon cancer, as CAROL CAMPBELL discovered.

The story began in the late 1980s in a small coastal town along the West Coast. It was fifteen years before the human genome was mapped, AIDS was still something new, and Dolly, the cloned sheep, was still just a theory. In this town, though, there was a family in trouble.

A significant proportion of the town's men and women - all members of the one extended family - were suffering from abdominal cramps around the time they reached the age of thirty. They all visited the same doctor, who discovered that these relatives were suffering from the same condition: colon cancer.

The doctor suspected that the cancer might be inherited, which would account for the fact that it seemed to be limited to members of the same family. The doctor rang a colleague in Cape Town to discuss the problem, and, soon after, it came to the attention of a medical geneticist from the University of Cape Town (UCT) and a colorectal surgeon from Groote Schuur Hospital.

These doctors travelled to the town, examined the patients and confirmed that the disease was indeed inherited. They then recruited some of the family members in order to do research aimed at finding the genetic defect underlying the disease.

Soon after joining the Division of Human Genetics at UCT in 1989, Prof Raj Ramesar (now director of the MRC/UCT Human Genetics Research Unit, and head of the Division of Human Genetics at UCT) took the project further, continuing with trips to the West Coast town to counsel the families about their genetic risk and to recruit additional family members for the research programme.

In 1994, while he was still working on the problem, Prof Ramesar was awarded the prestigious Fogarty fellowship, which allowed him to continue his research at the University of Chicago Medical Center in the USA. Although he had other priorities while in the United States, he began to search for something unusual in the genetic material of the extended family.

Shortly before his return to South Africa, Prof Ramesar found what he was looking for: the precise genetic mutation that caused the colon cancer in the members of the West Coast family.

The mutation he discovered is located in one of the genes responsible for creating the protein - called a mismatch repair protein - that repairs mistakes when DNA is copied during replication of the cell's genetic material. The mutation in that particular gene means that the repair protein can't do its job properly, and mistakes creep into the fabric of the DNA when it is copied.

RIGHT: Map of the Northern Cape and Western Cape Provinces of South Africa, illustrating the extent of a single mutation (red dot).

Although there are many other genes that can cause colon cancer if they malfunction, this discovery was hugely valuable: it gave researchers a specific gene to test for, which allowed them to identify very early on whether someone was at risk of developing this inherited form of colon cancer. Up until this point, all blood relatives of an affected person were considered to be at risk, and counselled for the need to undergo regular clinical screening for pre-cancerous growths in their colons. This involved getting a colonoscopy, an internal examination of the colon using a small camera attached to a flexible tube, and which requires sedation.

'We now know that it is necessary to offer colonoscopies only to those family members who test positive for the genetic mutation. Genetics tests are cheaper to administer - and less physically bothersome - than colonoscopies,' says Associate Professor Paul Goldberg of Groote Schuur Hospital, the surgeon on the project.

But how do you tell someone that they carry a mutation that could potentially mean a death sentence for themselves and their children?

'Heritability, risk and preventative screening are complex issues that have to be carefully negotiated with people - some of whom might not even have been exposed to a health care worker before,' says Prof Ramesar.

'This is the work of a genetic counsellor, and because of the need for such trained people, an MSc in genetic counselling has been set up within the Division of Human Genetics at UCT,' he says.

It is now standard practice to introduce the concept of genetic testing and to offer it to all blood relatives of patients with colorectal cancer to see whether they also carry the gene defect.

For those who do have the defect, a clinical screening programme has been set up: it involves trips to the remote towns of Clanwilliam, Springbok/O'Kiep and Kleinzee - often over very rough terrain - to provide colonoscopies. These trips were originally marshalled by Groote Schuur's Dr Mike Madden (currently at Chris Barnard Hospital), and are currently organised by Prof Goldberg.

Pivotal to this operation is a liason person who has the interests of the communities at heart, and who is experienced in the clinical and research environment: Sr Ursula Algar, the clinical research coordinator in the Colorectal Cancer Surgical Unit at Groote Schuur Hospital, who has been involved in the project for several years.

'Although our discovery won't help people who are already affected with colon cancer,' she says, 'those related to an affected individual in whom a mutation has been found can now get tested - and once they know that they carry the mutation, the risk for a disastrous outcome may be reduced by being vigilant and going for regular clinical check-ups.'

Part of the clinical management team that travels to three hospitals along the West Coast to provide clinical screening for those family members identified to be at risk.

Those who carry the gene are advised to have a colonoscopy every two years before the age of thirty and every year thereafter. 'This means that pre-cancerous growths can be detected on time, which allows effective management of the disease,' says Sr Algar.

'The major challenge is to get information about the disease to as many of the people at risk as possible,' says Prof Ramesar. 'With the levels of migration between the Western Cape and other parts of South Africa (and indeed the world) being as high as it is, this challenge is very real and requires a national level of coordination,' he says.

RIGHT: Sr Algar (first left) and Dr Felix (first right) outside the clinic in O'Kiep (N Cape Province) with the local nursing sisters.

The good news is that those individuals identified as carrying these mutations may now be eligible for a range of pharmaceutical drug trials aimed at neutralising the effect of the defective gene.

Although there is no genetic test for colorectal cancer available for the general population, those with a strong family history of this disease may, through their medical care givers, contact the UCT Division of Human Genetics for more information about testing. Call Sr Elize Pietersen on (021) 406-6373 or Prof Raj Ramesar on (021) 406-6337.

The research aspect of the project was made possible by funding from the University of Cape Town, the South African Medical Research Council, CANSA, De Beers Chairman's Fund, the Sainsbury and Lindbury Trust and THRIP.

This article has been adapted from the January 2004 issue of African Scientist, a publication of the Human Sciences Research Council.

Tracing colon cancer's family tree
In the years since Prof Ramesar identified the mutation, Dr Rebecca Felix, a molecular biologist who spent ten years working alongside Prof Ramesar on this project, was tasked with looking for disease-causing mutations in other individuals and families suspected of having inherited colon cancer. The disease is characterised by a relatively early age of onset (before the age of 50), and by affecting two or more blood relatives in an extended family.

She analysed DNA from 260 South African families where a family member had been diagnosed with the disease, and found thirteen other families who carried the exact same mutation as the one found in the original West Coast family. This work was taken further more recently by Ms Alvera Vorster and Tich Savanhu, who showed that the mutation was present in a common ancestor and very likely occurred eighteen generations ago. A search for the origin and the spread of the specific mutation is part of ongoing research at the Human Genetics Research Unit.

Since Prof Ramesar's initial discovery of the mutant gene and the work of Dr Felix and others in the 'Ramesar group', the International Collaborative Group on HNPCC (or inherited colon cancer) has identified and described more than four hundred related mutations - all affecting the mismatch repair protein - in over five hundred families with inherited colon cancer worldwide.

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