An international team of medical scientists has made an important advance in our understanding of the second most fatal form of cancer in the industrialized world. Professor Jeremy R. Jass, who holds a Canada Research Chair in Gastrointestinal Pathology at McGill University in Montreal, and colleagues in Australia and Japan have shown that in some cases colorectal cancer can be inherited.

The new syndrome is characterized by distinctive clinical, pathological and molecular features:

• Early age at onset
• More common in females
• More common in right side of colon
• Little evidence of tumour immunity
• Frequent mutation of an oncogene called BRAF (also mutated in cancer of thyroid, ovary and melanoma)
• Frequent DNA methylation (chemical change which inactivates many genes)
• Frequent but variable levels of DNA instability across different colorectal cancers occurring in members of same family
• Origin in serrated polyps (considered previously to be completely benign)

Colorectal cancer is the second most frequent cause of death due to cancer (after lung cancer) in Canada and the industrialized world. It has become clear in recent years that colorectal cancer is not a single disease but a group of diseases, each with a different cause and behaviour. The genetic basis of this new syndrome is not known but it is speculated that affected families have a genetic predisposition to develop DNA methylation. There is already evidence that subjects with colorectal cancer showing DNA methylation are more likely to have a family history of colon cancer and other types of cancer. Moreover, the colorectal cancers appear to develop in polyps that have been considered to be entirely harmless and have therefore been ignored up to now. These polyps also show mutation of the oncogene BRAF and DNA methylation. It is likely that the same polyps may sometimes become malignant in patients who are not members of high-risk families.

Although familial — or inherited — forms of cancer are uncommon, they are of major importance for three reasons, says Dr Jass:

1. Such cancers often occur in young subjects and result in loss of many years of life. An appreciation of the problem can lead to cancer prevention by a combination of prevention or detection of early cancer.
2. High-risk families provide an opportunity for investigating novel approaches of cancer prevention by the use of diet or chemical compounds. The results may be generalizable to the average-risk population.
3. An understanding of the genetic defect may provide important insight into the basic cause of the common non-inherited forms of the same type of cancer.

The findings of Dr Jass and his colleagues are reported in the March 2005 edition of Clinical Gastroenterology and Hepatology, published by the American Gastroenterological Association.