Change for the worse

if the molecular-remodelling trick used by the body to defend itself against any disease goes wrong, a deadly form of cancer can result, new research suggests. ( Nature , 341--346, July 19, 2001)

The molecular stunt is called 'hypermutation'. This rapid dna change occurs as the immune system's 'memory cells', b -cells, attempt to hone the molecular fit of the antibodies they produce. Hypermutation re-writes antibody-coding genes, helping memory b -cells to make antibodies of the most appropriate shapes to attach to disease agents.

Normally, hypermutation occurs only in the antibody-producing region of b -cell dna , but Riccardo Dalla-Favera at Columbia University, New York, and his colleagues now show that it can run amok, making other parts of the genome more vulnerable to breaks and possibly leading to cancer.

"This is the first clue that hypermuation occurs elsewhere," says Raju Chaganti, a geneticist at the Memorial Sloan-Kettering Cancer Centre in New York and a member of the research team.

The b -cell diffuse large-cell lymphoma ( dlcl ) is one of the more common and deadly forms of a complex family of cancers known as non-Hodgkin's lymphomas. The disease occurs when b -cell development goes awry. Instead of entering the blood, the cells stay in their cellular nurseries, the lymph glands. Here they divide uncontrollably, forming tumours.

Several genes have been implicated in dlcl tumours. However, which of these 'proto-oncogenes' are important and how they came to be continually switched on in tumours had been a mystery.

Screening over 100 tissue samples from a range of b -cell lymphomas, Dalla-Favera's team found that one or two previously identified proto-oncogenes were undergoing hypermutaion in some types of lymphoma. Four such genes were hypermutated in dlcl .

Runaway hypermutation alone is not enough to cause cancer, says Chaganti, but is a crucial first step.