The body uses a hair-raising molecular-remodelling trick to arm itself against disease. If the trick goes wrong, a deadly form of cancer can result, new research suggests
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 Center in New York and a member of the research team.
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. About 50 per cent of DLCL cases are fatal.
Several genes have been implicated in DLCL tumours. However, which of these 'proto-oncogenes' are most 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 hypermutaion alone is not enough to cause cancer, says Chaganti, but is a crucial first step. Hypermution outside the antibody-coding region causes the genome to become more susceptible to breakage.
When breaks occur in the DNA of rapidly dividing cells - such as developing B-cells - genes can be moved (translocated). "Translocation drives tumour formation," says Chaganti.
Dalla-Favera's team propose that because they are more susceptible to breaks, hypermutating proto-oncogenes in DLCL tumour cells are separated from their regulatory genes and hence cannot be switched off. This confuses the B-cell into thinking that it is still developing.
"They just sit there and keep dividing," says Chaganti. Trapped in the lymph nodes, the uncontrolled B-cell division can then lead to tumour formation.
What causes hypermutation to spread from B-cells' antibody-coding DNA remains a mystery. Chaganti nonetheless thinks that the four hypermutation-prone proto-oncogenes in DLCL could be excellent drug targets.
"It surprised me," says geneticist Bert Vogelstein of Johns Hopkins University in Baltimore, Maryland. "We saw [B-cell lymphomas] as less complex, genetically, than other tumours; this research emphatically shows that they're not simple at all."
However, Vogelstein is not so confident about improved prospects for treating the disease. Dalla-Favera's team has identified the process that may be turning at least four proto-oncogenes nasty. "[This] suggests there are many more possible mutations," says Vogelstein.