NEWS OF THE WEEK

GENES GONE AWRY: Clues to cancer mechanism found

The idea that changes in methyl groups along DNA molecules could be important in cancer cells and also in cells undergoing normal, ge­netically programed changes now is being fortified by independent research efforts. On a separate front, o ther medical researchers have repor ted that certain chemicals known to promote tumor develop­ment may do so by subverting part of the body's defense mechanism.

During the past few years, sever­al research groups have established a general (but not universal) rule for higher organisms: Genes lacking methyl groups on specific cytosine residues along the DNA are more likely to be active than they would be if methyl groups were present. Now, medical researchers Andrew P. Feinberg and Bert Vogelstein at Johns Hopkins University school of medicine in Baltimore find that the order maintained by this seeming rule is disrupted, if not lost outright, for several genes in human tumor cells [Nature, 301,89 (1983)].

In an independent effort, molecu­lar biologist Suzanne Bourgeois of Salk Institute in San Diego and her collaborators there and at Institut Pasteur in Paris also have found that the methyl groups along DNA in tumor cells are "unstable/' More­over, according to Bourgeois, hor­mones can influence the degree of methylation along DNA in cells— perhaps explaining how specific hormones turn on genes in certain cells, but not others [Proc. Natl. Acad. Sri., 80,110 (1983)].

The Johns Hopkins researchers looked at DNA for three genes: two encoding for parts of the oxygen-carrying protein hemoglobin, and one for growth hormone. The three genes are located on different chro­mosomes, and none would be ex­pected to work in the colon- and lung-tumor cells that Vogelstein and

Vogelstein: DNA methylation may be of far-reaching import

Feinberg were looking at. Never­theless, all three of those genes were consistently "undermethylated" in tumor cells but not in normal lung or colon cells. According to Vogel­stein, whether that unexpected de­crease in methyl groups turns on those genes abnormally in tumor cells is not yet known. But such a "lack of control of gene expression could have far-reaching conse­quences/ ' he notes.

A derangement in the way these and other genes are methylated in tumor cells might be central to what goes wrong in such cells. This derangement, however, might be "totally secondary" to the funda­mental defects in tumor cells, Vogel­stein cautions.

Instead of human tumor cells,

Bourgeois and her colleagues are s tudy ing mouse tumor cells in culture. Such cells retain many tell­tale normal properties, such as the ability to respond to hormones. These particular mouse tumor cells, which derive from white blood cells, are responsive to glucocorticoid hor­mones, Bourgeois says. That re­sponse typically entails the turning on of specific genes in the cells, including certain tumor-virus genes routinely found there. Removing the hormone usually turns such genes off again.

However, long-term exposure of these cells to hormone can lead to permanent demethylation or under-methylation of specific genes, such as those viral genes, Bourgeois and her colleagues find. That biochemi­cal change occurs in a region known as a "long terminal repeat," believed to control the gene. Similar changes, occurring in other genes, might ex­plain how hormones control devel­opment, Bourgeois says.

In another independent effort, the indirectly related question of how some chemicals encourage tumor de­velopment long after an initial in­sult has been registered on a cell is closer to being answered. Medical researcher Alan B. Weitberg and his colleagues at Massachusetts Gener­al Hospital in Boston find that phorbol ester, a tumor promoter, can cause sister chromatid exchange in cells—that is, a rearrangement in chromosomes associated with oth­er kinds of gene disruptions [New England } . Med., 308, 26 (1983)]. Importantly, the phorbol ester ex­erts this effect with help from phagocytes, disease-fighting cells that produce a burst of oxygen-activated and potentially damage-inflicting chemical species. Together, these chemical ingredients may con­vert a chronic disease situation into malignancy, Weitberg says. D

8 January 17, 1983 C&EN