The Great Escape: Tumor-Suppressor Genes and Male-Female Cancer Disparity Reply

by Richard L. Lobb
American Association for Cancer Research

Stand Up To Cancer’s Innovative Research Grant (IRG) recipients,  early-career investigators who take fresh approaches to critical questions about cancer, continue to generate interesting and compelling research.

One of these IRGs is David M. Weinstock, MD, of Dana-Farber Cancer Institute and Harvard Medical School, who was awarded a grant to help develop a rapid system for the identification of molecular abnormalities that drive cancer causation.  Recently he was part of a team that studied a puzzling question:  Why is cancer more prevalent in men than women?

Glioblastoma, the most common type of brain cancer, occurs twice as often in men as in women, as does kidney and renal pelvis cancer and stomach cancer; liver cancer is even more likely to occur in men than women. Overall, men are 20 percent more likely than women to develop cancer, for reasons not fully understood.

The team came up with a possible explanation: Women have more copies of certain genes that fight cancer.

The sex of a human being is determined by the X and Y chromosomes. Men have one of each, so they are XY, while women have two X chromosomes, so they are XX. Since only one X chromosome is needed for proper development and growth, one of the female copies of the X chromosome is turned off. This process is called X-inactivation.

However, not all the genes on the chromosome are turned off. Some are said to “escape” from inactivation, and some of these play a role in suppressing tumors. The team named the gene set “escape from X-inactivation tumor suppressor” (EXITS) genes. The “escape” gives a woman an extra copy of some of these genes, an example of “biallelic expression,” whereas a man has only one copy.

To examine whether EXITS genes have anything to do with the greater predominance of cancer in men, the team studied alterations in genes that occurred during the patient’s life.

The team studied genetic sequencing data from more than 4,000 tumors across 21 different types of cancer, looking for genes that had mutations which caused the genes to lose their functions in human biology. They found six genes with loss-of-function mutations that are found more often in male tumors than female. Some of these genes are known to be tumor suppressor genes. Further, some of these mutations are known to be associated with glioblastoma and kidney cancer — which offers a potential mechanism for male bias in these tumor types.

“Male based mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon,” the team wrote in the journal Nature Genetics. “We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.”

Gene mutations in EXITS are not the only reason for the differences in cancer incidence in men and women, but this study offers insight into how specific genes play a role in sex-specific differences in tumor genetics.

The disparity in the burden of cancer between men and women has never been fully explained. The hypothesis that it may be linked to tumor suppressor genes that escape X-inactivation is potentially an important step forward in understanding this disparity. (Other scientists are suggesting that escape from X-inactivation may also help explain disparities in other conditions, such as lupus and certain neurological disorders.) The research on EXITS by Weinstock and others is an example of SU2C’s support for basic as well as translational research.

Richard L. Lobb is Director, Communications, SU2C, at the AACR, scientific partner of SU2C.

Originally published on the blog of Stand Up To Cancer


Science: Major journal retracts anti-GMO paper Reply

A year ago, in November 2012, opponents of genetic modification in food and agriculture had reason to celebrate: a major scientific journal published an article claiming that genetically modified corn and the herbicide closely associated with it, glyphosate, caused tumors in

Unfortunate rat in Seralini experiment

Unfortunate rat in Seralini experiment

laboratory rats. Pictures of the unfortunate rats with enormous tumors flashed around the world. The principal author, veteran anti-GMO campaigner Gilles-Eric Seralini, was hailed as a hero by the anti-GMO crowd.

The flimsy structure of this particular exercise in rigged science has now come crashing down. The journal that published the study, Food and Chemical Toxicology, has retracted the article. The editors finally admitted what everyone else knew as soon as the study was published: it was bogus through and through.

The editors could not bring themselves to state the case quite that plainly. Instead they said, “There is a legitimate cause for concern regarding both the number of animals in each study group and the particular strain selected.” The strain of rats, that is. Seralini was careful to select a type of rats that are known to develop mammary tumors at about two years of age (which is old for a lab rat). He fed the rats genetically modified corn and spiked their drinking water with glyphosate. Then he kept the experiment going until the rats developed the tumors you would expect anyway, and claimed that the tumors resulted from the corn and herbicide.

Seralini’s published data did not even begin to support his conclusions. The German scientific academy, in an earlier review of the study, found his data presentation “incomprehensible.” He resisted requests for the raw data – although authors are supposed to provide it upon request. Apparently he eventually acceded to a request for the raw data, and the FCT editors delicately concluded that “no definitive conclusions could be drawn” from the data.

The rigging was so transparent that many prominent scientists pointed it out immediately, and it is still a mystery why a relatively prestigious journal like FCT published the article to begin with. Scientists around the world erupted in condemnation of the article, and scientific academies across Europe denounced it. But it took the editors of FCT a year finally to own up to their mistake and retract the article. They did so in a news release.

Hopefully the retraction will remind both scientists and scientific journals that peer review is supposed to occur before an article is published, not as the result of an all-out scientific war after publication. FCT could have saved itself a serious blow to its prestige by taking peer review a bit more seriously.