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US Team Fingers Tyrosine Phosphatase Mutations as Drivers of Colon Cancer

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A team of researchers in the United States said they have identified mutations in a family of six genes linked to a significant number of colon cancer cases.

The scientists, from the Johns Hopkins Kimmel Cancer Center and the Howard Hughes Medical Institute, said their findings may help drug makers develop “more options for creating personalized therapies tailored to counteract mutated gene pathways present in individual tumors.”

To arrive at their results, the team, led by Victor Velculescu, an assistant professor of medicine at the Johns Hopkins Kimmel Cancer Center, analyzed 157 colon cancer tumors and found 77 mutations in six genes that make tyrosine phosphatases.

These phosphatases are tumor-suppressing enzymes that help coordinate signals that manage cellular growth, apoptosis, differentiation, and “tissue invasion.” But in cancer, the genes responsible for these enzymes are mutated, according to the researchers. To date, research has shown it is “difficult to restore a mutated suppressor gene with cancer drugs” — thus giving credence to the fact that phosphatases are “not good drug targets.”

However, for every tyrosine phosphatase there is a tyrosine kinase that “plays an opposite role, turning a pathway on and accelerating cellular events,” the researchers said in a statement. Indeed, tyrosine kinases have played significant roles in drugs such as Herceptin, Gleevec, and Iressa.

Studying their six genes, Velculescu and colleagues found mutations linked to “more than 30 percent” of all colon cancer cases. More than two-thirds of colon cancer cases have mutations in the tyrosine kinase and phosphatase families, as well as another kinase gene the researchers recently identified.

Velculescu’s team plans to conduct additional research “to explore tyrosine phosphatase pathways and match them up with corresponding kinases in order to find targets for potential inhibitory drugs,” according to Zhenghe Wang, a postdoc at Johns Hopkins and first author of the paper, which appears in the May 21 Science.

“What makes this discovery significant is that we’ve found mutations that directly affect cancer development,” Velculescu said in the statement. “Most gene discoveries today focus on finding increased or decreased activity of a gene that may not affect cancer progression. … What we’ve found are the brakes of the bus.”

Tyrosine phosphatase mutations were also found in 18 percent of lung cancers, 17 percent of gastric cancers, and 9 percent of breast cancers. More than 147,500 cases of colon cancer are diagnosed in the United States each year. Around 57,100 people will die from the disease this year.

— KL

 

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