Combination of Two Mutations Implicated in Development of Adrenal Cancer

A cancer research team with members in Brazil and the USA has found that disruption of two molecular pathways was necessary for development of a rare form of adrenal cancer.

Adrenocortical carcinoma (ACC), which afflicts about 600 Americans every year, is typically diagnosed in late stages when there are no effective treatment strategies and little chance of survival beyond five years. A team of investigators from the University of Michigan (Ann Arbor, USA) and the University of Sao Paulo (Brazil) recently evaluated clinicopathological and molecular data on adrenal tumors from 118 adult patients. Follow up experiments were conducted using an adrenal cancer mouse model.

Results published in the September 2012 issue of the American Journal of Pathology revealed an increase in CTNNB1 (the gene encoding beta-catenin) mutations and abnormal beta-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival.

Beta-catenin is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. Beta-catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. The gene that codes for beta-catenin can function as an oncogene. An increase in beta-catenin production has been noted in those people with basal cell carcinoma and leads to the increase in proliferation of related tumors.

The mouse model showed that benign adrenal tumors had a high percentage of mutations in beta-catenin, but insulin-like growth factor 2 (IGF2) upregulation was rare. On the other hand, most of the adrenocortical carcinomas exhibited IGF-2 upregulation. IGF-2 is one of three protein hormones that share structural similarity to insulin. The major role of IGF-2 is as a growth-promoting hormone during gestation.

Cancers that also had beta-catenin mutation were associated with high-grade disease and worse survival, compared to tumors with only IGF-2 upregulation.

“Because adrenal cancer is so rare, it has been challenging to find enough patients who can provide tissue samples for research. Only through collaboration can we do this,” said senior author Dr. Gary Hammer, professor of internal medicine at the University of Michigan. “It is more complex than just finding genes that cause cancer. Early results targeting IGF2 alone, while promising, do not look as robust as we had initially hoped. That could be because we need to attack both IGF2 and beta-catenin. As cancer treatments move more toward targeted genetic approaches, it is likely that these therapies will need to be used in combination.”

Related Links:
University of Michigan
University of Sao Paulo