While mutations in both copies leads to cancer, paper in Cancer Research suggests that colon cells under the one hit-stage are also abnormal.

A team of researchers from Fox Chase Cancer Center report that loss or change of even a single copy of the adenomatous polyposis coli (APC) tumor-suppressing gene is enough to change colon cells and increase the likelihood that they could become cancerous. The group was led by Alfred Knudson Jr., M.D., Ph.D., who 30 years ago showed that a person must lose both their paternal and maternal copies of these genes to develop cancer.

The original theory was called the two-hit hypothesis. By studying people who have inherited the first hit in every cell in the body, the Fox Chase researchers believe that they have discovered a source for some of the earliest molecular changes that signal the presence of colorectal cancer.

“We hypothesized that an inherited one-hit gene mutation can, by itself, lead to changes in the proteins of normal-looking cells,” explains Anthony Yeung, Ph.D., lead author of the paper. “While these cells are just another hit away from becoming cancerous, their altered patterns of protein production may represent new biomarkers of cancer and novel targets for preventive and therapeutic drugs a chance to strike at cancer before a second hit can happen.”

The investigators studied patients with familial adenomatous polyposis (FAP), an inherited disorder that also serves as a classic model in support of the two-hit hypothesis. Patients with FAP, which predisposes people to colon cancer, carry mutations in one of their two copies of APC.

The APC gene acts to prevent the colon cells from growing out of control and becoming cancerous. The APC gene is also mutated in most cases of sporadic colorectal cancer.

The study determined that roughly 13% of 1,695 known proteins were abnormally produced in patients with FAP, indicating that a colon cell under the one-hit state is already abnormal. Additionally, they found that many of the changes affect molecular pathways consistent with the function of the APC protein as a tumor suppressor, including how the cell moves, interacts with other cells, divides, responds to free radical damage, and self-destructs when growth threatens to go out of control.

The findings are published in the September 15 issue of Cancer Research.

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