Rare gene discovery dramatically improves cancer treatment

This discovery could lead to more accurate diagnosis and ultimately personalized treatment that targets the protein expressed by the gene. (CREDIT: Creative Commons)

EPFL scientists have discovered a rare gene in the tumors of some colorectal cancer patients. This discovery could lead to more accurate diagnosis and ultimately personalized treatment that targets the protein expressed by the gene.

Colorectal cancer is one of the most common forms of cancer in the Western world, especially in people over the age of 50. In Switzerland alone, about 4,500 patients are diagnosed each year. Major therapeutic advances in recent decades have drastically reduced the death rate, but scientists are still trying to understand the molecular abnormalities that lead to tumor formation. And diagnosing colorectal cancer can be difficult, as symptoms usually don’t show up until the disease has progressed to an advanced stage where effective treatment options are lacking.

Colorectal cancer occurs when changes in the DNA of cells in the lining of the colon or rectum cause the cells to proliferate and become tumors. To better understand the underlying mechanisms, a team of scientists from the EPFL Virology and Genetics Laboratory (Trono Lab) analyzed data from a study in Denmark that analyzed the tumors of more than 300 colorectal cancer patients. They found that some tumors contain a gene that promotes the growth and metastatic potential of cancer cells. Their results have been published in Nature Communications.

“This was a particularly interesting and unexpected biological discovery – a surprise presented to us by virology.” Laia Simo Riudalbas said.

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Trono Lab scientists specialize in transposons, mobile DNA elements that are a bit like viruses. Transposons have always been a feature of the human genome and can influence the expression of certain types of genes. Using sophisticated analysis methods to study transposons in colorectal cancer cells, the research team found that aberrant transposon activation triggers the expression of the POU5F1B gene and that expression of this gene is associated with the most severe tumors.

“Now we know that if the tumor of a colorectal cancer patient expresses the POU5F1B gene, there are likely to be serious consequences,” says Laia Simo Riudalbas, a scientist at the Trono Lab and lead author of the study. “The survival rate for these patients is lower than for patients whose tumors do not express the gene.”

POU5F1B as an anoncogen

The data from the Danish study show that the gene is present in 65% of cancer cells, but only in 3.8% of the surrounding non-cancerous tissue. “It was a particularly interesting and unexpected biological discovery, a surprise presented to us by virology,” says Simo Riudalbas. “We still don’t know what physiological purpose the gene serves, if there is one. It exists only in humans and large apes.”

Immunohistochemistry of endogenous POU5F1B in adjacent normal colon and primary colon adenocarcinoma specimens from a patient with CRC. Two levels of magnification of the representative field out of three are shown. (CREDIT: Nature Communications)

Scientists believe that the oncogenetic nature of POU5F1B is related to the fact that the protein it expresses tends to interact with other proteins that play an important role in the formation and mechanical functioning of cancer cells.

In addition to studying cells in vitro, Simo Riudalbas conducted experiments on laboratory mice to study how POU5F1B functions as an oncogene. She transplanted two types of human cancer cells into mice, some expressing the gene, others not.

Colorectal cancer as seen during a colonoscopy. (CREDIT: Creative Commons)

“It was very important for us to use mice in this study because we need to contextualize the disease in order to answer very specific questions,” she says. “Cancer cells cultured in vitro are significantly transformed, making them extremely different from real tumors. They also grow in a completely different environment, without factors such as hormonal stimulation, for example.”

The lab’s experiments were approved by the cantonal veterinary authorities – as is required for all animal testing in Switzerland – and carried out in accordance with the strict EPFL regulations.

Promising medical implications

Trono Lab’s findings have a number of implications for cancer treatment. First, if doctors can detect POU5F1B in tumor cells at the time of biopsy, they can move on to a faster and more aggressive form of treatment.

Second, because the protein expressed by this gene is rare in the tissues of “normal” adults, and given that some perfectly healthy people lack the gene altogether, it is a good candidate for targeted therapy.

“The better we can target a drug to only interact with cancer cells, the less toxic it will be to the rest of the body,” says Simo Riudalbas. “The next step will be to identify methods of POU5F1B inhibition.”

What’s more, because the gene is expressed in other types of tumors, treatments developed for colorectal cancer could eventually be used for other cancers as well.

Simo Riudalbas continues his research to uncover the specific mechanisms by which POU5F1B acts as an oncogene, with the goal of finding a drug that can weaken, destabilize, or inactivate it.

To learn more about science and technology, visit our New Discoveries section at The bright side of the news.

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