In healthy cells, RET proteins transmit signals to divide, mature, and specialize to the cell. When the RET gene is altered, this signal can get stuck in the “on” position, causing unchecked cell growth.
Inherited RET mutations are passed down from a parent and cause the inherited disease multiple endocrine neoplasia type 2 (MEN2), which can lead to a particular type of thyroid cancer known as medullary carcinoma of the thyroid (MTC).
Testing requires a simple blood draw. Patients who test positive have a nearly 100 percent chance of developing thyroid cancer during their lifetimes, and may choose to undergo thyroid screening or surgery to remove the thyroid before cancer forms.
Acquired RET mutations are present in 1 to 2 percent of patients with non-small-cell lung cancer (NSCLC). Testing for an acquired mutation requires a tumor sample, ideally acquired during a recent biopsy.
The targeted drugs vandetanib and cabozantinib, known as RET tyrosine kinase inhibitors, are FDA-approved to treat advanced medullary thyroid cancer (MTC). Trials to see if these drugs are effective in treating NSCLC are ongoing. Other therapies that target RET signaling are in clinical trials.
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The thyroid produces hormones affecting key vital signs—the rate of a beating heart, the pressure exerted by blood, body temperature—and in doing so, controls growth and metabolic rate. In 2014, there were more than 60,000 new cases of cancer in this butterfly-shaped gland, and nearly 2,000 patients died from the disease. Thyroid cancer accounts for nearly 4 percent of all new cancer cases in the U.S.
In 1993, researchers discovered that a mutation in the RET gene was the cause of a hereditary disease known as multiple endocrine neoplasia type 2 (MEN2), which accounts for approximately 3 to 4 percent of all thyroid cancers. Today, the American Thyroid Association recommends that all family members of MEN2 patients receive genetic testing to detect the RET gene changes that are linked to MEN2. These tests, which are highly sensitive, can identify nearly 100 percent of mutation carriers, allowing doctors and patients to take immediate steps to treat or prevent thyroid cancer.
MEN2 has three subtypes—MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC)—and is associated with tumors of the endocrine system. In nearly all cases, MEN2, which affects approximately 1 out of every 35,000 people, results in a specific form of thyroid cancer known as medullary carcinoma of the thyroid (MTC). Patients who are left untreated or who are treated after the cancer has spread to the lymph nodes often succumb to the disease.
In 1961, as the field of genetics was gaining momentum, John Sipple at the State University of New York in Syracuse recognized that MEN2 was hereditary—that is, genetically transmitted from a parent to a child. But because the genetic origins of MEN2 were unknown, doctors were limited in their ability to diagnose and treat the illness, in large part because many patients do not exhibit symptoms.
To test for MTC, a patient’s blood was tested for calcitonin—a hormone used as a marker to indicate the presence of the disease. But this test had its limitations, as it could not provide an indication of how aggressive the cancer was. As a result, treatment could not be tailored to specific cases. Removing the thyroid was often the recommended course of action, even if it wasn’t immediately warranted.
Years later, the fate of MTC patients changed dramatically. In 1985, a young researcher named Masahide Takahashi, then a postdoc at Harvard Medical School, was working at Dana-Farber Cancer Institute in Boston, Massachusetts, when he identified a new gene. What Takahashi and his research team didn’t know at the time was how significant this discovery would be in the field of cancer research. At the time of his discovery, there were very few known oncogenes or tumor suppressor genes responsible for cancer development, and the proto-oncogene RET (“rearranged during transfection”) was one of the first to be discovered. A proto-oncogene is a normal gene that can become a cancer-triggering one (or oncogene) with only a slight alteration in its genetic code. “The discovery of the RET mutation dramatically changed diagnosis and treatment, particularly for MEN2 patients,” said Takahashi.
RET provides the code to produce a protein involved in signaling within cells. One end of this protein is located on the cell’s surface while the other end is housed inside the cell, allowing it to receive signals from the outside and communicate those signals to the cell so it can respond, much like a game of telephone, though with fewer misinterpretations. RET proteins are critical for the development of several kinds of nerve cells, such as those in the intestine, those involved with involuntary body functions such as heart rate, and those used for kidney development.
Less than 10 years after the discovery of RET, a research team from Washington University School of Medicine linked mutations in this gene to MEN2. Following this discovery, it became possible to test for MEN2 using a blood sample, where doctors assess a person’s DNA for signs of the mutated gene.
Today, genetic testing detects nearly 100 percent of RET mutation carriers. Patients who carry the mutated gene have a 1 in 2 chance of passing it on to their offspring. Due to the hereditary nature of MTC, genetic testing for RET mutations can help identify the carriers and ultimately prevent the development of MTC. It’s an example of the role of DNA in personalized medicine. With MEN2, DNA testing has enabled the diagnosis and management of individual clinical cases.
In late 2011, a mutation in RET was linked to the leading cause of cancer-related mortality worldwide: lung cancer. In 2012, the findings from several independent studies were published, identifying new fusion genes—pieces of two genes that have joined together—in DNA tumor samples. In one study, a fusion gene made up of part of RET and part of another gene, called KIF5B, was identified in a tumor sample that came from a 44-year-old man with non-small-cell lung cancer (NSCLC) who had never smoked.
RET mutations are found in 1 to 2 percent of patients with NSCLC, which make up the vast majority (about 85 percent) of all lung cancers. Therefore, identifying even a small percent of NSCLC patients with genetic abnormalities who could respond to targeted treatment could have a huge impact.
Today, researchers around the world are testing a class of targeted cancer drugs known as kinase inhibitors. Unlike standard chemotherapy drugs that attack all rapidly growing cells, including cancer cells, kinase inhibitors attack specific targets on cancer cells. Many of these treatments are being tested today in clinical trials to treat thyroid and, now, lung cancer. In some cases, drugs have already been shown to be effective in treating cancer patients.
Back in 1985, Takahashi was unaware of the potential significance of his discovery of the RET gene. Thirty years later, he reflected on his discovery: “I consider myself lucky in that I discovered a very important gene whose mutation is responsible for several human cancers,” he said. Its discovery has enabled doctors to better diagnose and treat patients carrying a RET mutation. And it has helped to shape the growing field of precision medicine.