The Story of PDGFRA

While its mutations are rare, this gene can be a harbinger of better outcomes in some stomach and brain cancers.

For most of the patients, a seizure was the first sign that something was wrong. Some experienced no further symptoms, while others also suffered headaches and memory loss. They scheduled the first of what would soon become a blur of doctor’s office visits. And within an average of five months, each patient received the same diagnosis: astrocytoma, a kind of cancer that originates in star-shaped cells in the brain.

Between 1986 and 1993, 43 of these men and women arrived at the Uppsala University Hospital in Sweden for treatment. At the time, their brain tumors represented an exasperating conundrum for doctors. Often occurring in younger patients – the average at Uppsala was just 40 years old – the tumors generally grew slowly, with patients surviving decades after diagnosis. But occasionally, doctors encountered a more aggressive form of the cancer that demanded faster, stronger treatment, and there existed no early means of distinguishing between the two forms. This left researchers in a bind, wondering whether it was better to pursue radiation or surgery for every patient, in hopes of catching the few aggressive cases, or to delay treatment and risk missing those cases.

A team of neuroscientists and pathologists at the Swedish hospital hoped to find a solution. Their goal, like several previous unsuccessful attempts, was to identify some chemical clue, or biomarker, that might help differentiate the slow-growing astrocytomas from the faster-growing ones.

In 2002, they announced the discovery of a promising candidate: a protein produced from the gene PDGFRA. By studying tumor tissues preserved a decade prior from the 43 Uppsala patients, the research team detected a correlation between tumors with an abundance of the PDGFRA protein and lengthy survival times. Men and women whose tumors were brimming with this protein, the findings
suggested, likely had less-aggressive cases and could forego harsh and invasive treatment options in the early stages of their cancer.

Even today, answering the question of whether doctors should let sleeping tumors lie remains a challenge. But the recognition of PDGFRA’s potential as a biomarker was a harbinger of future tools to help answer that question.

A team of National Cancer Institute (NCI) scientists first identified PDGFRA in 1989, but a decade
passed before its role in cancer biology began to come into focus. The gene, an abbreviation for
platelet-derived growth factor receptor alpha, lives on chromosome 4 of the 23 we inherit from each parent. Platelet-derived growth factors are a family of proteins that trigger cell division, making them important to such processes as organ development and wound healing. This trait becomes deranged and distorted in cancerous cells, where mutations in the original gene can transform normal cell division into the unhinged growth that is a hallmark of cancer.

Since its discovery, researchers have linked several such PDGFRA mutations to cancers. In addition to astrocytomas, abnormal PDGFRA genes have been found in adults with leukemia and gastrointestinal tract tumors.

The last of these has generated a great deal of attention and studies in recent years. Gastrointestinal stromal tumors, or GISTs, occur along the digestive tract and arise from a group of cells involved in smooth muscle contraction. While stomach cancer remains one of the most common forms of cancer globally, GISTs are rare. The majority of these tumors exhibit mutations in KIT, a closely related gene that neighbors PDGFRA on chromosome 4. In the early 2000s, however, evidence of GISTs with abnormal PDGFRA instead of KIT began accumulating.

A team of doctors from the Armed Forces Institute of Pathology undertook a large survey of GIST tissue samples to learn more about the PDGFRA-positive tumors. Before being shuttered by Congress in 2011, the Institute of Pathology offered scientists an impressive storehouse of tissue samples, of which the research team analyzed 1,000 from military, veteran, and civilian GIST patients.

Their analysis, published in 2004, pinpointed several noteworthy features of PDGFRA-mutated GISTs. The two primary variants of GISTs, PDGFRA and KIT, appeared mutually exclusive; patients exhibited mutations in one but not both genes. PDGFRA mutations were rare, occurring in about 5 percent of all GISTs, and almost always found in the stomach.

Most interesting of all though, in a compelling similarity to the Swedish study of astrocytomas, the majority of PDGFRA-mutated GISTs were found to be far less malignant than those with KIT mutations.
When the researchers tracked down the patients whose GIST tissues they’d studied, they learned that 83 percent of the tumors remained benign and had not, even 11 years after diagnosis, required any treatment.

The PDGFRA gene is a known transforming gene oncogene, due to its ability to spontaneously turn on and fire instructions to the cell after certain changes to its DNA; this is known as ligand-independent receptor activation. Mutations in this gene have been found in many cancers (glioblastoma, melanoma, acute myeloid leukemia, peripheral nerve sheath tumors, and neuroendocrine carcinoma), but also play a well-known role in both PDGFRA-associated chronic eosinophilic leukemia and gastrointestinal stromal tumors. The former is a type of blood cancer caused by a somatic (acquired) mutation and characterized by an increased number of eosinophils. Eosinophils are a type of white blood cell that are involved in allergic reactions. The most common PDGFRA mutation involved in this type of cancer is a deletion of genetic material that results in a gene fusion product, a combination of two genes that leads to what is called a FIP1L1-PDGFRA hybrid protein. Single base pair mutations can also cause the unregulated activation of the gene, but those are more rare. Unlike the normal version of the PDGFRA protein, this fusion protein does not require binding of the platelet growth factor for activation. This means that the “on” signal which turns the gene from its inactive to active state is broken, leaving the gene in the “on” position. This constitutive activation means that the cell has increased proliferation and survival, the hallmark of cancer cells. Specifically, when the FIP1L1-PDGFRA gene mutation occurs in early blood cells, the growth of eosinophils is uncontrolled, leading to the gene’s namesake chronic leukemia. It is unclear why these cell types are preferentially affected.

The other type of cancer strongly associated with PDGFRA mutations are gastrointestinal stromal tumors, or GISTs. Occurring in the GI tract, most commonly in the stomach or small intestine, these mutations are acquired during a person’s life and are only present in certain cells. (Less commonly, there are inherited mutations that can lead to familial GISTs.) Like the mutations in PDGFRA-associated chronic eosinophilic leukemia, the mutated PDGFRA genes in GISTs feature signaling pathways that are always activated, leading to increased cell growth and survival. PDGFRA mutations have also been found in 40 percent of glioblastoma multiformes; the findings of this study also suggest that the gene rearrangements featured in these cancers have been considerably underestimated in other cancer types.

“GISTs are pretty uncommon tumors,” said Dr. Michael Heinrich, an Oregon Health and Science University oncologist. Clinical trials for such cancers can thus take longer to recruit enough patients and publish findings, he said (about a dozen are currently recruiting). Nevertheless, a flood of studies followed the 2004 survey of PDGFRA-mutated GISTs and has, for the most part, confirmed the initial discoveries. Many GISTs with PDGFRA mutations are not benign, subsequent research showed, but still tend to predict a more positive outcome for patients – smaller tumor size, lower rates of metastasis and recurrence – than those with KIT mutations.

PDGFRA mutations in GIST patients present one possible disadvantage, though. While the drug imatinib (marketed as Gleevec) has been used with success against KIT-mutated GISTs, PDGFRA-mutated GISTs have shown conflicting responses. In a 2005 study of 80 of these tumors, all but one kind of mutation showed a positive response to imatinib. Unfortunately, that single resistant mutation made up 63 percent of the tumors tested.

“We found the most common [PDGFRA] mutation was not at all inhibited by imatinib,” Heinrich said, so
treating that mutation “remains an unmet medical need in GISTs.”

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