GIST Biology

Symptoms | Genes and Protein Expression | Oncogenes and Tumor Suppressor Genes | C-kit | Atypical GIST

Introduction

Gastrointestinal stromal tumors (GISTs) belong to a group of cancers called soft tissue sarcomas. Sarcomas are a rare type of cancer that can occur in connective tissues, bones, muscles, fat, nerves, blood vessels, and cartilage. Sarcomas are derived from the general class of cells known as "mesenchymal cells". In contrast, most of the "common" cancers, such as lung cancer, skin cancer, and prostate cancer, are derived from a different type of cell, known as "epithelial cells", the cells which line the body's many surfaces. Why does this distinction matter? Because carcinomas and sarcomas behave very differently and are treated differently. Sarcomas are much less common than carcinomas. As a result, there are relatively few oncologists who specialize in treating sarcomas.

Although the exact incidence is still somewhat unclear, it is now estimated that, in the United States, between 3,000 and 5,000 people each year develop GISTs.

About 40-70% of GISTs arise from the stomach, 20-40% arise from the small intestine, and 5-15% from the colon and rectum. GISTs can also be found in the esophagus (<5%). Sometimes GISTs develop outside the intestinal tract in the abdominal cavity.

GIST often spreads from the original (primary) site to distant locations. If this happens, these tumors are called metastases (or simply, "mets"). If GIST tumors metastasize they usually travel to the liver, or the peritoneum. Metastases to the lymph-nodes and lungs are rare, but do occur. Metastases are usually harder to treat than primary tumors.

When GIST spreads to the liver, the liver tumors are GIST tumors, not liver cancer. GIST metastases in the liver are still derived from GIST cells and must be treated like GIST cells. Liver cancer is a completely different cancer that starts in the liver.

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Symptoms

GIST tumors often grow quite large before they are discovered and primary tumors often produce few symptoms. Metastatic tumors can be quite numerous. GISTs are often discovered during emergency surgery for unexpected perforation of the gastrointestinal tract and consequent bleeding. When GIST tumors are first discovered, the most common symptoms are:

Although the term "GIST" was first used in 1983 (by Mazur and Clark), the 1998 discovery by Hirota that GIST tumors can contain mutations in the c-kit gene marked the beginning of a new understanding and reclassification of sarcomas of the GI tract. Prior to the year 2000, GISTs were previously classified as one of many types of soft tissue sarcoma (STS) including tumors of smooth-muscle origin (most commonly leiomyosarcoma, and also leiomyoma or leiomyoblastoma) and of neural-crest origin (eg, schwannoma, or nerve sheath tumor). Most tumors previously diagnosed as Gastrointestinal Autonomic Nerve Tumors (GANTs) are also now classified as GISTs and contain essentially the identical KIT mutations as GIST. What establishes GIST as a separate diagnoses from these other soft tissue sarcomas in not just the description of where the tumor is located, but also the additional factor that it is KIT (CD117-positive (although a small percentage of GISTs are KIT-negative). Most GIST patients are also CD34 positive and desmin negative.

KIT-positive? Desmin-negative? What does that mean? Well, one of the best ways to identify the cancer cell type (aside from just looking at the cells under a microscope) is to determine the proteins that the cell makes. Specialized tests allow the pathologist to do this, usually by determining whether the cell will bind antibodies against the protein of interest. So, "KIT-positive" means that the cell makes the protein "KIT"; desmin-negative means that the cell does not makes the protein "desmin".

With the development of new effective therapies for GIST, it is vitally important that patients with soft tissue sarcomas of the GI tract have their tumor slides tested for KIT (CD117) by a pathologist experienced with GIST and KIT. Some (perhaps many) patients with pathology reports that were done prior to 2001 may think they have leiomyosarcoma, leiomyoma, leiomyoblastoma, or GANT when in fact their pathology slides were never tested for KIT and they may have GIST.

GISTs were previously thought to arise from smooth muscle cells of the GI tract. The discovery that GISTs express the KIT protein helped establish that GISTs do not originate from smooth muscle. The current thinking is that GIST tumors arise either from stem cells that differentiate towards Interstitial Cells of Cajal or directly from Interstitial Cells of Cajal (ICCs). The Interstitial Cells of Cajal are the pacemaker cells of the GI tract, (they are named after a great Spanish biologist and microscopist named Cajal; pronounced "ca-hal") they stimulate the movement (contractions) of the GI tract. These movements ('peristalsis") are the waves of contraction which force the digested food through the gut.

GIST research and even GIST clinical practice is moving very quickly. The information presented on this website is believed to be accurate. However, the authors are not medical professionals and the information presented should not be used as a substitute for consultation with a doctor that is experienced with GIST.

No one can take the place of an experienced GIST team of doctors. This may include a pathologist, oncologist, and a surgeon. GIST is such a rare type of cancer that few doctors have much experience in treating it. The hospitals with top sarcoma treatment centers are likely to have more experience with GIST. This is especially true with the hospitals that conducted or are conducting clinical trials with Gleevec and Sutent (SU11248). They have seen many more GIST patients and are more familiar with their unique needs, with treatment options, managing side effects, monitoring considerations, and what to do if the initial treatment fails.

The introduction of the drug Gleevec for the treatment of GIST has sparked a tremendous amount of interest and research. Gleevec is a molecularly targeted drug that is both more effective and has fewer side effects than traditional chemotherapy. This area of research is very fast moving so recent information is important. Because of this, we have tried to provide a date for key information provided. Such dates will appear in the text where appropriate and will be formatted similar to this: (date of comment: February, 2005). Also please check the " last modified" date at the bottom of each page.

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Genes and protein expression

The human genome has approximately 30,000 different genes. Each of these genes is contained within the DNA in each cell in the body. When genes are “expressed”, they tell the cell to manufacture specific types of proteins. Some of these proteins are used to communicate with other cells/genes. Cells use “receptors” (and other methods) to listen for the protein messages of other cells. These receptors are manufactured according to instructions provided by their respective gene within their own cell.

Oncogenes and tumor suppressor genes

The most important discovery ever made in basic cancer research is that cancer cells have mutations in specific genes, called "oncogenes" and "tumor suppressor genes". Harold Varmus and Michael Bishop discovered the first oncogene in 1976, and won the Nobel prize for the discovery. Many other oncogenes were discovered later, including "kit".

Oncogenes are genes that are involved in promoting or regulating cell growth. When mutated, these are the genes that contribute to or cause cancer. A normally functioning (non-mutated) oncogene is called a "proto-oncogene". When mutated and involved in cancer it is called an "oncogene". The normal function of proto-oncogenes is the cell-signaling pathway. It is through this pathway that cells receive the stimulus to undergo mitosis (division) or apoptosis (programmed cell death).

Tumor suppressor genes are involved in inhibiting cell growth. Mutations that inhibit or inactivate tumor suppressor genes contribute to cancer. Oncogenes and tumor suppressor genes can be compared to a car. In cancer cells oncogenes act like a stuck gas pedal, and tumor suppressor genes act like broken brakes. C-kit appears to be the dominant oncogene in GIST. In fact, GIST seems, in some ways, to be a very simple cancer, in terms of its genetics. Activated KIT (or, in a few cases, a closely-related protein called PDGFR-alpha) is the primary cellular event that causes GIST.¹

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C-kit

The c-kit gene contains instructions that tell the cell how to manufacture the KIT receptor. The KIT receptor is a protein at the outer membrane of the cell. A portion of the receptor is outside of the cell (the extracelluar domain), a portion is inside the cell (the intracellular domain) and these two domains are connected by a portion that spans the membrane of the cell (the transmembrane domain).

A "domain" is simply a region of a protein. Just as a house contains several connected rooms, most proteins contain several connected domains. In a house, particular rooms (bathroom, kitchen, dining room) may have specific functions. Other rooms may not have any obvious specialized function ("should we make that room a bedroom, a reading room, or an office?"). The same is usually true of proteins. Some domains clearly have specialized functions, while others do not.

In a normally functioning cell that expresses c-kit, another protein called "stem cell factor" binds to the outer portion of the receptor and activates the receptor through a process called phosphorylation. The phosphorylation starts a series of chemical reactions inside the cell. Activation of the KIT receptor causes downstream signaling that results in cell proliferation and survival. Other names for stem cell factor are, steel factor, kit ligand, and mast cell growth factor.

In GIST cells, the c-kit gene is mutated approximately 80% of the time. When the c-kit gene is mutated, the KIT receptor is not assembled perfectly. Mutations in c-kit result in a change in shape and function of the KIT receptor. Mutations in the c-kit gene cause the KIT receptor to be continuously activated! This is a very important concept. This means that even without the normal signal to divide (stem cell factor), the receptors are still providing a constant stimulus for the GIST tumor cells to divide and survive. See KIT Receptor Image.

What about the GISTS which apparently do not have mutated c-kit? In some cases, the scientists may just have made a mistake and overlooked the mutation. But we now know that some of the GISTS that don't have a mutation in KIT have a mutation in another protein, PDGFR-alpha, which is very similar to KIT. About 7% to 8% of all GISTs have a mutation in the PDGFRA gene.

Mutations in the c-kit gene are a very large part of what drives a GIST cancer cell. Because of this it makes a great target for therapeutic intervention. Modern medicine has only recently begun to be able to rationally design drugs or other therapy to block the signaling of specific cancer causing genes such as c-kit in GIST. The current superstar drug in the world of cancer is Gleevec, a drug that inhibits both KIT signaling and PDGFR-Alpha as well as a similar type of protein, BCR-ABL, that causes Chronic Myelogenous Leukemia (CML).

The information in genes is divided into different sections called exons and introns. Exons contain coding information and introns do not. Mutations is different exons in the gene cause changes is shape in different parts of the KIT receptor. Mutations in the following exons of the c-kit gene are known to occur in GIST.

Some GIST tumor cells do not contain c-kit or PDGFRA mutations. This is called "wild-type" GIST. Wild-type GISTs do not respond as well as other types, but since some signaling may still occur through the KIT receptor treatment with Glivec is still beneficial in some cases.

Important biochemical concept: specific exons usually correspond to specific domains of a protein. That is, exons are like blueprints for particular rooms in a house. This explains why GISTS with mutations in a particular exon, say exon 9, often behave similarly - but differently from GISTS with mutations in another exon - say, exon 11. By "behaving differently" we mean that they may cause primary tumors at different places in the GI tract, and they may respond differently to drugs like Gleevec.

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Atypical GIST

In some cases, patients with c-kit–positive GIST may not respond to Gleevec. In particular, point mutations in the c-kit gene may lead to increased kinase activity but prevent the binding of Gleevec to KIT. There are also rare cases in which c-kit mutations result in the elimination or inactivation of the ligand-binding domain, rendering the tumor c-Kit negative but still responsive to Gleevec. It may be possible in these cases to detect such mutations by mutational testing.

Want more detailed information? Take a look at the Slide presentation presented at the London GIST conference by Dr. Jonathon Fletcher, Molecular Biology of GIST.

Also read the article "Imatinib, Gene Expression, and Resistance: A Conversation With Jonathan C. Trent, MD, PhD".

Also, two articles about genotyping:

KIT & PDGFRA mutations in GIST: A to Z by Dr. Michael Heinrich

Looking for kinase mutations in GISTs: how, when and why? by Dr. Christopher Corless

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References

1. Michael C. Heinrich, MD, Drian P. Rubin, MD, PhD, B. Jack Longley, MD, and Jonathan A. Fletcher, MD-Biology and Genetic Aspects of Gastrointestinal Stromal Tumors: KIT Activation and Cytogenetic Alterations

2. Differential Diagnosis of GIST in the Era of Molecularly Targeted Therapy Rediscovering GIST (Novartis)