thanks to Jerry Call for assistance in preparation of this talk
Gastro-Intestinal Stromal Tumor
An uncommon type of cancer;
about 5,000 cases/year, USA
A type of Sarcoma
About 1% of G.I. cancers are GISTs
The organ in which a cancer begins is important,
but the type of cell that forms the cancer is even
more important, and defines the cancer.
Even if a GIST arises in
the stomach, it is not a
Major cancer classifications according to cell type:
Cancers that arise from cells of connective
tissues, blood vessels, cartilage, bone, etc.;
much less common than carcinomas, which arise in
epithelial (“lining”) tissues, such as skin, colon,
lung, bladder, and breast.
probably – the “Interstitial Cells of Cajal” (ICCs)
ICC’s are the “pacemaker”
cells of the GI tract: they
coordinate peristalsis –
the waves of muscle
which force food through
“Location, location, location”?
All GIST tumors arise in the same cell type and
are variations of the same disease,
regardless of location along the GI tract.
“Location, location, location”?
All GIST tumors are variations of the same disease, regardless of
location along the GI tract.
Nevertheless, location does matter … There are some
biological differences between GISTs arising in
different locations, e.g., different patterns of c-kit
Lasota and Miettinen, Clinical significance of oncogenic KIT and
PDGFRA mutations in gastrointestinal stromal tumours,
Histopathology 53: 245-266, 2008.
Prior to 2000, most GISTs were misclassified
(leiomyosarcoma, leiomyoma, leiomyoblastoma, etc.)
Many of these patients have had no recurrence and
may still be misclassified.
Today, the opposite may be happening: cancers
mistakenly labeled as GISTs!
15 cases per million people per yr.
5-10,000 new cases per year, U.S.A.
Most GISTs arise for unknown reasons.
GIST can be inherited (“running in the family”), but
this is extremely rare.
No environmental, occupational, or lifestyle
causes of GIST are known – and if there were any
obvious causes, they would have been noticed by
Local growth of tumor may disrupt function of a vital
organ, cause bleeding, etc.
Metastases can damage vital organs (e.g., liver,
Cancers can suppress immune function
Therapy can cause serious side effects
Metastasis is spread of the cancer to new and
sites in the body, distant from the “primary”.
Cells detach from the original tumor, travel through
the circulation (blood, lymph), attach in distant
locations, and “seed” new tumors.
Liver is the most common site for GIST metastasis –
also the peritoneum (lining of the abdominal cavity)
and other sites within the abdomen; occasionally the
bone, lung, etc.
Metastases of a tumor have the biological
properties of the primary tumor, irrespective
of the site of the metatasis.
GIST metastases in the liver, brain, or lung are
still GIST tumors (GIST cell type) and are
treated like GISTs –
they are not “liver cancers” (cancers arising
from liver cells), brain cancers, or lung cancers.
Pathology is critical!
Microscopic examination of the tumor cells is key.
Immunohistochemistry (discussed later) is essential.
The experience of the pathologist matters.
Biopsy and patient history aid diagnosis.
Even “benign” GISTs have malignant potential.
Pathology should include assessment of the
risk of recurrence/ metastasis.
Two important criteria are tumor size
and mitotic index (a measure of how quickly
the cells are dividing, as seen under the
80-85% of GISTs show
mutations in the KIT gene.
This discovery (1998) revolutionized our
understanding of GIST biology and
Genes (DNA) are the code (blueprints) for
construction of the cell’s proteins.
Each human cell has
genes for about
30,000 different kinds
- Cell structure and architecture
- Catalysts of metabolism
- Regulation of cell behaviour
- Transport of molecules within the cell
- Communication within and between cells
- Cell-cell recognition
- Immune function (antibodies)
All human cells contain the same
complement of genes.
Different cell types express different genes,
i.e., they make different proteins.
Gene expression is what makes one cell type
different from another.
Kit is a specific protein; it is made by only a few
types of adult cells, including most GIST cells.
The most important step in diagnosing GIST is
testing whether the tumor cells express Kit.
This is done by staining the tissue sample
with an antibody that recognizes Kit:
Kit (a.k.a. c-Kit or “CD117”) is the most
important stain for diagnosis of GIST.
about 95% of GISTs express Kit
- and few, if any, other cancers do so.
Institute of Pathology,
University of Basel,
- Signal transduction protein
- Kit gene is an Oncogene
An oncogene is a gene which, when mutated,
encodes a protein product that tells the cell to
keep dividing: a “stuck gas pedal”
Kit plays important roles in
regulation of normal cell functions:
- Blood cell formation
- GI tract contractions (ICC)
- Skin pigmentation
Chemical messages are sent between cells.
Receptor proteins receive these messages.
Normal cells respond to these signals by
appropriately changing their metabolism and
behavior, e.g., cell divides when told to do so.
Structure of Kit/
stem cell factor
Yuzawa et al., 2007
In normal ICC (pacemaker) cells:
A message molecule (a “growth factor”)
called “stem cell factor” binds to Kit
(“pushes the gas pedal”).
Two Kit molecules join together (Kit
dimerizes), activating Kit
Metabolic changes occur in the cell,
stimulating it to grow and divide.
In GIST cells:
An altered form of Kit is produced.
This form is “always turned on”, even in the
absence of stem cell factor. The GIST cell
keeps dividing, in an uncontrolled manner.
“Stuck gas pedal”
The Kit mutations in GIST tumors are almost
always somatic – not germline - mutations
- occurring in cells of the body during
development or adulthood, but not
affecting germ cells (egg or sperm cells)
- the somatic Kit mutation is inherited by all
of the tumor cells, but it cannot be passed
on to a patient’s children
10-15% of GISTs do NOT have Kit
- in 5-7%: a closely related gene, PDGFRA, is mutated
- the remainder are “wild-type” GISTs; mechanism of
tumor growth still unknown
Mutations in GISTs can arise in many different sites within the
Kit gene, affecting many different sites within the Kit protein.
The site of the mutation influences the biology of the disease:
- anatomical site
- drug response
Mutation testing should be performed on all new GIST cases
(Baveno declaration, 2008)
(and also of the related proteins Abl and PDGFR-alpha)
H 3 C
100 mg Gleevec Tablets
Gleevec prevents KIT from transmitting its signal
to the GIST cell (“gas pedal is released”).
In the absence of signaling, GIST cell stops
dividing and undergoes apoptosis:
“programmed cell death” or “cell suicide”.
Tarn et al., Therapeutic effect of imatinib in gastrointestinal
stromal tumors: AKT signaling dependent and independent
mechanisms, Cancer Res. 66: 5477-5486, 2006
1 2 3 4 5 6
RNA synthesis and
mRNA (exons only)
DNA testing identifies the exon which is mutated
Exon 9: 13%
Exon 11: 71%
Exon 13: 4%
Exon 17: 4%
Locations of primary and
during treatment) KIT
mutations are indicated
by blue, yellow and red
Lasota and Miettinen, 2008
KIT exon 11 - favorable response
KIT exon 9 - intermediate response
– lower response
◦ Sutent (for Gleevec-resistant GIST)
KIT exon 11 – lower response
KIT exon 9 – favorable response
– favorable response
◦ Newer drugs