David Josephy- GIST 101 - The Life Raft Group

liferaftgroup.org

David Josephy- GIST 101 - The Life Raft Group

David Josephy

Life Fest

Sept. 2008

djosephy@uoguelph.ca

thanks to Jerry Call for assistance in preparation of this talk

1


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

2


Cancer Classification

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

“stomach cancer”

(adenocarcinoma).

3


Major cancer classifications according to cell type:

- Carcinoma

- Sarcoma

- Leukemia

4


Sarcomas

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.

5


probably – the “Interstitial Cells of Cajal” (ICCs)

ICC’s are the “pacemaker”

cells of the GI tract: they

coordinate peristalsis –

the waves of muscle

contraction/ relaxation

which force food through

the gut.

6


“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.

esophagus


“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

mutations.

Lasota and Miettinen, Clinical significance of oncogenic KIT and

PDGFRA mutations in gastrointestinal stromal tumours,

Histopathology 53: 245-266, 2008.

8


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!


Estimated:

15 cases per million people per yr.

5-10,000 new cases per year, U.S.A.

10


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

now.

11


Local growth of tumor may disrupt function of a vital

organ, cause bleeding, etc.

Metastases can damage vital organs (e.g., liver,

lung, brain)

Cancers can suppress immune function

Therapy can cause serious side effects

12


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.

13


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.

14


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.

15


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

microscope).

16


80-85% of GISTs show

mutations in the KIT gene.

This discovery (1998) revolutionized our

understanding of GIST biology and

treatment.

17


Genes (DNA) are the code (blueprints) for

construction of the cell’s proteins.

DNA

mRNA

mRNA

nucleus

cytoplasm

Each human cell has

genes for about

30,000 different kinds

of proteins.

protein

18


Almost everything!

- 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)

- etc.

19


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.

20


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:

immunohistochemistry.

21


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.

22


Stephan Dirnhofer,

Institute of Pathology,

University of Basel,

Switzerland

23


- 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”

24


Kit plays important roles in

regulation of normal cell functions:

- Blood cell formation

- Fertility

- GI tract contractions (ICC)

- Skin pigmentation

25


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.

26


cell

membrane

signal

molecule

nucleus

receptor

27


outside

inside

membrane

Signal is

transmitted

to intracellular

proteins

biological effects


Structure of Kit/

stem cell factor

complex

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.

30


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”

31


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

32


10-15% of GISTs do NOT have Kit

mutations

- in 5-7%: a closely related gene, PDGFRA, is mutated

- the remainder are “wild-type” GISTs; mechanism of

tumor growth still unknown

33


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

- prognosis

- drug response

Mutation testing should be performed on all new GIST cases

(Baveno declaration, 2008)

34


(and also of the related proteins Abl and PDGFR-alpha)

H

N

N

H 3 C

O

N

NH

N

N

100 mg Gleevec Tablets

35


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

36


Actin

38


gene (DNA)

1 2 3 4 5 6

RNA synthesis and

“splicing”

protein

synthesis

exons

protein

mRNA (exons only)

39


DNA testing identifies the exon which is mutated

Exon 9

Exon 11

Exon 13

Exon 17

40


ligand-binding

domain

Exon 9: 13%

Exon 11: 71%

Exon 13: 4%

juxtamembrane

domain

extra-cellular

environment

cytoplasm

cell

membrane

Exon 17: 4%

41


Locations of primary and

secondary (detected

during treatment) KIT

mutations are indicated

by blue, yellow and red

dots, respectively.

adapted from

Lasota and Miettinen, 2008

42


◦ Gleevec

KIT exon 11 - favorable response

KIT exon 9 - intermediate response

Wild-type

– lower response

◦ Sutent (for Gleevec-resistant GIST)

KIT exon 11 – lower response

KIT exon 9 – favorable response

Wild-type

– favorable response

◦ Newer drugs

???

43

More magazines by this user
Similar magazines