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CANCER GENETICS

3

Alternative Pathways to Cancer

The paths that cells ta ke on their way to becoming malignant are highly v ariable.

The paths that cells ta ke on their way to becoming malignant are highly v ariable. Within a given cancer type mutation of part icular target genes such as

ras or p53 may be

found in only a subset of

otherwise histologicall y identical tumors.

In familial cancer cas es, the cancer occurs more frequently in the fam ily than in the population

they already have.

Onset is also frequent as

already 1 copy is in herited, 1 more has to be acquired. In Familial A denomatous Polyposis when

2 copies are mutated malignant.

then benign tumor becomes

Familial cancer sugg ests a clustering of cancers that probably occurre d by chance. In other words, there may be a comb ination of genetic and non- genetic (i.e., envi ronmental) factors that contributed to the dev elopment of cancers within a family. In such instan ces, where an alteration in a single major gene is n ot likely or is not identified, individuals may still fa ce elevated risks of cancer.

 
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
 
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way
CANCER GENETICS 3 Alternative Pathways to Cancer The paths that cells ta ke on their way

Deletion or inactivation of tumor su ppressor genes can give rise to either famil ial or sporadic cancer. For

example, it was shown in the slide on

the evolution of colon cancer that deletions

of chromosome regions 18q

and 17p, which contain the DCC (delet ed in colon carcinoma) and the p53 genes, res pectively, are involved in the progression of colon carcinoma.

 
 

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The Rb gene and the p53 gene will be the subjects of further discussion. The next three slides look at the mechanisms by which tumor suppressor genes get mutated to give rise to familial and sporadic cancers.

RETINOBLASTOMA PROTEIN

 

The retinoblastoma protein (abbreviated pRb, RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins. Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer.

About 40% retinoblastoma cases are familial

It inherits as incompletely penetrant dominant character

Familial cases are bilateral, whereas the sporadic forms are unilateral

Age-of-onset distribution of bilateral cases is consistent with a single mutation, while sporadic cases followed two-hit kinetics.

In 1971Knudson proposed that all retinoblastoma involved two hits , but that in the familial cases one hit was inherited

The Rb gene and the p53 gene will be the subjects of further discussion. The next

The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers (familial) are primarily caused by an inherited genetic defect.

 
 

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Retinoblastoma arises when both copies of the RB gene are inactivated . In the inherited form

Retinoblastoma arises when both copies of the RB gene are inactivated. In the inherited form of the disease, one parental chromosome carries an alteration in this region. A somatic event in retinal cells that causes loss of the other copy of the RB gene causes a tumor. In the sporadic form of the disease, the parental chromosomes are normal, and both RB alleles are lost by (individual) somatic events.

In 1978 Yunis and Francke showed that retinoblastoma tumor had deletion in chromosome 13q14.

In 1983, recessive nature of the retinoblastoma gene was hypothesized and it was suggested that both alleles of this gene would need to be inactivated for retinoblastoma to arise

RFLP analysis of the 13q14 region showed heterozygous state in normal cells of a Rb patient but hemizygous ( only one allele instead of two in a diploid cell) in the tumor tissue of the same individual.

This loss of heterozygosity (LOH) suggests that Rb arises through loss of both functional RB alleles

Loss of both wild type alleles is seen both in familial and sporadic form of Rb.

In the familial form, one germline mutation is inherited, followed by a 2 nd somatic event; in the sporadic form both events are somatic.

Cell-cycle dependent phosphorylation of Rb

 
Retinoblastoma arises when both copies of the RB gene are inactivated . In the inherited form
Retinoblastoma arises when both copies of the RB gene are inactivated . In the inherited form
 
 

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Function of the Rb protein

Function of the Rb protein Tumour suppressors may control the cell cycle As well as occurring

Tumour suppressors may control the cell cycle

Function of the Rb protein Tumour suppressors may control the cell cycle As well as occurring

As well as occurring in RB itself, mutations are found in the small inhibitory proteins (most notably pi6 and possibly p21), and D cyclin(s). Although these proteins (most notably RB) play a role in the cycle of a proliferating cell, the role that is relevant for tumorigenesis is more probably their function in the quiescent (GO) state. In quiescent cells, RB is not phosphorylated, D cyclin levels are low or absent, and pi6, p21, and p27 ensure inactivity of cdk-cyclin complexes.

 
 

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Chromosomal mechanisms that could lead to heterozygosity (LOH) loss of function due to loss of Detection
Chromosomal mechanisms that could lead to
heterozygosity (LOH)
loss
of function due to
loss of
Detection of TSG by LOH Analysis
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The p53 Functional Circuit Cancer genetics-©Aayudh Das Page 6
The p53 Functional Circuit
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Tumor suppressor p53 suppresses growth or triggers apoptosis Cancer genetics-©Aayudh Das Page 7
Tumor suppressor p53 suppresses growth or triggers apoptosis
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The Mutation Spectrum of p53 p53 is a DNA-binding protein that recognizes an interrupted palindromic 10
The Mutation Spectrum of p53
p53 is a DNA-binding protein that recognizes an
interrupted palindromic 10 bp motif. The
ability to bind to its specific target sequences is
conferred by the central domain.
 p53 activates transcription at promoters that
contain multiple copies of this motif. The
immediate N-terminal region provides the
transactivator domain. p53 may repress other
genes; the mechanism is unknown.
 p53 also has the ability to bind to damaged
DNA. The C-terminal domain recognizes single-
stranded regions in DNA.
 p53 is a tetramer (oligomerization is a
prerequisite for mutants to behave in a
dominant negative manner). Oligomerization
requires the C-terminal region.
A (putative) signaling domain contains copies
of the sequence PXXP, which forms a binding
site for SH3 domains.
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RB-p53-CDKN2A (INK4A)-p21Network Cancer genetics-©Aayudh Das Page 10
RB-p53-CDKN2A (INK4A)-p21Network
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APC and FAP

 

Intracellular protein

Truncations in APC

 

Aberrant activation of Wnt pathway

Increased cell proliferation and adenomatous lesions

 

Autosomal dominantly inherited disease

Hundreds or thousands of polyps in the colon and rectum

Mutations in APC also found in:

 

Sporadic colon cancer

Several types of tumours

Hepatocellular carcinoma

 

Wnt signaling and cancer

 
 
APC and FAP • Intracellular protein – – • Truncations in APC Aberrant activation of Wnt
 
 

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