Cancer Genetics Lec 3 and 4

7/30/2019 Cancer Genetics Lec 3 and 4

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Cancer genetics-Aayudh Das

CANCER GENETIC

Alternative Pathways to Cancer

Deletion or inactivation of tumor su

example, it was shown in the slide o

and 17p, which contain the DCC (delet

progression of colon carcinoma.

3

The paths that cells ta

malignant are highly v

type mutation of part

ras or p53 may beotherwise histologicall

In familial cancer cas

frequently in the fa

they already have.

already 1 copy is in

acquired. In Familial A

2 copies are mutated

malignant.

Familial cancer sugg

that probably occurre

there may be a comb

genetic (i.e., envi

contributed to the dev

family. In such instan

single major gene is n

individuals may still fa

ppressor genes can give rise to either famil

the evolution of colon cancer that deletions

ed in colon carcinoma) and the p53 genes, res

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ke on their way to becoming

riable. Within a given cancer

icular target genes such as

found in only a subset ofy identical tumors.

es, the cancer occurs more

ily than in the population

Onset is also frequent as

herited, 1 more has to be

denomatous Polyposis when

then benign tumor becomes

sts a clustering of cancers

by chance. In other words,

ination of genetic and non-

ronmental) factors that

elopment of cancers within a

ces, where an alteration in a

ot likely or is not identified,

ce elevated risks of cancer.

ial or sporadic cancer. For

of chromosome regions 18q

pectively, are involved in the


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Cancer genetics-Aayudh Das Page 2

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, RBor 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 enzymessuch 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 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 of the disease, one

parental chromosome carries an alteration in this

region. Asomatic 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 RBalleles are lost by (individual)somatic events.

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

In 1983, recessive nature of the retinoblastoma gene was hypothesized and it was suggested thatboth

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 sameindividual.

This loss of heterozygosity (LOH) suggests thatRb 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 2nd somatic event; in the

sporadic form both events are somatic.

Cell-cycle dependent phosphorylation of Rb


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Function of the Rb protein

Tumour suppressors may control the cell cycle

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 loss of function due to loss of

heterozygosity (LOH)

Detection of TSG by LOH Analysis


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The p53 Functional Circuit


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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 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


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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


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Cancer Genetics Lec 3 and 4

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