Molecular Biology for Clinicians

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Moleculf

CliniProf Ernesto

Instituto Oncolo

Universidad

r Biologyr

iansGil Deza MD

ico Henry Moore

de Salvador

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Objectives

Definition

Pathogenesis

Clinical applications

Objec

tives

Definition

Pathogenesis

Clinical applications

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Molecular Diagnostic Tools

DNA

Citogenetics

FISH and CISH

CGH

CGH arrays

SNPs

PCR sequencing

Southern blot

Microsatelliteinstability

Microarray

Molecular Dia

gnostic Tools

RNA

Transc. Pro iling

Northern blot

RT-PCR

ISH, FISH & CISH

Proteins

Western blot

2D electro horesis

MALDI-T F

S LDI-T F

IHC

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Some pr blems

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Sample tissue

Gross Tumor Specimen

Fine Needle Aspiration

Microdissection of Pure Tumor Cells

Paraffin block

Frozen sample

Fresh tissue

Sample tissue

Gross Tumor Specimen

Fine Needle Aspiration

Microdissection of Pure Tumor Cells

Paraffin block

Frozen sample

Fresh tissue

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Huma

Nuclear

3000 Mb

~30.000 genes

Genes

30 %

Extragenetic

70%

Encoded Non encoded

L10% 90%

Quan

Genome

Mitocondrial

16.6 kb

37 genes

ow number

of copies

Higher number

of copies

80%20%

itative

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Statistics

0 000 50 000 genetic features

for only few outcomes:

Response/No responce

Recurrence/No

recurrence

Survival/death

Greater chances of false positive

results

Statistics

0 000 50 000 genetic features

for only few outcomes:

Response/No responce

Recurrence/No

recurrence

Survival/death

Greater chances of false positive

results

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Patho enesis

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Oncog

Hannahan and W

enesis

einberg Cell 2000

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Preinv

Invas

Genetic in

sive

ive

tability

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Clinical a plications

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Clinical applications

Risk predictionCancer diagnosis

Differential diagnosis

Tumor subtypification

Pharmacogenetics

Prediction of clinical outcomes

Novel targeted therapeutics

Modified

orkman Johnsto JCO October 10th 005

Clinical applications

Risk predictionCancer diagnosis

Differential diagnosis

Tumor subtypification

Pharmacogenetics

Prediction of clinical outcomes

Novel targeted therapeutics

Modified

orkman Johnsto JCO October 10th 005

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Risk prediction

ow penetrance high risk

BRCA1

BRCA

High penetrance low risk

Risk prediction

ow penetrance high risk

BRCA1

BRCA

High penetrance low risk

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Ethica issues

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Cancer diagnosis

Differencial diagnosis ADH DCIS CDI

DNA microarray of ductal lavage

Nanoparticles and blood products

Cancer diagnosis

Differencial diagnosis ADH DCIS CDI

DNA microarray of ductal lavage

Nanoparticles and blood products

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Tu

Subtypi

or

ications

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Disagree ent in ICH

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Molecular Breast Canc r Subtype Dendrogram

Carey - ASCO 2005

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Te

Classification

to

equirements

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Prog osis

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2000

Prognostic and

500 BC1870

atural history

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0

20

40

60

80

100

120

Bajo

Inte

rmedio

Alto

3G+

10G+III

0

20

40

60

80

100

120

Bajo

Inte

rmedio

Alto

3G+

10G+III

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Due to the nature of t

21 gene assay, which areand ER-related genes, it

assay is an expensive replacement fo

ass

Paik and K

e genes included in the

ainly proliferation genescould be argued that the

r ER and Ki67 inmunohistochemical

ys

m, page 21

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Molecular predictive

factors

ER

PR

Her

All are good NEGATIVE predictors

Molecular predictive

factors

ER

PR

Her

All are good NEGATIVE predictors

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Expectations and reality

e canIdentify hallmarks in tumorigenesis

Classify tumors according to molecular subtypes

Predict high risk in a few patients

Avoid toxicity in some patients

Design more sophisticated predictive tools

But

Can we save lives cure more or take care of our

patients better than we do actually?

Expectations and reality

e canIdentify hallmarks in tumorigenesis

Classify tumors according to molecular subtypes

Predict high risk in a few patients

Avoid toxicity in some patients

Design more sophisticated predictive tools

But

Can we save lives cure more or take care of our

patients better than we do actually?

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Concl

Sir illiam Osler

1880

usion

I have loved no darkness,

Sophisticated no truth,

Nursed no delusion,Allowed no fear

Aequanimitas

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Thank youfor your

very muchttention