CONCEPTOS BASICOS EN GENETICA Y CANCER

BRADY BELTRAN GARATE

OCTUBRE 2012

BASES CELULARES DEL CANCER

Cncer es un conjunto de enfermedades caracterizadas por un crecimiento incontrolado y anormal. La disrupcin puede resultar de: 1)crecimiento incontrolado 2)inmortalizacin de la clula ( inhibicin de apoptosis)

Cellular equilibrium
Proliferation Differentiation Death

Transit

Renewing

Proliferating Exiting
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Cancer: disruption of cellular equilibrium

Proliferation

Differentiation

Death
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Invasin and Metstasis

Abnormal cells proliferate and spread (metastasize) to other parts of the body Invasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vessels

CAUSAS DEL CANCER

Cncer es causado por alteraciones o mutaciones en el cdigo gentico. Puede ser inducido por:

Carcinognicos qumicos
Radiacin Virus Hereditario- 5%

Oncogenes Cell cycle Apoptosis Tumor Suppressor

Angiogenesis

Inv. and Mets

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Hanahan and Weinberg, Cell 100: 57, 2000

CANCER: ENFERMEDAD GENOMICA

prdida DNA ganancia DNA cambios en nucletidos efectos epigenticos

MUTACIONES CAMBIO ESTRUCTURAL

CAMBIO FUNCIONAL

Genetic and Epigenetic Silencing of Tumor Suppressor Genes

Plass - 2002

THE CAUSES OF GENOMIC CHANGES IN CANCER

UV

Carcinogenic chemicals

Replication Errors Radiation

Normal cell Damaged DNA Point mutations

Viruses

Rearrangements (translocation, deletions, amplifications)

Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal)

Cancer cell

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BASES GENETICAS DEL CANCER Approximately 90-95% of all cancers are sporadic. 5-10% are inherited.

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GENES INVOLUCRADOS EN EL DESARROLLO DEL CANCER

Oncogenes Genes supresores tumorales Genes de apoptosis Genes reparadores del DNA
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What are the genes responsible for tumorigenic cell growth?

Normal
Proto-oncogenes Tumor suppressor genes

++

Cell growth and proliferation

Cancer
Mutated or activated oncogenes Loss or mutation of Tumor suppressor genes Malignant transformation

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ONCOGENES
Oncogenes son formas mutadas de los protooncogenes. Proto-oncogenes codifican protenas celulares las cuales regulan el crecimientocelular normal y la diferenciacin.
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Five types of proteins encoded by protooncogenes participate in control of cell growth:

Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins

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Functions of Cellular Proto-Oncogenes

1. Secreted Growth Factors

2. Growth Factor Receptors

3. Cytoplasmic Signal Transduction Proteins

4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes

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A generic signalling pathway

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Oncogenes
proto-oncogene = ras Oncogene = mutados Siempre activado Siempre estimulando la proliferacin

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Activation mechanisms of proto-oncogenes

proto-oncogene --> oncogene

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Oncogenes are usually dominant (gain of function)

cellular proto-oncogenes that have been mutated (and activated)
cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and activated) virus-specific genes that behave like cellular protooncogenes that have been mutated to oncogenes (i.e., activated)

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GENES SUPRESORES TUMORALES

Funcin normal inhibir la proliferacin celular PERDIDA DE FUNCION Ausencia/inactivacin del inhibidor --> cncer Ambas copias de los genes deben ser alterados
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KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES

Familial RB (%30) RB

rb

Normal cells

RB LOH

rb RB

rb
Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation.

Tumor cells

Normal cells

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KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES

Normal Cells

RB

RB

RB

RB

RB LOH

RB Mutation

Tumor cells

Inactivation of a tumor suppressor gene requires two somatic mutations.

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TUMOR SUPPRESSOR GENES

Disorders in which gene is affected
Gene (locus) DCC (18q) Function cell surface interactions transcription Familial unknown Sporadic colorectal cancer lung cancer

WT1 (11p)

Wilms tumor

Rb1 (13q)

transcription

retinoblastoma

small-cell lung carcinoma breast, colon, & lung cancer

p53 (17p)

transcription

Li-Fraumeni syndrome

BRCA1(17q)
BRCA2 (13q)

transcriptional
regulator/DNA repair

breast cancer

breast/ovarian tumors
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CELL CYCLE
Daugther cell

Mitosis

Gateway Growth Factors

S
DNA replication

CELL CYCLE

Cell cycle inhibitors Control Point

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Rb gene
Rb protein controls cell cycle moving past G1 checkpoint Rb protein binds regulatory transcription factor E2F E2F required for synthesis of replication enzymes E2F - Rb bound = no transcription/replication Growth factor --> Ras pathway --> G1Cdk-cyclin synthesized Active G1 Cdk-cyclin kinase phosphorylates Rb Phosphorylated Rb cannot bind E2F --> S phase
Disruption/deletion of Rb gene Inactivation of Rb protein

--> uncontrolled cell proliferation --> cancer

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p53
Phosphyorylated p53 activates transcription of p21 gene p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity) Cell cycle arrested to allow DNA to be repaired If damage cannot be repaired --> cell death (apoptosis)
Disruption/deletion of p53 gene Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancer

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GENES REPARADORES DEL DNA

These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as protooncogenes and tumor suppressor genes. i.e. Breast cancer susceptibility genes (BRCA1 and BRCA2) Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1, PMS1, PMS2) have DNA repair functions. Their mutation will cause tumorigenesis.
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Molecular mechanisms of DNA double strand break repair

BRCA1/2

Van Gent et al, 2001

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IMPORTANCIA REPARACION DNA

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GENES DE APOPTOSIS
Clula existe equilibrio entre genes de apoptosis e inhibidores de apoptosis.
Cncer se rompe el equilibrio en favor de genes antiapoptosis Inmortalizacin de la clula

o
Cellular

Progresin tumoral

Una vez ocurridos los cambios genticos para inducir cncer ( 9 mutaciones aprox) Mutaciones sucesivas se producen generando incremento de potencialidades del cncer

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Translocation and Bcr-Abl fusion in CML

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STI-571 against Bcr-Abl

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Smart bullet STI-571 lockes itself to the target molecule

STI-571
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Thousands of Targets
?

?
? ?

?
HERCEPTIN

? ?

STI-571

?
? ?

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MOLECULAR BIOLOGY & INFORMATICS

Biyoinformatik

~3.000.000.000 bp DNA

~30.000 genes ~300.000 protein ~3.000.000 interaction 1 human cell

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GRACIAS!

Istituto Sergnoli - Bologna