癌症的分子基础

Acquired Environment (next lecture) Inherited (Germ line) Monoclonal (X-linked isoenzyme)

Tumors arise from a single progenitor cell


Target Genes

Simplified Cancer Pathogenesis
Normal
Damage
Gene Expression
Kumar et al. Basic Pathology 6th ed. Fig. 6-16
Malignancy
ONCOGENES

PROTO-ONCOGENES

NORMAL CELLULAR GENE ALTERATIONS GIVE ONCOGENE
Proto-oncogenes, TSG, Apoptosis, DNA repair

Multistep Process
MONOCLONALITY: X-Linked Isoenzyme
Polyclonal
Monoclonal
Kumar et al. Basic Pathology 6th ed. Fig. 6-15



Increased number of mutations Increased risk of developing carcinoma Inherited recessive fashion
AUTOSOMAL RECESSIVE SYNDROMES OF DEFECTIVE DNA REPARAIR
N-myc - NEUROBLASTOMA

GENE REARRANGEMENTS


GENE AMPLIFICATION

BURKITT’S LYMPHOMA

ONCOGENE ACTIVATION BY CHROMOSOME REARRANGEMENT

TRANSLOCATION OF 8 AND 14 [t(8,14)] c-myc (chr 8) to immunoglobulin heavy chain (chr 14)

ACUTE RETROVIRAL TRANSDUCTION

ACUTE TRANSFORMING VIRUSES

(V-ONC)

INSERTIONAL MUTAGENESIS

SLOW TRANSFORMING VIRUSES NOT ASSOCIATED WITH VIRUSES

DNA TRANSFECTION (IN VITRO)

c-able to bcr = hybrid gene with tyrosine
kinase activity
Chronic Myelogenous Leukemia
bcr-abl gene product
Department of Pathology, Utah web site
Kumar et al. Basic Pathology 6th ed. Fig. 6-19
FAMILIAL RETINOBLASTOMA 1. FIRST MUTATION IS INHERITED (GERMLINE) 2. SECOND MUTATION OCCURS LATER (2nd HIT)
Pathogenesis of Retinoblastoma
Department of Pathology, Kansas web site
Department of Pathology, Utah web site

RECIPROCAL TRANSLOCATION BETWEEN LONG ARMS OF CHR 22 AND 9

t(9;22), PHILADELPHIA CHROMOSOME (Ph1)

MUTATION AND ACTIVATION OF CANCER CAUSING GENE

ret, c-erb B-2 (Her2/neu)


Mutated “on” Signal Transducers ras: Most common abnormality Mutated “on” Nuclear Transcription Proteins

myc

Control transcription genes, Bind DNA Cyclin and Cyclin-Dependent Kinases

Protein Products of Oncogenes

Oncoproteins

Resemble normal products except:

Devoid of regulatory elements Production does not depend on growth factors or external signals
Role of pRb in Cell Cycle
Kumar et al. Basic Pathology 6th ed. Fig. 6-22
Kumar et al. Basic Pathology 6th ed. Fig. 6-23
Role of p53
Normal Cell
Loss of p53



TERMINAL EVENTS OF PCD DNA FRAGMENTATION CYTOPLASMIC PROTEASES ARE INVOLVED (ICE FAMILY OF PROTEASES) APOPTOSIS IS A CYTOPLASMIC EVENT NOT THE SAME AS NECROSIS E.G. BCL-2 BLOCKS PCD

LOSS OF HETEROZYGOSITY

NORMALLY SUPPRESS UNCONTROLLED GROWTH

Rb (RETINOBLASTOMA) p53 (70% OF ALL CANCERS) WT-1 (WILM’S TUMOR)
RETINOBLASTOMA

LOSS OR INACTIVATION OF TUMOR SUPPRESSOR GENE
Regulation of Cell Death
Proliferati百度文库n: Malignancy
Kumar et al. Basic Pathology 6th ed. Fig. 6-24
P53: Molecular Policeman
APOPTOSIS = PROGRAMMED CELL DEATH (PCD)
Genes that Regulate DNA Repair

Normal cells can repair DNA damage

Set of complex DNA repair genes/proteins

Cells with abnormal (mutated) DNA repair genes

Mutations favor proliferation
Model of Action of ras Gene
Kumar et al. Basic Pathology 6th ed. Fig. 6-17
Role of Cyclins and CyclinDependant Kinases (CDK)
Gene Amplification: Neuroblastoma
Kumar et al. Basic Pathology 6th ed. Fig. 6-20
TUMOR SUPPRESSOR GENES


EXERT ONCOGENIC INFLUENCE WHEN DELETED OR INACTIVATED NEED MUTATION OF BOTH ALLELES
NEUROBLASOMA


ONCOGENE ACTIVATION BY GENE AMPLIFICATION N-myc


DOUBLE MINUTES (DM’S) HOMOGENEOUSLY STAINING REGIONS (HSR’S) LEVEL OF AMPLIFICATION CORRELATES TO AGGRESSIVENESS OF TUMOR


HOW THEY ARE ASSOCIATED WITH MALIGNANCY PROPOSED FUNCTIONS GENETIC ALTERATIONS ASSOCIATED WITH THEIR ACTIVATION OR LOSS
FUNDAMENTAL PRINCIPLES

Non-Lethal genetic damage (Mutations)
Hit #1 (inherited)
Hit #1 Hit #2 Hit #2
Familial
Kumar et al. Basic Pathology 6th ed. Fig. 6-21
Sporadic
Protein Products of Tumor Suppressor Genes



Growth Inhibitory Factors BRCA-1, BRCA-2 Regulate Cell Adhesion Deleted in Colon Cancer (DCC) Cadherins APC Molecules that Regulate Signal Transduction NF-1 Molecules that Regulate Nuclear Transcription and Cell Cycle Rb P53: Molecular policeman, Li-Fraumeni syndrome
Department of Pathology, Kansas web site
Burkitt’s Lymphoma
Department of Pathology, Kansas web site
Kumar et al. Basic Pathology 6th ed. Fig. 6-18
Chronic Myelogenous Leukemia
Kumar et al. Basic Pathology 6th ed. Fig. 6-18
Cell Cycle
cdkConstitutively expressed
PROTO-ONCOGENE ACTIVATION

POINT MUTATIONS

ras - COLON CANCER
t(8;14) - BURKITT’S t(9;22) – Chronic myelogenous leukemia (CML)

INTERSTITIAL DELETION -13q14 LOCATION OF Rb GENE HOMOGENOUS MUTATION OR LOSS (KNUDSON’S TWO HITS)
Department of Pathology, Kansas web site
KNUDSON’S TWO MUTATION HYPOTHESIS

Effect key proteins

Cell growth Development Differentiation Cell Death
PROTO-ONCOGENES


Growth Factors sis, hst-1, int-2 Over expressed Growth Factor Receptors
CARCINOGENESIS: MOLECULAR BASIS OF CANCER
DAVID LEWIN MD
OVERVIEW

BASIC CONCEPTS OF ONCOGENES, TUMOR SUPPRESSOR GENES, APOPTOSIS, DNA REPAIR & TELOMERES

MUTATIONS, AMPLIFICATION, RETROVIRAL TRANSFER


DEFINE MOLECULAR BASIS FOR CANCER EXPLAIN MUTAGENS EFFECT ON CANCER DEVELOPMENT
LABORATORY IDENTIFICATION OF ONCOGENES