Genetics of the Cancer Celland of the

Tumor-Bearing Host

Folder Title: CxGenes

Updated: April 04, 2012

CxGenTtl

Part 1 of Biology of Cancer: What is Cancer LikeWhat is Cancer Like?

Why do we need to know about Cancer ? (Intro501)

What are cancers like as clinical diseases ? (Clinical)

What are incidence patterns of cancers like? (Epidemio)

How are cancers defined and classified ? (DefClass)

What do we study in cancer biology and cancer medicine? (Models)

When we study cancer cells, what features do we see? (CellProp)

Cancers as a collection of heterogenous cell populations. (Hetero)

Aberrant differentiation and progression in Cancer (Progress)

Invasion and metastasis in Cancer (Inv&Mets)

Cancer growth in culture, in non-human animals, and in patients (Growth)

Not Covered in 2012: Models in the study of cancer metastasis (MetModels)

Part 2 of Biology of Cancer: Why is Cancer Like ThatWhy is Cancer Like That?

What accounts for the phenomenology of cancer that we see?

How do cancers get that way?

What maintains them in their pathology?

Why do they progress in their pathology and become malignant?

What can we do about it?

How can we prevent the appearance of cancers?

How can we manage the cancers when they appear?

How can we treat cancer patients in clinical oncology based on our understanding of what makes cancers “tick”?

Why Does All of This Matter?Age Group and Lifetime Risk of Developing Invasive Cancers

Genetics in the Biology of CancerGenetics of What?

Genetics of the Host

Before the Cancer Starts

In Response to the Cancer After It Appears

Genetics of the Cell that Gets TransformedPredisposing Factors in the Host

Genetics of the Cancer Cell

After Transformation - During Progression

GeneWhat

Why Genetics Must Be Intimately Involved in the Biology of Cancer

Multiple Apparently Unrelated Causative Agents:• All Can Affect Genetics of Cells and of HostDefinition of Neoplasia: "Heritable Cellular Phenotype"Long Latent PeriodsProgressive Acquisition of the Full Neoplastic PhenotypeDiversity and Heterogeneity in NeoplasiasChromosomal Anaplasia• Chromosomal Anomalies and Cancer Progression• Specific Chromosomal Anomalies & Specific CancersSpecific Hereditary Diseases Linked to Specific CancersIncidence of Some Heritable Cancers

GenesWhy

How Might Genetics Be Involved in the Basic Biology of Cancer?

In the Genes of the Cancer Cell

Genome of the Host Cell that Becomes Transformed• Genetic Predisposition Facilitating Transformation Familial Cancer Genes: e.g. DCC in Colon Cancer Weak or Labile Spots in Chromosomal Structures Vertical Transmission of Pro-virus or Germ-line Altered Gene• Chance Mutagenic Event

Genomes of Neoplastic Cell Sub-populations During Progression (Genetics of the Cancer Cell After Transformation)

GeneHow1

How Might Genetics Be Involved in the Basic Biology of Cancer?

In the Genes of the HostGenome of the Host Prior to Transformation Host Genetics Facilitating Transformation• Activation of Carcinogens• Viral Receptors• Inability to Repair DNA Damage• Inability to Respond to Altered CellGenome of the Host After Transformation of Host Cell• Inability to Recognize and Respond to Growing Tumor• Response Facilitating Tumor Growth• Genetically-based Non-immunological Respones e.g. Stress, Hormones

GeneHow2

Groups of Individuals with High Leukemia Risk: Genetic Associations

• Identical Twin of Child with Leukemia 1 in 5 (within weeks or months)• Bloom's Syndrome 1 in 8• Hiroshima Survivors at 1000 meters 1 in 60• Down's Syndrome (Trisomy 21) 1 in 95• Radiation-treated Patients with Ankylosing Spondylitis 1 in 270• Sibs of Children with Leukemia 1 in 720• U.S. Caucasian Children to 15 Years 1 in 2,880

From Pitot, Fundamentals of Oncology, 3rd Edition, p. 117

GeneGrps

Relationship Between Specific Genetics Diseases and Associated Neoplasms

Fanconi's Anemia (AR)

Bloom's Syndrome (AR)Xeroderma Pigmentosum(Autosomal Recessive)Retinoblastoma (Bilateral) (AD)Familial Polyposis Coli (AD)Gardner's Syndrome (AD)

Severe Combined Immune Deficiency (Sex-linked)

Acute Myelogenous Leukemia & Hepatocellular CarcinomaLeukemia & Intestinal CancersSkin Cancers

Ocular Neoplasms & SarcomaColon CarcinomaColon Carcinoma; Pancreatic,Thyroid, Adrenal, Bone, &Connective Tissue NeoplasmsLymphoma, Leukemia, Sarcoma

AR = Autosomal RecessiveRed - Autosomal Dominant GenIllCx

Figure 12.25 The Biology of Cancer (© Garland Science 2007) p. 499

Xeroderma Pigmentosum: Skin Lesions and Progression to Squamous Cell Carcinoma and Malignant Melanoma

Figure 12.26 The Biology of Cancer (© Garland Science 2007) p. 499

Age of Onset of Skin Cancers in X. Pigmentosum Patients vs General Population

Specific Chromosomal Abnormalities Associated with Specific Cancers

Chronic Myelogenous Leukemia

Burkitt's Lymphoma

Myelodysplasia and Acute Myelogenous Leukemia

Meningioma

Reciprocal Translocation, 9&22

Reciprocal Translocation, 8&14

Trisomy 8

Monosomy 22

SpecCx

Figure 4.6b The Biology of Cancer (© Garland Science 2007), p. 101

Amplification of HER2/Neu Gene Expression in Breast Cancer:

Relationship to Prognosis

Figure 4.11a The Biology of Cancer (© Garland Science 2007) p. 107

Amplification of N-Myc Gene in Neuroblastoma: Relationship to

Survival

Figure 4.11b The Biology of Cancer (© Garland Science 2007) p. 107

Amplification of N-Myc Gene in Neuroblastoma: Relationship to Survival

Amplification of the N-Myc gene in Neuroblastoma is associated with the

pathobiology of this cancer. This makes the myc gene an example of an

__ __ __ __ __ __ __ __

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Chromosomal Translocations:Oncogenes as Fused Partial Normal Genes

The Philadelphia Chromosome

Figure 2.23b The Biology of Cancer (© Garland Science 2007) p. 49

Chromosome-specific Probe Analysis of Reciprocal Translocation (9 to 22) in Chronic Myelogenous Leukemia

Chromosome 9 (White); Chromosome 22 (Purple)

Figure 4.15a The Biology of Cancer (© Garland Science 2007) p. 113

Fusion Oncoprotein in Chronic Myelogenous Leukemia

Figure 4.13a The Biology of Cancer (© Garland Science 2007) p. 109

Reciprocal Translocation (8 to 14) in Burkitt’s Lymphoma

Figure 4.13b The Biology of Cancer (© Garland Science 2007 p. 109)

Myc Oncogene (Chromosome 8) Expression Controlled by Fusion with Immunoglobulin Heavy Chain Gene (Chromosme 14) in Burkitt’s Lymphoma

Genetic Aberrations in Cancer:

What Can Go Wrong? Inherent or Induced Initial non-Random Genetic InstabilityProgressive Random Genetic InstabilityPoint Mutations and Failure to Repair DNATranslocations and Inversions of Chromosomal Material• To Where?• Next to What? Activated?, Repressed? Amplified?• Fused to What? Mis-regulated?Deletions• Of Entire Chromosomes• Of Parts of Chromosomes• Of Specific GenesAdditions• Aberrant Chromosome Replication: Trisomy & Aneuploidy• Amplifications and Repeats

GoWrong

Be sure to send in your name under “Send User Data” as usualThe picture below is showing one kind of genetic anomaly in cancer. What kind

of anomaly is it showing? What is happening here?

This is reciprocal _ _ _ _ _ _ _ _ _ _ _ _ _.

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Genetic Aberrations in Cancer:What Genes are Messed Up?

• What gene has been mutated, amplified, derepressed, activated, fused and mis-regulated, repeated?

• What is it product, and what does that product normally do?

CancerGenes or Oncogenes

• What gene has been inactivated, repressed, lost?• What is its product, and what does that product

normally do? Suppressor Genes or Anti-Oncogenes

WhoWrong

Chromosomal Deletions Associated with Specific Neoplasms

5q Familial Polyposis Coli, Colorectal Cx

11q Wilm's Kidney Tumor, Breast Cx, Rhabodmyosarcoma, Bladder Cx

13q Retinoblastoma, Osteogenic Sarcoma Small-cell Ling Cx, Ductal Breast Cx

17p Small-cell Lung Cx, Colorectal Cx, Breast Cx, Osteosarcoma

17q Neurofibroma

18q Colorectal Cx

From: JNCI, 83:92 (1991) GenLost1

Chromosomal Deletions Associated with Specific NeoplasmsWhat's Missing?

5q APC Familial Polyposis Coli, Colorectal Cx

11q WT1 Wilm's Kidney Tumor, Breast Cx,Rhabodmyosarcoma, Bladder Cx

13q Rb1 Retinoblastoma, Osteogenic SarcomaSmall-cell Ling Cx, Ductal Breast Cx

17p p53 Small-cell Lung Cx, Colorectal Cx,Breast Cx, Osteosarcoma

17q NF1 Neurofibroma

18q DCC Colorectal Cx

From: JNCI, 83:92 (1991) GenLost2

Chromosomal Deletions Associated with Specific NeoplasmsWhat do the missing proteins usually do in the cell?

5q APC Colon Crypt Stem Cell Migration and Maturation (Control of b-catenin degradation)

11q WT1 Transcription Factor

13q Rb1 Cell Cycle Entry

17p p53 Transcription Factor; Cell Survival

17q NF1 Deactivates RAS pathway

18q DCC DNA Repair?

From: JNCI, 83:92 (1991) GenLost2

The picture below shows a kind of genetic anomaly in cancer. What kind of anomaly is this? (for example: point mutation?, amplification?, or what?)

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Human Cancers with Strong Hereditary Predispositions in Sub-Groups of Patients

Retinoblastoma (AD)

Wilm's Tumor (AD)

Colon Carcinoma APC Polyposis Coli Hereditary Non-Polyposis

Breast Cancer Linked with Ovarian Not ovarian-linked

Multiple malignancies

Rb1 Gene Chromosome 13

WT1 Gene Chromosome 11

APC (5), DCC (18), p53 (17)nMLH1 (3), nMSH2 (2) (DNA repair gene products)

BRCA1 (17) ( involved in DNA repair

BRCA2 (13) see p. 510)

Li Fraumeni Syndrome (p53)

HeredCx

Figure 7.4b The Biology of Cancer (© Garland Science 2007)

Figure 7.4c The Biology of Cancer (© Garland Science 2007)

Figure 7.5a The Biology of Cancer (© Garland Science 2007)

The kind of genetic anomaly shown in the two examples below leads to high incidence rate of different kinds of cancer.

These genes being lost are a special kind of cancer genes called___ ___ ___ ___ ___ ___ ___ ___ ___ ____ genes.

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Clonal Origins of Human Cancers

Do cancers arise from a single cell being transformed, or from multiple cells being transformed?

Sometimes only one?Sometimes more than one?

at the same time?at different times?

How can we tell?

Figure 2.17 The Biology of Cancer (© Garland Science 2007) p. 40

Clonal Origins of Spontaneous Cancers Determination of ClonalityImmunoglobulin products of plasma cell leukemiasUnique T-Cell receptor genes in T-Cell leukemiasX-Linked Isoenzyme Markers

Results of Clonal AnalysisMonoclonal: CML, Lymphomas, Most carcinomasPolyclonal:• Some neoplasms linked to heredity• Spontaneous leukemias in inbred leukemic mice• High dose carcinogen-induced fibrosarcomas in mice• Virally-induced cancers

Clonal

Figure 2.18c The Biology of Cancer (© Garland Science 2007) p. 41

Monoclonality of Tumors from Women Heterozygous for X-linked Glucose-6-Phosphate Dehydrogenase

Figure 2.19a The Biology of Cancer (© Garland Science 2007) p. 42

Monoclonality of Plasma Cell Tumors

If Cancer is fundamentally a condition arising from Genetics of the host and of the Cancer Cells, what would we expect to see?

Groups at risk for specific cancersAssociation of genetic diseases with cancerFamilial cancersSpecific genetic anomalies and specific cancersSpecific cancer genesLoss of genes associated with cancersGain of genes associated with cancersAlterations in genes associated with cancersChromosomal effects and cancersInability to repair DNA associated with cancersDefective apoptosis involving genes controlling apoptosisDefective senescence involving genes controlling cell immortalization

Cancer-Associated Syndromes with Dominant Inheritance

• Retinoblastoma (bilateral). Controls E2F transcription factor and cell cycle entry)

• Wilm's Tumor (bilateral childhood kidney cancer)• Family Cancer Syndrome (p53)

• Adenomatous polyposis coli (APC gene controlling b-catenin degradation

• Neuroblastoma (N-Myc amplification and Telomerase activity? See p. 383)

• Gardner's Syndrome

• Multiple Endocrine Adenomatosis• Basal Cell Nevus (basal cell skin cancer)

(loss of “patched signaling receptor (PTCH)

Some Questions to Ask About Reciprocal Translocation:

1.There are paternally and maternally inherited chromosomes. Does it matter which of the two chromosomes is the translocation “donor” and which of the two is the translocation “recipient”?

2.Are there cases of translocations involving the X or y chromosomes? If so, is the incidence and/or pathobiology of the resulting cancer different in girls vs boys?