Genetics of the Cancer Celland of the

Tumor-Bearing Host:Oncogenes and

Tumor Suppressor GenesFolder Title: CxGenes(NoTP)

Updated: April 9, 2015

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)

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

Invasion and metastasis in Cancer (Inv&Mets)

Metastasis Models (MetModels)

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 Promoting or protecting the cancer Interfering with therapy approaches

Genetics of the Cell that Gets TransformedPredisposing Factors in the Host

Genetics of the Cancer Cell

After Transformation - During Progression

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

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

(DCC = gene deleted in colon carcinoma)

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)

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

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

*Short stature, sun-sensitive skin (Fragile Chromosomes)

• 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

** Arthritis of spine; spinal disk fusion

• Sibs of Children with Leukemia 1 in 720• Unrelated U.S. Caucasian Children to 15 Years 1

in 2,880

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

Relationship Between Specific Genetic 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 Carcinoma

Leukemia & Intestinal Cancers

Skin Cancers (Squamous cell carcinoma and Malignant Melanoma

Ocular Neoplasms & Sarcoma

Colon Carcinoma

Colon Carcinoma, Pancreatic, Thyroid, Adrenal, Bone, & Connective Tissue Neoplasms

Lymphoma, Leukemia, Sarcoma

AR = Autosomal RecessiveRed - Autosomal Dominant

Congenital Abnormalities Associated with Increased Cancer Incidence(from Online Medical Dictionary)

Bloom’s Syndrome: Congenital telangiectatic erythema (rash), primarily butterfly distribution, on face, hands, forearms, with sensitivity to skin lesions and dwarfism with normal body proportions except for narrow face and altered skull. Chromosomes are excessively fragile. (Autosomal recessive inheritance.)

Fanconi’s Anemia: Aplastic anemia with increased risk of leukemia(DNA repair defect)

Gardner’s Syndrome: Multiple polyposis of the colon predisposing to colon carcinoma. Also multiple tumors including osteomas of the skull, epidermoid cysts, fibromas. (Autosomal dominant inheritance.)APC Gene Defect (Adenomatous polyposis coli gene)

Li-Fraumeni Syndrome: Incrased risk of early onset multiple cancers(p53 Suppressor gene defect)

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 Genetic Anomalies Generating Cancers:

Oncogenes and Suppressor Genes

Specific Chromosomal Abnormalities Associated with Specific Cancers

Chronic Myelogenous Leukemia

Human Breast Cancer

Burkitt's Lymphoma

Myelodysplasia and Acute Myelogenous Leukemia

Meningioma

Neuroblastoma

Reciprocal Translocation, 9&22

Her2Neu Amplification

Reciprocal Translocation, 8&14

Trisomy 8

Monosomy 22

N-Myc Amplification

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

Amplification of HER2/Neu Gene Expression in Breast Cancer:

Relationship to Prognosis

Her2/Neu = growth factor receptor associated with cancer when mis-expressed.Therefore called a cellular onocogene.

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

Amplification of N-Myc Gene in Neuroblastoma: Relationship to

Survival

From Myc Cancer Gene Web-site:

The MYC cancer gene contains instructions for the production of the c-Myc protein. The c-Myc protein is now known as a transcription factor or a regulator of other genes. It is a protein that binds DNA at specific sites and instructs genes whether or not they should be transcribed into messages for cells to make additional or other new proteins.

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

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

This is a Turning Point Slide:It is inserted here to allow you to ask me

questions or to make observations

Are you here?

Any questions or other statements?

Chromosomal Anomalies and Expression of Oncogenes

9 to 22 reciprocal translocation (Switching pieces)Miss-expression of c-abl oncogene

8 to 14 reciprocal translocation

Reciprocal Translocation in Chronic Myelogenous Leukemia

The Philadelphia Chromosome

c-Sis and c-abl are endogenous cellular oncogenes like c-myc

Chromosomal Translocations:Oncogenes as Fused Partial Normal Genes

The Philadelphia Chromosome

c-sis and c-abl are endogenous cellular oncogenes

c-sis encodes platelet-derived growth factor beta chains

c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division

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

c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division.

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

Activation of c-myc oncogene from Chromosome 8by translocation to Chromosome 14

The effect of immune-activationby exposure to infectious disease: Epstein-Barr Virus

Myc overexpression or mis-expression in cancers, affects the cell cycle, apoptosis, differentiation, cellular metabolism and genomic stability. Myc proteins are potent transcription factors involved in 80% of human cancers .

See slides 16 and 17

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

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?

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

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

Chromosomal Deletions Associated with Specific Neoplasms:Cancer Suppressor Genes

5q Familial Polyposis Coli, Colorectal Cx

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

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

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

17q Neurofibroma

18q Colorectal Cx

From: JNCI, 83:92 (1991)

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 Lung 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)

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)

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)

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)

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

A-FormExpressed

A-FormExpressed

B-FormExpressed

B-FormExpressed

Tissue Cells are Mosaic for Forms A or B of G6PDH(Glucose-6-phosphate Dehydrogenase).Express one or the other but not both

Distinct different enzyme isoforms coded on the X-chromosomes.e.g. Glucose-6-phosphate dehydrogenase. Only one X-chromosome expressed in each cell female cell

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

For Monoclonal Tumors get one form or the other of G6PDH, Not both!

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)