Cancer Genetics

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Cancer Genetics
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Cancer

• Unregulated clonal growth
• Programmed cell death

Apoptosis
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Tumors Are Clonal Expansions
Normal
Tumor
ASCO
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Benign vs. Malignant Tumors

• Adapted from Steve Gruber, MD

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Initiation and Promotion

• Initiation is a process within one or more cells
  as a result of the action of a chemical,
  physical, or biologic agent that alters in an
  irreversible manner the DNA of the cell ,
  resulting in a cell having the potential of
  developing into a clone of neoplastic cells.
• Promotion is the process by which initiated cells
  within a tissue develop focal proliferations, one
  or more of which may act as precursors for
  subsequent steps in the carcinogenic process.
• Adapted from Steve Gruber, MD

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Cancer Genetics

• Tumor Suppressor Genes
• Proto-oncogenes and oncogenes
• DNA damage response genes, e.g. mismatch repair
  genes
• Chromosomal Translocations
• Carcinogens that interact directly with the genome

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Some Dominantly Inherited Cancer Syndromes
Syndrome
Associated Gene
RB1 TP53 APC MLH1, MSH2, MSH6, PMS1,
PMS2 WT1 BRCA1, BRCA2 VHL PTEN
Familial retinoblastoma Li-Fraumeni Familial
adenomatous polyposis Hereditary nonpolyposis
colorectal cancer Wilms tumor Breast and ovarian
cancer Von Hippel-Lindau Cowden
ASCO
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Some Recessively Inherited Cancer Syndromes
Syndrome Ataxia telangiectasia Bloom
syndrome Xeroderma pigmentosum Fanconi anemia
Primary Tumor Lymphoma Solid tumors Skin
cancer AML
Associated Gene(s) ATM BLM XPB, XPD, XPA FACC,
FACA
ASCO
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Tumor Suppressor Genes

• Tumor suppressor gene products inhibit cell
  proliferation.
• Mutant versions in cancer cells have lost their
  function.
• Both alleles of a tumor suppressor gene must be
  inactivated to change the behavior of the cell.
• (definition from Strachan and Read)
• Cellular Brakes

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Tumor Suppressor Genes
Normal genes (prevent cancer)
1st mutation (susceptible carrier)
2nd mutation or loss (leads to cancer)
ASCO
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The Two-Hit Hypothesis
First hit
Second hit (tumor)
First hit in germline of child
ASCO
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• Knudsons Two-hit Hypothesis
• Knudson, Alfred G. Mutation and Cancer
  Statistical Study of Retinoblastoma. 1971 PNAS
  688 820-823

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Mechanisms Leading to Loss of Heterozygosity
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Tumor Suppressor Genes

• Disease examples
• Retinoblastoma, pRB (nuclear phosphoprotein)
• Wilms tumor, WT-1
• Li-Fraumeni syndrome, p53 (transcription factor)
• Colon carcinoma, DCC
• Breast cancer, BRCA1

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Retinoblastoma Rb gene on 13q14

• 90-95 of children with one inherited mutant
  allele of Rb develop retinal tumors
• Tumor cells contain a second mutation.
• Function of Rb protein product represses entry
  into the cell cycle
• Sporadic cancers loss of both alleles in a
  cingle cell, rare event (1x10-9/gen).
• Children get tumors in one eye
• Adult tumors small cell carcinomas, bladder
  cancer

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Features of Retinoblastoma

• 1 in 20,000 children
• Most common eye tumor in children
• Occurs in heritable and non-heritable forms
• Identifying at-risk infants substantially reduces
  morbidity and mortality

ASCO
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Genetic Features of Heritable Retinoblastoma

• Autosomal dominant transmission
• RB1 gene on chr 13 (first tumor suppressor gene
  discovered)
• Penetrance gt90
• Prototype for Knudsons two-hit hypothesis

ASCO
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Knudsons Two-Hit Model for Retinoblastoma
Normal 2 intact copies
Predisposed 1 intact copy 1 mutation
Affected Loss of both copies
ASCO
Modified from Time, Oct. 27, 1986
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Nonheritable vs Heritable Retinoblastoma
Feature Tumor Family history Average age at
dx Increased risk of second primaries
Nonheritable Unilateral None 2 years No
Heritable Usually bilateral 20 of cases lt1
year Osteosarcoma, other sarcomas, melanoma,
others
ASCO
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Wilms Tumor

• Childhood kidney cancer arising from embryonic
  cells
• Affects one child in 10,000
• Occurs in heritable and nonheritable forms
• Multiple genes involved
• True familial Wilms tumor rarely observed

Sporadic, unilateral gt90
Bilateral (presumed heritable) 57
Familial 1
ASCO
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Genetic Heterogeneity in Wilms Tumor Syndromes
Locus WT1 gene at 11p13 11p13 region 11p15
region Xq26 17q12-21 19q13
Syndrome Denys-Drash WAGR Beckwith-Wiedemann Simp
son-Golabi-Behmel Familial Wilms Familial Wilms
ASCO
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p53

• Functions prevents G1 or slow S (replication) to
  allow and facilitate DNA repair. Also involved
  in apoptosis induction.
• Transcription factor, target genes include
• p21 inhibits replication
• BAX induces apoptosis

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p53 mutations

• Dominant negative effect in some cases (missense
  mutations, interaction with MDM2, viral oncogenes
  which completely inactivate)
• Li-Fraumeni syndrome with one inherited mutant
  allele Susceptibility to a large variety of
  cancers, especially breast cancer

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p53
Eric R. Fearon Human Cancer Syndromes Clues to
the Origin and Nature of Cancer Science 1997
November 7 278 1043-1050
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Li-Fraumeni Syndrome

• Rare autosomal dominant syndrome
• Early onset of bone and soft tissue sarcomas,
  breast cancer, brain cancer, leukemia,
  adrenocortical carcinoma, and other tumors
• Multiple primary tumors
• TP53 germline mutations associated with most
  cases
• Testing in children and adults raises important
  ethical and psychosocial issues

ASCO
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Li-Fraumeni Family
Noncarrier
Bilateral breast, 40
TP53-mutation carrier
Leukemia, 33
Breast, 40 Osteosarcoma, 42
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Affected with cancer
Breast, 35
Brain tumor, 32
Soft tissue sarcoma, 7
Leukemia, 6
ASCO
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Tumor Sites in Families with TP53 Germline
Mutations
Breast
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Bone
12.6
Brain
12
Soft tissue
11.6
GI
7
Gynecol
5.3
Hematol
4.2
Adrenal
3.6
Other
14.1
0
5
10
15
20
25
30
of all tumors
ASCO
Kleihues P et al. Am J Pathol 1501, 1997
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Protooncogenes and Oncogenes

• Proto-oncogene A gene that normally functions to
  control cell division and may become a cancer
  gene (oncogene) by mutation
• Oncogene A gene that induces or continues
  uncontrolled cell proliferation
• act in an autosomal dominant fashion
• gas pedal

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Oncogenes
1 mutation sufficient for role in cancer
development
ASCO
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Oncogene Discovery

• Discovered in 1911 by Peyton Rous
• Observed that cancer can be transmitted
• Induced tumors in health chickens by injecting a
  preparation of cell free filtered extract from
  chicken tumors
• Later, it was discovered that the causative agent
  is the rous sarcoma virus (RSV) - a retrovirus

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Oncogene Activation

• Altered gene function
• Base substitutions
• Amplification
• Altered regulation
• Viral insertion

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Classes of Oncogenes

• Growth factors
• sis
• Growth factor receptors
• erbB, fms,trk
• Intracellular transducers
• src, abl, raf, gsp, ras
• Nuclear transcription factors
• jun, fos, myc, erbA

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Chromosomal Rearrangements

• Often seen in leukemias
• Example Chronic myelogenous leukemia caused by
  chromosomal translocation t(922), called the
  Philadelphia chromosome.

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DNA Damage Response

• Nucleotide Excision Repair pathway
• Xeroderma pigmentosa
• Mismatch Repair genes
• e.g. Hereditary NonPolyposis Colorectal Cancer
  (HNPCC)

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DNA Mismatch Repair
ASCO
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Cancer is a complex group of disorders

• Not all types of cancer develop in the same way,
  i.e. via the same pathway
• Not all cancers are single gene diseases most
  are complex diseases, with interactions between
  genes, and between genes and environmental
  exposures.
• Genetic heterogeneity mutations in different
  genes may cause same disease
• Other ways to get cancer other than TS genes and
  oncogenes include mmr genes, adducts, radiation,
  infection (EBV, HPV)

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Example of a complex disease Colorectal Cancer

• Genetic heterogeneity
• Familial vs. sporadic
• Multiple steps in carcinogenesis
• Gene X Environment Interactions

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Risk Factors for Colorectal Cancer (CRC)

• Aging
• Personal history of CRC or adenomas
• High-fat, low-fiber diet
• Inflammatory bowel disease
• Family history of CRC
• Hereditary colon cancer syndromes

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Risk of Colorectal Cancer (CRC)
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Genetics of FAP

• Autosomal dominant inheritance
• Caused by mutations in APC tumor suppressor gene
  on chromosome 5q
• Up to 30 of patients have de novo germline
  mutations
• Most families have unique mutations
• Most mutations are protein truncating
• Genotype/phenotype relationships emerging

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FAP Age and Development of Adenomas and CRC
FAP
Adenomas
CRC
of patients with neoplasia
General population
20
40
60
80
Age
ASCO
Bussey HJR. Familial Polyposis Coli, 1975
Petersen GM et al. Gastro 1001658, 1991
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FAP Family With APC Mutation
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FAP Key Points

• CRC risk is 100 in untreated FAP patients
• Genetic testing identifies most APC mutation
  carriers
• Endoscopic surveillance and prophylactic
  colectomy can improve survival in at-risk
  patients
• Noncarriers can be spared anxiety and the need
  for increased surveillance

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Genetic Features of HNPCC

• Autosomal dominant inheritance
• Penetrance 80
• Genes belong to DNA mismatch repair (MMR) family
• Genetic heterogeneity (MLH1, MSH2, MSH6, PMS1,
  PMS2)

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Genetic Heterogeneity in HNPCC
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Cancer Risks in HNPCC
with cancer
ASCO
Aarnio M et al. Int J Cancer 64430, 1995
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HNPCC Pedigree
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Mismatch Repair Failure Leads to Microsatellite
Instability
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HNPCC Key Points

• Genetic testing in HNPCC can identify mutation
  carriers
• Low test yield and genetic heterogeneity limit
  clinical utility
• Colonoscopic surveillance can improve survival in
  at-risk individuals
• Benefits of surveillance for most extracolonic
  cancers are unproven
• Noncarriers can be spared anxiety and the need
  for increased surveillance

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Public Health Significance

• Mutation Detection
• Gene X Environment Interactions
• Policy Development
• Screening Programs