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Cancer Genetics I: Understanding the Role of Genetic Alterations in Cancer, Slides of Genetics

A lecture script from a cancer genetics course, focusing on the various types of genetic alterations that contribute to the development of cancer. The script covers subtle alterations, chromosome number changes, chromosomal translocations, amplifications, and exogenous sequences. It also discusses the evidence that mutations cause cancer and the multistage model of carcinogenesis. The lecture also introduces oncogenes, tumor suppressor genes, and DNA repair genes.

What you will learn

  • How do oncogenes and tumor suppressor genes contribute to cancer development?
  • How do chromosomal translocations contribute to cancer development?
  • What are the different types of genetic alterations that contribute to cancer?
  • What are some examples of oncogenes and tumor suppressor genes?
  • What is the multistage model of carcinogenesis?

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2020/2021

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Lecture 21
Cancer Genetics I
Stephen B. Gruber, MD, PhD
November 18, 2002
“Cancer is, in essence, a genetic disease. Although
cancer is complex, and environmental and other
nongenetic factors clearly play a role in many
stages of the neoplastic process, the tremendous
progress made in understanding tumorigenesis in
large part is owing to the discovery of the genes,
that when mutated, lead to cancer.”
Bert Vogelstein (1988)
NEJM 1988; 319:525-532.
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Lecture 21

Cancer Genetics I

Stephen B. Gruber, MD, PhD

November 18, 2002

“Cancer is, in essence, a genetic disease. Although

cancer is complex, and environmental and other

nongenetic factors clearly play a role in many

stages of the neoplastic process, the tremendous

progress made in understanding tumorigenesis in

large part is owing to the discovery of the genes,

that when mutated, lead to cancer.”

Bert Vogelstein (1988) NEJM 1988; 319:525-532.

Cancer Genetics: I

Lecture Goals

  • Types of Genetic Alterations in Cancer
  • Evidence that Mutations Cause Cancer
  • Multistage Model of Carcinogenesis
  • Oncogenes, Tumor Suppressor Genes,

DNA Repair Genes

Cancer Arises From Gene Mutations

Germline mutations Somatic mutations

Somatic mutation (eg, breast)

Mutation in egg or sperm

All cells affected in offspring

Parent Child

l Present in egg or sperm l Are heritable l Cause cancer family syndromes

l Occur in nongermline tissues l Are nonheritable

THE BIG RED DOG RAN OUT.

THE BIG RAD DOG RAN OUT.

THE BIG RED.

THE BRE DDO GRA.

THE BIG RED ZDO GRA.

Point Mutations

Normal

Missense Nonsense Frameshift (deletion)

Frameshift (insertion)

Point mutation: a change in a single base pair

Chromosome Number Changes

  • Aneuploidy
    • somatic losses or gains
  • Whole chromosome losses often are associated with a duplication of the remaining chromosome.
  • LOH
    • loss of heterozygosity

Chromosome Translocations

  • Random translocations
    • breast, colon, prostate (common epithelial tumors)
  • Non-random translocations
    • leukemia, lymphoma

FISH

  • Certain chromosomal translocations are easily detected by FISH
  • Fluorescent in Situ Hybridization - probes on different chromosomes fluoresce

Review: Types of Genetic

Alterations in Cancer

  • Subtle alterations
  • Chromosome number changes
  • Chromosomal translocation
  • Amplifications
  • Exogenous sequences

Each type represents one of the mutations a cell can accumulate during its progression to malignancy

Evidence that

Mutations Cause Cancer

  • Most carcinogens are mutagens
    • Not all mutagens are human carcinogens
  • Some cancers segregate in families
    • Genes cloned, mutations lead to cancer in animals
  • Oncogenes and Tumor Suppressor Genes
    • found in human tumors, enhance growth
  • Chromosomal instability
  • Defects in DNA repair increase prob of cancer
  • Malignant tumors are clonal

Multi-Step Carcinogenesis

(eg, Colon Cancer)

Normal epithelium

Hyper- proliferative epithelium

Early adenoma

Late adenoma Carcinoma^ Metastasis

Loss of APC

Activation of K-ras

Loss of 18q

Loss of TP

Other alterations

Adapted from Fearon ER. Cell 61:759, 1990

Inter- mediate adenoma

ASCO

Tumors Are Clonal Expansions

Normal Tumor

Oncogenes, Tumor Suppressor

Genes, and DNA Repair Genes

  • Oncogenes
  • Tumor Suppressor Genes
  • Retinoblastoma and the “2-hit Hypothesis”
  • DNA Repair Genes

Oncogenes

Normal genes (regulate cell growth)

1st mutation (leads to accelerated cell division)

1 mutation sufficient for role in cancer development

Oncogenes Activated in Non-viral

Human Cancers

  • Gene fusions / translocations
  • Point mutations

Effects of Oncogenes are Dominant

  • Positive effect on growth
    • even in the presence of a normal (inactivated) version of the gene
  • Example
    • Oncogenes derived from growth factor receptors confer the ability to bypass the growth factor requirement…independent growth.

Tumor Suppressor Genes

Key Attributes

  • Familial Cancer Syndromes
  • Inactivation in Common Human Cancers
    • Loss of Heterozygosity
  • “Recessive” at a cellular level
  • Two-hit hypothesis

Tumor Suppressor Genes

Familial Cancer Syndromes

  • Most familial cancer syndromes are related to

Tumor Suppressor Genes

  • Retinoblastoma, FAP, Li-Fraumeni, Familial Breast- Ovarian, VHL, Melanoma, Tuberous Sclerosis...
  • Only 3 known syndromes related to Oncogenes
  • RET, MET, CDK
  • Few DNA repair syndromes
  • XP, AT, Bloom, Fanconi, Werner, HNPCC

Tumor Suppressor Genes

  • Loss of Heterozygosity (LOH)
  • 2 copies of each gene
  • 1 is lost or inactived
  • Only 1 remains…
    • no longer heterozygous
    • one copy of a defective gene, same as no gene

Mechanisms Leading to

Loss of Heterozygosity

Normal allele Mutant allele

Chromosome loss

Deletion Unbalanced translocation

Loss and reduplication

Mitotic recombination

Point mutation

Loss of normal allele

Features of Retinoblastoma

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

Genetic Features of

Heritable Retinoblastoma

  • Autosomal dominant transmission
  • RB1 gene on chr 13 (first tumor suppressor gene discovered)
  • Penetrance >90%
  • Prototype for Knudson’s “two-hit” hypothesis

Bilateral RB, 1 yr d. 78

Bilateral RB, 1 yr osteosarcoma, 16

Bilateral RB, 6 mo

Bilateral RB, 1 mo

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 <1 year Osteosarcoma, other sarcomas, melanoma, others

Presentations of Retinoblastoma

Nonheritable ~60%

Heritable ~40%

All Retinoblastoma

Heritable Retinoblastoma

Bilateral ~80% Trilateral (rare)

Unilateral ~20%

The RB1 Gene

  • Large gene spanning 27 exons, with more

than 100 known mutations

  • Gene encodes Rb protein which is involved in

cell cycle regulation

1 2 3 4 5 6 7 8 9 10 12 14 17 18 19 20 21 22 23 25 27

Nonsense Missense Splice Site Adapted from Sellers W et al. J Clin Onc 15:3301, 1997

Long-Term Survival of Children

With Heritable Retinoblastoma

35 30 25 20 15 10 5 0

Mortality (%)

Radiotherapy

No Radiotherapy

1 10 20 30 40 Years after diagnosis Eng C et al. J Natl Can Instit 85:1121, 1993

DNA Repair Genes

  • DNA repair genes
    • targeted by loss of function mutations
  • Differ from tumor suppressor genes:
    • TSG directly involved in growth inhibition or differentiation
    • DNA repair genes are indirectly involved in growth inhibition or differentiation

DNA Repair Genes

  • Inactivation of DNA repair genes
    • increased rate of mutation in other cellular genes
    • proto-oncogenes
    • tumor suppressor genes
  • Accumulation of mutations in the other

cellular genes is rate limiting…

  • tumor progression is accelerated