Genetics Exam Iii: Cancer Genetics

Front 1

What is a cancer?

Back 1

Group of diseases that share similar features:

1. Uncontrolled cell growth
2. Invasive ability into surrounding tissues

Cancer does not differentiate and instead die.

Front 2

Is cancer genetic?

Back 2

Yes, but this does NOT mean that it is hereditary. When we say it is genetic diseas we mean it is due to mutations that occur in our genes.

Front 3

Cause of cancer?

Back 3

Mutations that are typically occuring in a single cell

1. Spontaneous errors during DNA replication
2. Induced errors when we have enviornment agents (carcinogens) which induce damage to our DNA such as radiation.

Front 4

What are the 2 main categories of cancer genes: mutations will lead to development of cancer.

Back 4

1. Oncogenes: gain of function
2. Tumor suppressor genes: loss of function

Front 5

What is the multi-hit concept of cancer initiation?

Back 5

Cancer does not occur after a single genetic change. It is when we cross a certain threshold of mutations do we actually have cancer developing.

Deregulation of cell increases-->cell fails to differentialte-->multiples w/o restraint.

Normal cell-->tumor/precancerous cell-->cancer

Front 6

Oncogenes

Back 6

Generally cause sporadic cancer, not usually hereditary.

Front 7

Proto-oncogene

Back 7

Normal state with no mutations occuring, regulates normal cell growth.
1. growth factors
2. growth factor receptors
3. signal transduction pathways (protein kinases)
4. transcription factors

Front 8

Mutations in Proto-oncogenes cause?

Back 8

Become active oncogenes which have the potential to contribute to cancer.

Front 9

What is the structure/function of proto-oncogene?

Back 9

And INCREASED normal expression of proto-oncogene which stimulates cell division and proliferation causes cancer

Front 10

Oncogenes act as dominant, heterozyous, or recessive?

Back 10

Dominant gene

It takes only one copy of an oncogene (a mutated proto-oncogene)is sufficient to cause phenotype-a heterozygote

Front 11

RET proto-oncogene

Back 11

Transmembrane tyrosine kinase receptor.

Normally induces signal transduction when bount to ligand.

Front 12

RET oncogene

Back 12

-Usually a point mutation
-activates receptor even in absence of ligand

Front 13

Disease as a result of RET oncogene?

Back 13

Multiple endocrine neoplasia (MEN2)

Autosomal dominant inheritance of RET oncogene.

Front 14

Medullary thyroid carcinoma

Back 14

95-100% risk of development if have MEN2

-Typically develops by childhood-early adulthood
-Age 5-25 for MEN2A
-Infancy in MEN2B

Front 15

What are the recommendations for Medullary thyroid carcinoma?

Back 15

Prophylactic thyroidectomy (removal of thyroid overwise we expect thyroid cancer to develop)

-By age 1 for MEN2B
-By age 5 for MEN2A

Front 16

Other features of MEN2

Back 16

1. Pheochromocytomas, adrenal gland tumors that are typically benign
2. parathyroid adenoma/hyperplasia, can become cancerous
3. MEN2B: mucosal neuromas of the lips and tongue, enlarged lips, marfanoid body (long)

Front 17

Sporadic chrom mutations occur in many cells, are they cancerous?

Back 17

Sporadic chrom mutations occur in many cells, but majority are benign

Front 18

What happens if a chromosomal rearrangement affects a proto-oncogene or tumor-suppressor gene?

Back 18

It can lead to cancer

These are typically sporadic cancers, not inherited.

Front 19

If we do a blood test on someone are we going to see cancer?

Back 19

No, they are only present in the cancer cells and not inherited.

Front 20

The Philadelphia chromosome

Back 20

translocation involving chrom. 9 & 22

Moves the proto-oncogene ABL from its normal position on chrom 9 to a place next to the BCR gene on chrom. 22

This alters function of the ABL gene-->increase tyrosine kinase activity-->increasing signal transduction in cell-->increasing cell proliferation

Front 21

What chromosome is present in majority of patients with CML (chronic myelogenous leukemia)

Back 21

The Philadelphia Chromosome.

Front 22

Tumor-suppressor genes

Back 22

Involved in the hereditary forms of all cancer, generally inherited.

Front 23

What are the normal function of tumor-suppressor genes?

Back 23

1. Control cell cycle growth & replication
2. DNA repair and maintaining genomic integrity

Front 24

Mutation in the tumor-suppressor gene leads to?

Back 24

Loss of function which leads to cancer INDIRECTLY by allowing other mutations to accumulate.

Front 25

How is the tumor-suppressor gene inherited?

Back 25

Autosomal dominant so heterozygotes usually develop disease.

Acts recessive at the cellular level, cancer does not develop until loss of function of both alleles

Front 26

What is Knudson's two-hit hypothesis? The two hit model of carcinogenesis?

Back 26

1. Sporadic cancer
2. Hereditary cancer

Front 27

Sporadic cancer

Back 27

1. Individual starts with 2 normal copies of any given tumor-suppressor gene
2. 1st hit/loss of one normal allel in one copy
3. 2nd hit/loss of 2nd allel and inactivates 2nd copy
4. Cancer!

Front 28

Hereditary cancer

Back 28

1. One inherited mutation (born with 1st hit in all cell bodies)
2. It only takes one acquired mutation or 2nd loss
3. Cancer!

Front 29

The 2nd hit in hereditary cancer

Back 29

Is a random event

Can see delayed age of onset or reduced penetrance.

Front 30

What are some inactivation methods of the second allele in Hereditary cancer?

Back 30

1. Point mutation or deletion (seen in inherited)
2. Chromosome rearrangement
3. Mitotic non-disjunction: loss of entire chrom
4. Mitotic recombination: loss of normal gene
5. gene amplification: over-expression of other proteins can inactivate tumor-suppressor gene.

Front 31

SporadicF Retinoblastoma

Back 31

60% of retinoblastoma

Rare to have two aquired mutations occur in the same cell

Front 32

Hereditary Retinoblastoma

Back 32

40% of retinoblastoma

High # of predisposed cells (1-2 million retinoblasts)

Front 33

Features of hereditary cancers

Back 33

1. Increased risk
2. Earlier age of onset
3. Bilateral/multifocal presentation: inc. chance of 2nd hit occuring
4. Multiple family members with related cancers
5. Rare or unsual cancers

Front 34

p53 Gene

Back 34

encodes a transcription factor that normally responds to DNA damage

halts the cell in G1 phase of the cell cycle allowing for DNA repair

If damage severe, it induces programmed cell death

Front 35

What happens if we have a mutation in the p53 gene?

Back 35

cells can escape DNA repair/death bc it won't stop the cell cycle to allow this to happen

Front 36

What is the most common mutated gene in human tumors?

Back 36

p53 gene

50% of all human solid tumors

Inherited p53 are rare

Front 37

Li-Fraumeni syndrome LFS

Back 37

-Inheritance of p53 mutations
-characterized by many tumors: breast, colon carcinomas, brain tumors, leukemias, soft-tissue sarcomas, osteosarcomas, leukemias, and adrenal corticoid tumors

-Person can have multiple tumor types w/ early age of onset

-risk 50% by age 40, 85-90% lifetime

Front 38

Classic LFS is defined by the following criteria

Back 38

1. A proband with a sarcoma diagnosed before 45 AND
2. A first-degree relative with any cancer under 45 AND
3. A first-or second-degree relative with any cancer under 45 or a sarcoma at any age