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Questions and Answers
What is the primary reason why cancer usually develops during the later decades of life?
What is the primary reason why cancer usually develops during the later decades of life?
What is the term used to describe the phenomenon where a single genetic mutation can lead to a higher likelihood of developing cancer?
What is the term used to describe the phenomenon where a single genetic mutation can lead to a higher likelihood of developing cancer?
What is the primary difference between hereditary and sporadic forms of cancer?
What is the primary difference between hereditary and sporadic forms of cancer?
What is the term used to describe the process by which a cell with a driver mutation becomes a cancer cell?
What is the term used to describe the process by which a cell with a driver mutation becomes a cancer cell?
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What is the primary mechanism by which environmental and lifestyle exposures contribute to cancer development?
What is the primary mechanism by which environmental and lifestyle exposures contribute to cancer development?
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What is the term used to describe the phenomenon where a family has multiple cases of cancer, which may or may not be due to a genetic cause?
What is the term used to describe the phenomenon where a family has multiple cases of cancer, which may or may not be due to a genetic cause?
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What is the characteristic of incomplete penetrance?
What is the characteristic of incomplete penetrance?
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What is the term for an individual who carries a mutation but has not yet developed the disease?
What is the term for an individual who carries a mutation but has not yet developed the disease?
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What is the site of a tumor suppressor gene revealed by?
What is the site of a tumor suppressor gene revealed by?
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What is the result of LOH by somatic recombination?
What is the result of LOH by somatic recombination?
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What is the purpose of PARP inhibition?
What is the purpose of PARP inhibition?
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What is the benefit of detecting genetic cancers?
What is the benefit of detecting genetic cancers?
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What is the characteristic of BRCA1 and BRCA2 negative cells?
What is the characteristic of BRCA1 and BRCA2 negative cells?
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What is the term for the joint action of multiple risk SNPs?
What is the term for the joint action of multiple risk SNPs?
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What is the purpose of genetic linkage analysis?
What is the purpose of genetic linkage analysis?
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What is the result of inhibiting PARP in cells with genetic instability?
What is the result of inhibiting PARP in cells with genetic instability?
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What is the result of knocking out BRCA in cells?
What is the result of knocking out BRCA in cells?
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Study Notes
Genetic of Cancer – Germline and Somatic Genetics
- Cancer development involves both germline and somatic mutations
- Hereditary diseases follow Mendelian inheritance patterns
- Acquired DNA changes occur during tumor development
The Multistep Nature of Cancer
- Time is a factor in cancer development
- Variants acquired during life can lead to cancer
- Environmental and lifestyle exposure can cause mutations
- Mutator phenotype leads to less protection during DNA replication, resulting in more mutations
- Counter measure: DNA damage repair
- Bad luck: starting life with a driver mutation
Driver Events
- Activated oncogenes
- Defective tumor suppressor genes
What We Have Learned So Far
- Cancer usually develops in later decades of life
- Multiple independent genetic events are needed for cancer to be detectable
- Somatic cell cancer development is a "tug-of-war" between mutagenesis and DNA repair mechanisms
- If born with a driver mutation, cancer usually develops earlier
Genetic Disease – Inheritance Patterns
- Many forms of cancer are common
- Clustering of cases in a family may be genetic or chance event
- Two categories: inherited cancer and family clustering (not defined by genes)
Late-Onset, Non-Penetrance & Phenocopies
- Penetrance: incomplete and age-dependent
- Obligate carrier: not defined, but should have the mutation
- Unaffected carrier: carries the mutation but has not developed the disease
- Phenocopy: has the disease but not the gene
Retinoblastoma
- First cancer for which genetic inheritance was elucidated
- 1 in ~20,000 newborns
- Manifests usually sporadic
- Bilateral cases are usually familial
The Two Hits
- Inactivate both alleles of the Rb gene
- Second (somatic) mutation is often loss of heterozygosity (LOH)
- LOH is not always identical to deletion
What We Have Learned
- Inheritance patterns of many common cancers are unclear
- Inherited cancers derive from a combination of germline and somatic mutations
- Two-hit inactivation of a tumor suppressor gene explains hereditary forms of cancer
- LOH reveals the site of a tumor suppressor gene
Inherited versus Familial – Common Cancers
- Genetic linkage analysis can identify disease genes
- Study the right families with candidate gene sequencing
- Genetic heterogeneity is a rule in common cancers
Genetic Contribution to Disease Risk
- Two hypotheses
- Genetic architecture of breast cancer
- Risk SNPs are common in the population and have low risk, but joint action causes higher risk
BRCA1 Germline Carrier
- Breast cancer risk in late age determines treatment options
Genetic Instability
- MEFs show replicative failure
- Increased expression of p53 and p21
- Increased sensitivity to mitomycin C
- Intact checkpoint responses
- Normal induction of apoptosis
PARP-Inhibitors
- BRCA1 and BRCA2 are candidates for PARP inhibitors
- PARP is an enzyme involved in base excision repair
- In cells that are BRCA1 and BRCA2 negative, the repair is no longer intact, leading to double strand breaks and cell death
Breast Cancer Characteristics
- Often occurs in premenopausal women
- Typically PR/ER-negative and HER2-negative
- High-grade breast cancer has a poor prognosis
Genetic Instability in Breast Cancer
- Knockout of BRCA genes leads to:
- Replicative failure
- Increased expression of p53 and p21
- Increased sensitivity to mitomycin C
- Intact checkpoint responses
- Normal induction of apoptosis
PARP-Inhibitors
- Inhibiting PARP leads to:
- Increased genetic instability
- Cell death
Genetic Basis of Familial Cancers
- All common cancers have familial forms, but their proportions are often small
- The genetic basis of familial common cancers is complex, involving:
- Multiple genes (monogenic, locus heterogeneity)
- Polygenic inheritance
- Genetic causes can lead to:
- High risk, moderate or low risk
- Specific disease-subtypes with specific treatments (precision medicine)
- Detecting genetic cancers can help prevent future cancers
Breast Cancer Characteristics
- Breast cancer is often premenopausal, PR/ER-negative, HER2-negative, and high-grade with a poor prognosis.
Genetic Instability and BRCA
- BRCA knockout leads to replicative failure, increased expression of p53 and p21, increased sensitivity to mitomycin C, intact checkpoint responses, and normal induction of apoptosis.
- PARP inhibitors lead to increased genetic instability, resulting in cell death.
Genetics of Cancer
- All common cancers have familial forms, but their proportions are often small.
- The genetic basis of familial common cancers is complex, involving multiple genes (monogenic, locus heterogeneity) and polygenic inheritance.
- Some genes cause high risk, others moderate or low risk, and genetic causes might give rise to specific disease-subtypes with specific treatments (precision medicine).
- Detecting genetic cancers will help prevent future cancers.
Multistep Nature of Cancer
- Cancer develops over time due to acquired variants and environmental/lifestyle exposure, leading to mutations.
- Mutator phenotype leads to less protected DNA replication, resulting in more mutations.
- Countermeasures include DNA damage repair.
Driver Events
- Driver events include activated oncogenes and defective tumor suppressor genes.
What We Have Learned
- Cancer usually develops during the later decades of life.
- Genetically, multiple independent events are needed before a cancer is detectable in an individual.
- In somatic cells, cancer development is a "tug-of-war" between mutagenesis and DNA repair mechanisms.
- If you are born with an event, cancer usually develops earlier than its "sporadic" counterpart.
Genetic Disease – Inheritance Patterns
- Many forms of cancer are common.
- Clustering of cases in a family can be due to genetics or chance.
- Age of onset is an important factor to consider.
Inherited Cancer
- Inherited cancer involves germline mutations.
- Family clustering is not defined by genes.
Late-Onset, Non-Penetrance, and Phenocopies
- Penetrance is incomplete and age-dependent.
- Obligate carriers have the mutation but may not develop the disease.
- Unaffected carriers carry the mutation but have not developed the disease.
- Phenocopies have the disease but not the gene.
Retinoblastoma
- Retinoblastoma is the first cancer for which genetic inheritance was elucidated.
- It affects 1 in 20,000 newborns and usually manifests sporadically.
- Bilateral cases are usually familial.
Two-Hit Inactivation of Tumor Suppressor Gene
- The two hits inactivate both alleles of the Rb-gene.
- The second (somatic) mutation is often loss of heterozygosity (LOH).
Linkage Analysis
- Genetic linkage analysis can identify disease genes.
- Study the right families – candidate gene sequencing.
Genetic Heterogeneity
- Genetic heterogeneity is a rule, rather than an exception, for common cancers.
Breast Cancer Risk
- Breast cancer risk is associated with 5 major breast cancer genes.
- Genetic contribution to disease risk involves two hypotheses.
Genetic Architecture of Breast Cancer
- Risk SNPs are common in the population and have a low risk, but the joint action of them causes a higher risk.
BRCA1 Germline Carrier
- Breast cancer in late age is determined by treatment options.
PARP Inhibitors
- BRCA1 and BRCA2 are candidates for PARP inhibitors.
- PARP is an enzyme involved in base excision repair.
- In cells that are BRCA1 and BRCA2 negative, the repair is no longer intact, leading to double-strand breaks and cell death.
Breast Cancer Characteristics
- Often occurs in premenopausal women
- Typically PR/ER-negative and HER2-negative
- High-grade breast cancer has a poor prognosis
Genetic Instability in Breast Cancer
- Knockout of BRCA genes leads to:
- Replicative failure
- Increased expression of p53 and p21
- Increased sensitivity to mitomycin C
- Intact checkpoint responses
- Normal induction of apoptosis
PARP-Inhibitors
- Inhibiting PARP leads to:
- Increased genetic instability
- Cell death
Genetic Basis of Familial Cancers
- All common cancers have familial forms, but their proportions are often small
- The genetic basis of familial common cancers is complex, involving:
- Multiple genes (monogenic, locus heterogeneity)
- Polygenic inheritance
- Genetic causes can lead to:
- High risk, moderate or low risk
- Specific disease-subtypes with specific treatments (precision medicine)
- Detecting genetic cancers can help prevent future cancers
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Description
Explore the genetic aspects of cancer, including hereditary diseases, mendelian inheritance patterns, and acquired DNA changes during tumor development. Learn about the multistep nature of cancer and the role of DNA damage repair.
