Cancer Genetics: Somatic vs. Germline Mutations

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Questions and Answers

What type of mutations are passed through generations via mutated gametes?

Gemline mutations (correct)

Non-reproductive mutations

Somatic mutations

Sporadic mutations

Which of the following is not an indication for inherited cancer?

Development of a cancerous tumor (correct)

Early onset of cancer

Having multiple cancers

Family history of mutations

Which gene is most commonly associated with breast cancer in inherited cases?

Rb gene

p53 gene

BRCA1 gene (correct)

APC gene

What is the Two-Hit Hypothesis primarily associated with?

Hereditary retinoblastoma Signup and view all the answers

Which type of cancer is associated with mutations in the Rb gene?

Retinoblastoma Signup and view all the answers

What explanation does the 'hereditary cases' of retinoblastoma provide?

They are inherited and can affect both eyes. Signup and view all the answers

Which mutation is less likely to occur in hereditary cancers?

Oncogene activation Signup and view all the answers

What percentage of hereditary retinoblastoma cases are bilateral?

40% Signup and view all the answers

What is a common characteristic of Li-Fraumeni syndrome?

Associated with the p53 gene Signup and view all the answers

Which gene is linked with familial multiple endocrine neoplasia?

MEN1 gene Signup and view all the answers

What is required for sporadic retinoblastoma to develop?

Two independent somatic mutations Signup and view all the answers

How does loss of heterozygosity (LOH) lead to cancer in individuals with inherited retinoblastoma?

It causes a homozygous mutant cell from a heterozygous state. Signup and view all the answers

What role does pRb play in the cell cycle?

Prevents progression from G1 to S phase Signup and view all the answers

What effect does phosphorylation of pRb have on its function?

Allows E2F to initiate S phase gene expression Signup and view all the answers

What is the phenotype resulting from the mutations in sporadic retinoblastoma?

Null recessive phenotype Signup and view all the answers

What is a significant characteristic of hereditary retinoblastoma compared to sporadic cases?

Always has a clear family history Signup and view all the answers

What initiates the transition from G1 to S phase in the cell cycle?

Binding of E2F to DNA Signup and view all the answers

What are the consequences of uncontrolled cell division related to pRb dysfunction?

Loss of cell cycle checkpoint control Signup and view all the answers

Which statement about mutations in sporadic retinoblastoma is true?

Mutations primarily affect the pRb gene. Signup and view all the answers

How is the regulation of the cell cycle related to growth factors?

Growth factors stimulate the phosphorylation of pRb. Signup and view all the answers

Study Notes

Somatic vs. Germline Mutations

Somatic mutations occur in non-reproductive cells and are not passed on to future generations.
Germline mutations occur in reproductive cells and are passed on to future generations.
Germline mutations can cause inherited cancer, while somatic mutations can cause cancer or cell death.

Inherited Cancer

Indications: Family history of cancer, early onset of cancer, multiple cancers in a single individual, rare cancers in a family.
Genetic testing: Can determine if a mutation is sporadic (only in the tumor) or inherited (in all cells).

BRCA1 and BRCA2: Mutations in these genes increase the risk of breast, ovarian, pancreatic, and prostate cancers.
APC and HNPCC genes: Associated with colorectal cancer.
p53 gene: Linked to Li-Fraumeni syndrome, which increases the risk of rare cancers.
Rb gene: Associated with retinoblastoma, a cancer of the retina in children.
MEN1: Tumor suppressor gene (TSG) involved in MEN (Multiple Endocrine Neoplasia) and mutations in the Ret gene, leading to abnormal dimerization, which can be constantly active.

Hereditary Cancers

Hereditary cancers primarily arise due to the loss of tumor suppressor genes.
Oncogene mutations in hereditary cancers are rare.
Oncogene mutations require specific conditions to cross the embryonic developmental barrier.

Retinoblastoma

A tumor in the retina, typically affecting children younger than 5 years.
Caused by mutations in the Rb gene (TSG).
Two forms:
- Hereditary: affects both eyes (bilateral), accounts for 40% of cases.
- Sporadic: affects one eye (unilateral), accounts for 60% of cases.
95% survival rate with treatment.
Retinoblastoma can be passed on to the next generation in hereditary cases.

Two-Hit Hypothesis

Hereditary retinoblastoma: Individuals inherit one mutated Rb gene (germline mutation) and only require one additional mutation (somatic) in the remaining normal allele for cancer to develop. Diagnosis can be as early as 2 months.
Sporadic retinoblastoma: Requires two independent somatic mutations in the Rb gene to cause cancer. Diagnosis occurs around 30 months of age.
Hereditary cancers need one hit after birth.
Somatic cancers need to develop two hits.

Loss of Heterozygosity (LOH)

Inherited retinoblastoma: Individuals are heterozygous at birth, with one normal and one mutated Rb gene.
A somatic mutation in the remaining normal allele leads to a homozygous mutant cell resulting in cancer.
LOH also occurs in sporadic retinoblastoma after the first Rb mutation.

pRb and Cell Cycle

pRb prevents uncontrolled cell division by preventing progression from the G1 to S phase of the cell cycle.
Growth factors stimulate the MAPK pathway, leading to the expression of cyclins D1, D2, D3, and E, along with CDK4 and 6.
These cyclins and CDKs reduce negative regulation of pRb, allowing cells to enter the S phase.
E2F is a transcription factor essential for the transition from G1 to S phase.
pRb binds to E2F, preventing its transcription activity, and maintaining the cell in the G1 phase.
Phosphorylation of pRb by CDKs leads to its inactivation, releasing E2F and allowing for cell cycle progression.

pRb's Role in Cell Cycle Regulation

pRb is a key regulator of the G1/S checkpoint.
A dysfunctional pRb leads to uncontrolled cell proliferation.
The retinoblastoma protein is a nuclear phosphoprotein that controls cell growth by binding and suppressing TFs such as the E2F family.

Sporadic (Non-Hereditary) Retinoblastoma

No family history of the disease.
Develops a single tumor around 5 years of age.
Requires two somatic mutations in the same retinal cells.
When both alleles are mutated, it leads to a null recessive phenotype, meaning the tumor suppressor protein isn't produced.
Mutations can be nonsense, deletions, or splicing errors.

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Description

Explore the key differences between somatic and germline mutations in the context of cancer. This quiz covers inherited cancer indicators, genetic testing, and critical cancer-related genes like BRCA1, BRCA2, and p53. Understand how mutations contribute to cancer risk and inheritance through family histories.