BRCA 1 and 2: Breast and Ovarian Cancer Susceptibility

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Questions and Answers

What is the percentage of breast cancer cases that are inherited?

50-80%

30-50%

5-7% (correct)

95%

What is the primary function of BRCA proteins?

Inducing apoptosis

Inhibiting oestrogen receptor gene expression

Stimulating cell proliferation

Regulating cell cycle and DNA repair (correct)

What is the result of loss of PTEN activity?

Unregulated cell proliferation and carcinogenesis (correct)

Inhibition of cell proliferation and apoptosis

Regulation of cell cycle and DNA repair

Suppression of oestrogen receptor gene expression

What is the characteristic of PTEN mutations in Cowden syndrome?

Autosomal dominant inheritance with a dominant negative effect Signup and view all the answers

What is the estimated frequency of Cowden syndrome in the population?

1:20,000 Signup and view all the answers

What is the percentage of prostate cancers that have mutant PTEN?

70% Signup and view all the answers

Which protein binds to responsive elements in gene promoters as a tetramer?

p53 Signup and view all the answers

What is the consequence of a mutation in p53 alleles?

Dominant negative effect Signup and view all the answers

What is the role of p21 in cell cycle regulation?

Inhibits Cyclin D/Cdk4 Signup and view all the answers

What is the consequence of extensive DNA damage in a cell?

Immediate apoptosis Signup and view all the answers

What is the role of p53 in angiogenesis?

Inhibits angiogenesis Signup and view all the answers

What is the characteristic of Li-Fraumeni syndrome (LFS)?

Inherited mutations in the p53 gene Signup and view all the answers

What is the result of some specific p53 mutations?

Dominant negative effect Signup and view all the answers

What is the effect of HPV E7 on Rb?

Inactivates Rb Signup and view all the answers

What is the role of p21 in DNA synthesis and repair?

Binds to PCNA Signup and view all the answers

What is the consequence of a lack of functional p53?

Poor apoptosis Signup and view all the answers

What is the function of HPV E6 in infected cells?

Prevents apoptosis of infected cells Signup and view all the answers

What is the impact of having both Arg alleles in the p53 gene?

Higher mutation rate Signup and view all the answers

What is the goal of combination therapies in cancer treatment?

To make treatment more effective Signup and view all the answers

Why do tumour cells vary in their sensitivity to therapy?

Due to differences in cell type, proliferation rate, and DNA repair efficacy Signup and view all the answers

What is the goal of chemotherapy in cancer treatment?

To cause DNA damage and induce apoptosis Signup and view all the answers

What is the purpose of clinical trials in drug development?

To test the safety of new drugs in humans Signup and view all the answers

Study Notes

BRCA1 and BRCA2

BRCA1 located on chromosome 17 and BRCA2 on chromosome 13; both exhibit autosomal recessive inheritance.
Increased familial risk of breast and ovarian cancer due to inherited mutations.
Individual lifetime risk for breast cancer is 50-80% and for ovarian cancer 30-50%.
BRCA proteins are critical for DNA repair mechanisms, particularly in addressing double-strand breaks.

PTEN and Tumor Suppression

PTEN gene encodes a phosphatase that dephosphorylates PIP3 to PIP2, antagonizing PI3 kinase activity.
Loss of PTEN leads to unregulated cell proliferation and potential carcinogenesis.
Germline mutations in PTEN are linked to Cowden syndrome, presenting growths and increased cancer risk, including breast, prostate, and thyroid cancers.

p53 and Cell Cycle Regulation

p53 is a vital tumor suppressor that regulates the expression of over 50 genes involved in the cell cycle and apoptosis.
Normal function requires binding with Mdm2; phosphorylation alters this interaction, allowing p53 accumulation.
p21, mediated by p53, inhibits Cyclin D/Cdk4 to pause the cell cycle at the G1/S checkpoint for DNA repair.

p53 in Apoptosis and Angiogenesis

p53 facilitates the expression of pro-apoptotic genes and can induce cellular apoptosis after extensive DNA damage.
The activation of caspases leads to apoptotic cell death; mutations in the p53 gene can hinder this pathway.
p53 also regulates genes that inhibit angiogenesis, such as thrombospondin.

p53 Gene Mutations

Most mutations in the p53 gene are missense mutations affecting the DNA binding domain, leading to loss of function.
Li-Fraumeni syndrome is characterized by inherited p53 mutations, resulting in a 25x increased cancer risk by age 50.
Some mutations may create dominant negative effects, impairing wild-type p53 function.

Viral Interference with Tumor Suppressors

Oncogenic viruses, like HPV, produce proteins that inhibit tumor suppressor proteins; HPV E7 inactivates Rb and E6 inactivates p53.
E6 and E7 facilitate cell proliferation and contribute to cancer development.

Cancer Treatment Approaches

Conventional treatments include surgery, radiotherapy, and chemotherapy; newer molecular therapies are emerging.
Surgical excision is often combined with other treatments to target remaining cancer cells or metastases.
Radiotherapy aims to induce DNA damage; however, it can also affect rapidly dividing normal cells.

Tumor Sensitivity to Therapy

Tumor heterogeneity leads to varying sensitivity to treatments based on cell type, proximity to blood supply, and mutations.
Chemotherapy aims for maximum efficacy with minimal side effects; the therapeutic index assesses the safety of drugs.

Chemotherapeutic Agents and Clinical Trials

Chemotherapy disrupts DNA, RNA, and protein functions to induce apoptosis, though it can also affect normal proliferating cells.
Drug testing progresses through multiple phases, including cell culture, animal models, and clinical trials (Phase I-III), evaluating efficacy and safety.

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Description

Learn about the BRCA 1 and 2 genes, their role in breast and ovarian cancer susceptibility, and the risks associated with inherited mutations. Understand the autosomal recessive inheritance pattern and the individual lifetime risk of cancer.