(4.8) CANCER GENETICS

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Questions and Answers

What is a key distinction between sporadic and inherited forms of cancer development?

Sporadic cancers are caused by genetic mutations.

Sporadic cancers are always hereditary.

Inherited cancers generally have a higher risk of early onset. (correct)

Inherited cancers result from environmental factors only.

Which of the following accurately describes the Knudson Two Hit Hypothesis?

Both hits occur in separate cells to cause cancer.

The first hit is usually an environmental factor.

Cancer develops after two genetic mutations in the same gene. (correct)

One hit is genetic while the other is always due to lifestyle.

What is a significant feature of Lynch Syndrome?

It primarily affects only breast tissue.

It is always associated with Rb mutations.

It is unrelated to genetic testing or diagnosis.

It involves mutations in mismatch repair genes. (correct)

Which mechanism primarily contributes to losing gene activity after inheriting a pathogenic variant?

Promoter methylation of the gene. Signup and view all the answers

In Hereditary Breast and Ovarian Cancer Syndrome, how do BRCA1 and BRCA2 mutations differ?

BRCA1 mutations lead to a higher lifetime risk than BRCA2 mutations. Signup and view all the answers

What differentiates hereditary cancers from hereditary syndromes with increased cancer risk?

Hereditary syndromes may increase cancer risk without defining a specific cancer. Signup and view all the answers

Which type of mutation is commonly associated with increased cancer risk due to hereditary factors?

Tumor suppressor genes Signup and view all the answers

What is the primary mode of inheritance for many hereditary cancer syndromes?

Autosomal dominant inheritance Signup and view all the answers

What is the Knudson two-hit hypothesis primarily concerned with?

The development of cancer through an inherited mutation and a subsequent acquired mutation Signup and view all the answers

Which gene is most commonly associated with early-onset retinoblastoma when mutated?

RB1 Signup and view all the answers

What range of lifetime risk for breast cancer is associated with BRCA1/BRCA2 mutations?

50-80% Signup and view all the answers

Which of the following mechanisms can serve as a 'second hit' in tumor suppressor gene mutation according to the two-hit hypothesis?

Excessive methylation of the promoter Signup and view all the answers

Which type of cancer is most commonly linked to mutations in the APC gene?

Colorectal cancer Signup and view all the answers

In families with multiple cases of breast cancer before age 60, what is the approximate risk percentage of breast cancer for those with BRCA mutations?

80% Signup and view all the answers

What is the primary function of glandular cells in the body?

They secrete hormones. Signup and view all the answers

What is the typical mean age at diagnosis for individuals with Lynch Syndrome?

44-61 years Signup and view all the answers

How does a high level of microsatellite instability (MSI) indicate a dysfunction in mismatch repair?

It indicates instability is found in greater than 30% of cells. Signup and view all the answers

Which gene mutation is specifically associated with bladder cancer?

HRAS Signup and view all the answers

What is the main purpose of molecular profiling in cancer treatment?

To assess treatments' effectiveness and prognosis. Signup and view all the answers

Which of the following FDA approved tests can identify cancer-associated alterations in over 300 genes?

Foundation One CDx (F1CDx) Signup and view all the answers

What is the typical risk of breast cancer for women with HBOC?

45-75% Signup and view all the answers

Which gene is associated with impaired bone marrow function in Fanconi Anemia patients?

FANCA Signup and view all the answers

What type of skin manifestation is most predominant in patients with Xeroderma Pigmentosum?

Severe sunburns Signup and view all the answers

Which of the following cancers is NOT commonly associated with Fanconi Anemia?

Breast cancer Signup and view all the answers

Which gene is responsible for the autosomal recessive form of Xeroderma Pigmentosum?

XPA and XPC Signup and view all the answers

What is the primary role of BRCA1 and BRCA2 genes in the context of hereditary diseases?

DNA repair Signup and view all the answers

What characteristic histopathology is BRCA1-related breast cancer more likely to exhibit?

Medullary type with high grade Signup and view all the answers

In individuals with HBOC, what is the approximate risk of ovarian cancer for those with a BRCA2 mutation?

10-20% Signup and view all the answers

Which hereditary syndrome primarily causes extreme sensitivity to UV rays and skin cancers?

Xeroderma Pigmentosum Signup and view all the answers

Which subtype of breast cancer is notably less common in BRCA2 mutation carriers?

Triple negative Signup and view all the answers

Study Notes

Cancer Genetics

Cancer genetics examines inherited cancer risks, inherited forms of cancers, and hereditary cancer syndromes.
Cancer development varies between sporadic and inherited forms.
Hereditary disorders increase cancer risk, while hereditary syndromes are the primary cancer risk.
Knudson two-hit hypothesis describes how cancer develops due to the loss of gene activity.
Mutation types include somatic mutations, and loss of heterozygosity.
Specific cancers have unique genetic changes associated. Examples include retinoblastoma, hereditary breast and ovarian cancer, Fanconi anemia, Xeroderma pigmentosa, and bladder cancer.
Genes like tumor suppressor genes (Rb, BRCA1) and oncogenes (HRas) affect cancer development.
Clinical features of hereditary cancers affect age of onset, multifocal/bilateral disease, higher cancer rates, and Mendelian inheritance.

Objectives

Describe the differences in cancer risk between sporadic and inherited cancers, including clinical differences in presentation.
Explain hereditary disorders with increased cancer risk and differentiate them from hereditary cancer syndromes.
Describe the Knudson two-hit hypothesis in relation to cancer development.
List and explain the mechanisms of gene activity loss following hereditary pathogenic variants.
Match specific cancers or syndromes to corresponding genetic changes (e.g., Retinoblastoma, hereditary breast/ovarian cancer, Fanconi anemia, Xeroderma pigmentosa, and bladder cancer).
Evaluate the consequences of gene alterations (tumor suppressor and oncogenes) on cancer development.
Identify the clinical features of hereditary diseases and relate them to associated gene/pathogenic variant, and cancer risk.
Compare/contrast BRCA1/2 and FANC mutations in cancer risk.
List hereditary colon cancer forms, highlighting Lynch syndrome features, including microsatellite instability.
Compare/contrast genetic and molecular tests in cancer risk assessment and diagnosis.

Sporadic vs Familial Cancer

Sporadic cancer is most common and not inherited.
Familial cancer has an increased risk in families, often inherited.

Hereditary Syndromes with Cancer and Hereditary Cancer

Mutations of a gene can cause a wide range of consequences, including increased cancer risk in specific inherited/genetic syndromes.
Cancer risk can be a secondary consequence.
Cancer risk in syndromes are often presented as primary risk.

Features of Increased Cancer Risk/Cancer Predisposition

Cancer predisposition is an increased risk due to inheritance of a mutation, most commonly associated with tumor suppressor genes.
Regulatory signals ("STOP" signals) are important.
Clinical presentations frequently include earlier age of onset, multifocal/bilateral disease cases, increase in rare forms of cancer, and inheritance patterns (typically dominant).

Knudson Two Hit Hypothesis

Cancer development usually requires mutations in both alleles of a tumor suppressor gene leading to the loss of the function.
In case of inheritance, the first hit is inherited, meaning the second hit occurs more readily, frequently earlier in life, when compared to sporadic forms.

Mechanism of Loss of Gene Activity

Loss of heterozygosity
Somatic Mutations
Chromosomal rearrangements (breakpoints within genes/positions effects)
Deletions
Excessive methylation (promoter).

Tumor Suppressor Genes

Loss of function in tumor suppressor genes often results in the development of disease.
Often, additional mutations are required to develop cancer.
Inherited mutations often represent nearly 100% risk of developing cancer.
Environmental factors also play roles in the development of cancer.

Retinoblastoma

Describes a childhood tumor of the retina.
Inherited form manifests earlier and affects both eyes.
Sporadic form affects only one eye.

Hereditary Breast and Ovarian Cancer (HBOC)

60-75% of inherited breast cancer cases is attributed to BRCA1/2 mutations.
Multiple breast tumor types (DCIS, invasive ductal, and invasive lobular) can occur.
Lifetime risk of breast cancer is 50-80% in families with multiple cases before 60.
Risk is lower if only one family member has been diagnosed before 50.

Genes Associated with Breast Cancer Risk

Several genes are associated, including BRCA1 and BRCA2.
Some genes are linked to increased risk for multiple cancer subtypes

BRCA1 and BRCA2 Role in HR Repair

BRCA1 and BRCA2 play key roles in DNA repair pathways, particularly homologous recombination.
Defects in these genes are highly associated with increased breast and ovarian cancer risks.

Breast Cancer Subtypes

Breast cancers are classified based on phenotypic characteristics. Types include luminal A, luminal B, HER2-enriched, basal-like, and triple-negative.
Various molecular subtypes exist.

Xeroderma Pigmentosum (XP)

Individuals with XP highly susceptible to UV light.
Increased risk of skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma) and other malignancies.
Affected children often present with skin changes and eye complications (such as cataracts) by age 15.

Lynch Syndrome

Affects multiple genes (MLH1, MSH2, MSH6, PMS2, and EPCAM).
Inherited/autosomal dominant mutation.
Significantly increased risk of colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, and other cancers.
Microsatellite instability is often present in Lynch syndrome cases.

Risk of Colorectal Cancer (CRC)

Risk factors vary based on family history, particular genetic mutations, and individual cases.
Common mutation types often include HNPCC and/or FAP.
Rates differ in population and cases.

Colon Cellular Structure

Description of colon cells, their types, and their function.
Include descriptions of the protective layer and immune cells.

Colonoscopy and Polyp Removal

Descriptions of colonoscopy procedures, including the removal of polyps (precancerous growths).

Molecular Profiling

Provides cancer prognosis by evaluating cancer cell behavior/gene expression.
Used to predict cancer recurrence, metastatic spread, and effective treatment options for cancer subtypes.

Recent FDA Approved Tests

New tests use Next Generation Sequencing technology (NGS) to profile tumors.

Cancer Genetic Test Takeaways

Predictive testing is available for inherited cancer predisposition.
Not all individuals need the type of genetic testing.
Defining subgroups/cancer subtypes, and prognostic information is available through cancer cell tests.

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Description

This quiz focuses on cancer genetics, exploring the risks of inherited and sporadic cancers, as well as hereditary cancer syndromes. You'll learn about the Knudson two-hit hypothesis, mutation types, and specific genetic changes associated with various cancers. Test your knowledge on cancer-related genes and their clinical implications.