Genetic predisposition to cancer Flashcards
Describe the basic mechanism of inherited predisposition to cancer & role of testing
for sporadic mutation in oncology.
Inherited Predisposition to Cancer
1. Mechanisms of Inherited Cancer Predisposition
Inherited cancer predisposition occurs when a person inherits a germline mutation in a tumor suppressor gene or oncogene. Germline mutations are present in all cells of the body and can be passed from parents to offspring. These mutations increase the risk of developing cancer but do not necessarily guarantee that cancer will occur.
The two main types of genes involved in inherited cancer predisposition are:
Tumor Suppressor Genes:
These genes normally function to prevent uncontrolled cell division by regulating the cell cycle, repairing DNA damage, or inducing apoptosis (programmed cell death).
Loss-of-function mutations in these genes can result in a loss of their protective function, allowing cells to proliferate uncontrollably.
Examples:
BRCA1 and BRCA2: Mutations in these tumor suppressor genes are linked to an increased risk of breast, ovarian, and prostate cancers.
TP53: The p53 protein, encoded by the TP53 gene, is a critical tumor suppressor. Mutations in TP53 are associated with the Li-Fraumeni syndrome, which predisposes individuals to various cancers, including sarcomas, breast cancer, and leukemia.
APC: Mutations in the APC gene are associated with familial adenomatous polyposis (FAP), which predisposes individuals to colorectal cancer.
Oncogenes:
Oncogenes are genes that, when mutated or overexpressed, promote excessive cell division and survival. Inherited mutations in oncogenes can lead to cancer by making the affected gene continuously active.
Gain-of-function mutations in these genes can result in the activation of pathways that drive cell proliferation and survival.
Examples:
RET: Mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia (MEN) type 2, a condition that predisposes individuals to medullary thyroid cancer.
KRAS: KRAS mutations are involved in several types of cancer, including lung, colorectal, and pancreatic cancers, though these mutations are more often acquired (sporadic) than inherited.
DNA Repair Genes:
Mutations in genes responsible for DNA repair can increase the likelihood of accumulating other mutations in the genome, promoting tumorigenesis.
Examples:
MLH1, MSH2: Mutations in mismatch repair genes (such as MLH1 and MSH2) are linked to Lynch syndrome, which increases the risk for colorectal, endometrial, and ovarian cancers.
Inheritance Patterns of Cancer Predisposition
Inherited mutations follow specific inheritance patterns, often autosomal dominant (one mutated copy of the gene is enough to increase cancer risk), although some inherited conditions exhibit autosomal recessive inheritance.
Autosomal Dominant Inheritance: A single copy of the mutated gene in each cell is sufficient to cause a predisposition to cancer.
Example: BRCA1/2 mutations in breast cancer; TP53 mutations in Li-Fraumeni syndrome.
Autosomal Recessive Inheritance: Both copies of the gene (one inherited from each parent) must be mutated to increase cancer risk.
Example: Retinoblastoma caused by mutations in the RB1 gene.
Sporadic Mutations and Their Role in Cancer
While inherited mutations contribute to cancer risk, the majority of cancer cases are due to sporadic mutations—mutations that arise de novo during an individual’s lifetime. These mutations occur in somatic cells (non-germline cells) and are not passed to offspring. Sporadic mutations can be caused by a variety of factors, including:
Environmental exposures (e.g., tobacco smoke, UV radiation, and chemicals)
Lifestyle factors (e.g., diet, alcohol consumption)
Aging (as cells accumulate mutations over time)
Errors during DNA replication (as a result of normal cellular processes)
Sporadic mutations can occur in both oncogenes and tumor suppressor genes and often lead to the formation of tumors. These mutations drive the carcinogenesis process through mechanisms like chromosomal instability, inactivation of tumor suppressors, and activation of oncogenes.
Testing for Genetic Mutations in Oncology
Both hereditary and sporadic mutations are important in oncology, and several molecular genetic tests are used to identify mutations that influence cancer risk, diagnosis, prognosis, and treatment.
- Testing for Inherited Cancer Predisposition
Genetic testing for inherited mutations allows for the identification of individuals at increased risk for specific types of cancer. Key applications include:
Genetic Counseling and Risk Assessment:
Testing for inherited mutations can help assess the likelihood of developing certain cancers and guide decisions about preventive measures, surveillance, and treatment. For example, women with BRCA1 or BRCA2 mutations may undergo enhanced screening for breast cancer or consider prophylactic mastectomy or ovarian cancer prevention strategies.
Germline Mutation Testing:
Tests can be conducted on blood or saliva samples to identify germline mutations that predispose individuals to cancer. Common genes tested include BRCA1/2, MLH1, MSH2, TP53, and RET.
Family Pedigree Analysis:
By analyzing the cancer history in a family, healthcare providers can identify patterns that suggest an inherited cancer syndrome, guiding genetic testing in affected family members.
2. Testing for Sporadic Mutations in Cancer
Sporadic mutations, which occur in cancer cells, can be identified through somatic mutation testing and are crucial for diagnosing cancer and personalizing treatment. Some key applications include:
Tumor Profiling:
Testing for somatic mutations in tumors using technologies like next-generation sequencing (NGS) allows oncologists to identify driver mutations—mutations that are key to the development and progression of the tumor.
Tumor profiling helps to identify actionable mutations, allowing for targeted therapies. For example:
EGFR mutations in non-small cell lung cancer (NSCLC) can be targeted with drugs like erlotinib or gefitinib.
BRAF V600E mutation in melanoma can be targeted with BRAF inhibitors like vemurafenib.
Monitoring Tumor Evolution and Resistance:
Cancer is a dynamic disease, and somatic mutations in tumor cells may change over time. Liquid biopsy (testing blood for circulating tumor DNA (ctDNA)) can be used to monitor tumor mutations in real-time, assess treatment efficacy, and detect resistance mutations that may arise during therapy.
Pharmacogenomic Testing:
In addition to identifying mutations that drive cancer, genetic testing can also help predict an individual’s response to chemotherapy or targeted therapies. For example, testing for mutations in the TPMT gene helps predict whether a patient will metabolize the chemotherapy drug mercaptopurine effectively or experience adverse effects.
Summary
Inherited Predisposition to Cancer: Germline mutations in tumor suppressor genes, oncogenes, and DNA repair genes can predispose individuals to cancer. Common examples include BRCA1/2 mutations in breast cancer, TP53 mutations in Li-Fraumeni syndrome, and MLH1 mutations in Lynch syndrome.
Sporadic Mutations: Most cancers are caused by somatic (non-inherited) mutations that accumulate over time due to environmental exposures, lifestyle, and random cellular errors.
Testing for Inherited Mutations: Genetic testing can help identify individuals at high risk for certain cancers and inform prevention and treatment strategies.
Testing for Sporadic Mutations in Oncology: Somatic mutation testing, such as NGS and liquid biopsy, is used to identify driver mutations in cancer cells and guide personalized treatments, such as targeted therapies.
Both inherited and sporadic mutations are critical to understanding cancer risk, diagnosis, and treatment. By identifying specific genetic alterations, oncologists can tailor cancer treatment more effectively and provide better outcomes for patients.
Describe the main reasons that individuals are referred to genetics to discuss a family
history of cancer
Here are the main reasons for a referral to genetics due to a family history of cancer:
- To Assess for Inherited Cancer Syndromes
Certain cancer types are known to run in families due to inherited genetic mutations. When there is a strong family history of a particular cancer type or cancers that share genetic links, genetics professionals can help assess whether a hereditary cancer syndrome is present. Examples of inherited cancer syndromes include:
Breast and Ovarian Cancer: Family history of breast or ovarian cancer, particularly in individuals under age 50, can suggest mutations in the BRCA1 or BRCA2 genes, which significantly increase the risk of these cancers.
Colon Cancer: A family history of early-onset colorectal cancer may indicate Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, or HNPCC), which is caused by mutations in mismatch repair genes like MLH1, MSH2, MSH6, and PMS2.
Endometrial Cancer: Inheritance of mutations in genes associated with Lynch syndrome can also predispose individuals to endometrial (uterine) cancer.
Li-Fraumeni Syndrome: A family history of various cancers, including breast cancer, sarcomas, leukemias, and brain tumors, may suggest Li-Fraumeni syndrome, caused by mutations in the TP53 gene.
Retinoblastoma: Family history of retinoblastoma in childhood may indicate an inherited mutation in the RB1 gene, which predisposes individuals to retinoblastoma and other cancers later in life.
These families may benefit from genetic testing to identify specific mutations that could influence their cancer risk and allow for early surveillance, prevention, or personalized treatment strategies.
- To Determine Hereditary Cancer Risk for Family Members
When an individual has a family history of cancer, other family members may be at increased risk for the same or related cancers. A genetics referral can help assess this risk in the following ways:
Risk Assessment: A genetics professional can assess whether a person’s family history suggests an inherited cancer syndrome that could affect other relatives. For example, a history of multiple relatives with breast cancer in multiple generations could indicate a higher likelihood of a BRCA1 or BRCA2 mutation, which increases the risk of breast and ovarian cancer for family members.
Cancer Screening and Preventive Measures: For families with a known hereditary cancer syndrome, genetics counseling can help recommend earlier and more frequent screening (e.g., mammograms, colonoscopies) or preventive measures (e.g., prophylactic surgeries, chemoprevention) for at-risk individuals.
Genetic Testing for Family Members: A referral to genetics may help offer genetic testing for family members to determine if they carry the same mutation and whether they have an increased risk of developing cancer.
- To Guide Cancer Treatment Decisions
Some cancers have specific genetic mutations that affect how the cancer behaves and how it responds to treatment. A referral to genetics can help in determining whether a person’s cancer is likely caused by an inherited mutation, which can influence treatment decisions:
Personalized Treatment: For example, HER2-positive breast cancers (caused by overexpression of the HER2 gene) can be treated with targeted therapies such as trastuzumab (Herceptin). Knowing whether a patient has inherited a mutation in a specific gene can inform treatment choices.
Targeted Therapy Options: In cancers with specific genetic mutations (e.g., EGFR mutations in lung cancer or BRAF V600E mutations in melanoma), identifying the mutation through genetic testing can allow for targeted therapy, potentially improving outcomes.
Pharmacogenomics: Genetic testing can also help predict how a patient will respond to certain chemotherapy drugs, such as mercaptopurine, by testing for variants in the TPMT gene. A family history of cancer, especially in the presence of known genetic mutations, may warrant pharmacogenomic testing to guide therapy.
- To Provide Counseling and Inform Decision-Making
A family history of cancer can cause emotional and psychological stress. Referral to genetics allows for counseling on the implications of a family history of cancer, including:
Cancer Risk Awareness: Genetics professionals help individuals understand their cancer risk based on their family history and provide information about hereditary cancer syndromes.
Psychosocial Support: Cancer risk in the family can create anxiety and uncertainty. Genetics counselors offer emotional support to help individuals process their concerns and make informed decisions about screening, surveillance, and preventive measures.
Informed Decision-Making: Genetics counseling provides individuals with the information they need to make decisions about whether to undergo genetic testing, what type of testing is appropriate, and how to interpret the results. For example, individuals may decide whether to pursue BRCA testing to evaluate their breast cancer risk.
- To Investigate Early Onset or Unusual Cancers
When cancer occurs in individuals at an unusually young age or when there are rare or unusual types of cancer in the family, this may suggest an underlying genetic predisposition.
Early Onset Cancer: If a cancer diagnosis occurs before age 50, it is more likely to have a hereditary cause. For instance, early-onset colon cancer (before age 50) may be linked to Lynch syndrome or familial adenomatous polyposis (FAP).
Rare Cancers: Certain cancers, such as childhood cancers like retinoblastoma or neuroblastoma, are more likely to have a hereditary cause, particularly if multiple family members are affected.
Multiple Cancers in a Single Individual: Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, are characterized by multiple primary cancers in the same individual. A family history of several different types of cancers, especially at young ages, can suggest a genetic predisposition.
- To Explore Options for Preventive Strategies
Genetic testing and counseling can help identify individuals at high risk for cancer and inform preventive measures. For example:
Prophylactic Surgery: In some hereditary cancer syndromes, such as BRCA1/2 mutations in breast cancer, preventive mastectomy or oophorectomy (removal of ovaries) may be offered to reduce cancer risk.
Enhanced Surveillance: Individuals who carry mutations associated with higher cancer risks (e.g., BRCA1/2, Lynch syndrome) may benefit from increased screening, such as more frequent mammograms, colonoscopies, or skin exams.
Chemoprevention: Medications like tamoxifen may be recommended for women at high risk of breast cancer, while aspirin may be suggested for individuals with Lynch syndrome to reduce the risk of colorectal cancer.
- To Clarify and Educate About the Family History
In some cases, families may not fully understand or appreciate the implications of their family history of cancer. Referral to genetics can help clarify the pattern of inheritance and explain the potential risks:
Family History Evaluation: A genetics professional can help assess the degree of relatedness and the number of affected family members, as well as the age of onset and types of cancers involved, to help establish whether a hereditary cancer syndrome is likely.
Inheritance Patterns: Understanding whether cancer is passed down in a dominant or recessive pattern is essential for determining the risk for other family members and guiding testing.
Summary
Referral to genetics for a family history of cancer typically occurs for one or more of the following reasons:
To assess for hereditary cancer syndromes (e.g., BRCA1/2, Lynch syndrome).
To evaluate cancer risk for other family members and provide guidance on screening and prevention.
To guide personalized treatment decisions based on genetic mutations found in cancer cells.
To offer counseling and decision-making support regarding genetic testing, risk management, and psychological impact.
To investigate early onset or rare cancers that suggest an underlying genetic predisposition.
To explore preventive strategies, such as prophylactic surgeries or enhanced surveillance.
To clarify and educate about the implications of family cancer history and inheritance patterns.
Genetic counseling and testing can significantly impact cancer risk management and help individuals make informed decisions about their health and preventive care.
