Comprehensive Cancer Genetic Testing: What's Included?

Genetic testing has revolutionized our approach to cancer prevention and early detection. For individuals with a personal or family history of cancer, comprehensive genetic testing can provide critical insights into hereditary risk factors. 

In this article, we'll explore the scope of comprehensive cancer genetic testing panels, focusing on the actionability of results and the varying levels of cancer risk associated with different genes.

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The Scope of Comprehensive Cancer Genetic Testing

Modern cancer genetic testing panels examine multiple genes simultaneously to identify inherited mutations that may increase cancer risk. These multi-gene panels have evolved significantly, from testing just a few well-known genes to analyzing dozens of genes associated with various cancer types.

For example, the MyRisk hereditary cancer test analyzes 48 genes associated with hereditary cancer syndromes. This comprehensive approach provides a complete picture of an individual's genetic risk factors compared to single-gene testing.

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Why Test Multiple Genes?

Cancer is complex, and genetic risk factors can vary widely between individuals. Multi-gene panels offer several advantages:

1. Efficiency: Testing multiple genes at once is more time and cost-effective than sequential single-gene tests.
2. Broad Coverage: Different genes can cause similar cancer types. Mutations in BRCA1, BRCA2, PALB2, ATM, CHEK2, and several others can influence breast cancer risk.
3. Unexpected Findings: Some families have cancer patterns that don't clearly point to a specific syndrome. Comprehensive testing can identify gene mutations that may not have been suspected.
4. Diverse Cancer Risks: Some gene mutations increase risk across multiple cancer types, making broad testing particularly valuable.

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Gene Selection Criteria: The Science Behind the Panel

Not all genes are created equal when it comes to cancer risk testing. Genes for comprehensive panels are selected using strict scientific criteria. 

Here are the key considerations for gene inclusion:

1. Association with Cancer Risk

The most fundamental criterion is that a gene must be associated with at least one type of cancer. The scientific evidence must demonstrate a clear link between mutations in the gene and increased cancer incidence.

For example, the BRCA1 and BRCA2 genes are well-established risk factors for breast, ovarian, pancreatic, and prostate cancers. These genes produce proteins that help repair damaged DNA, and when they don't function properly, genetic damage can accumulate, leading to cancer.

Other genes have more specific associations. HOXB13 mutations primarily increase prostate cancer risk, while VHL gene mutations are strongly associated with renal cancer and other types of tumors.

2. Evidence-Based Risk Assessment

Genes included in comprehensive panels must significantly increase cancer risk, as demonstrated in peer-reviewed literature or recognized by professional society guidelines. This ensures that testing focuses on genes with scientifically validated associations rather than theoretical connections.

The level of risk varies significantly between genes:

• High-penetrance genes like BRCA1, BRCA2, and TP53 confer a substantial lifetime risk of developing certain cancers (often 40-80%).

• Moderate-penetrance genes such as ATM, CHEK2, and PALB2 typically confer a 2-4-fold increased risk compared to the general population.

• Low-penetrance genes may only slightly increase risk but can still be clinically relevant, especially when combined with other risk factors.

This stratification is essential for individuals and healthcare providers to understand when interpreting test results and making medical management decisions.

3. Clinical Actionability

The most crucial criterion for gene inclusion is clinical actionability. This means that a positive result (finding a pathogenic mutation) should lead to considerations or recommendations for changes in medical management.

For example, individuals with BRCA1 and BRCA2 mutations may be offered:

• Earlier and more frequent breast cancer screening
• Risk-reducing surgical options
• Chemoprevention strategies
• Specific targeted therapies if cancer develops

Genetic testing results' actionability allows individuals and their healthcare providers to make informed decisions about cancer surveillance, risk reduction, and treatment strategies.

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Breaking Down the Gene Panel by Cancer Type

Comprehensive cancer genetic panels include genes associated with various cancer types. 

Here's a breakdown of key genes tested for common hereditary cancers:

Breast Cancer

Several genes on comprehensive panels are associated with increased breast cancer risk:

• BRCA1 and BRCA2: The most well-known breast and ovarian cancer susceptibility genes conferring a 45-85% lifetime risk.
• PALB2: Confers risks similar to BRCA2.
• ATM, CHEK2, and BARD1: Moderate-risk genes that approximately double breast cancer risk.
• TP53: Associated with Li-Fraumeni syndrome and very high malignancy risks, often at young ages.
• PTEN: Associated with Cowden syndrome and increased risk of breast and other cancers.
• STK11: Linked to Peutz-Jeghers syndrome and elevated breast cancer risk amongst other cancers.
• CDH1: Associated with lobular breast cancer and diffuse gastric cancer.

Ovarian Cancer

Genes associated with ovarian cancer risk include:

• BRCA1 and BRCA2: Confer 10-60% lifetime risk of ovarian cancer.
• MLH1, MSH2, MSH6, PMS2, and EPCAM: Lynch syndrome genes associated with increased ovarian cancer risk.
• RAD51C, RAD51D, and BRIP1: Moderate-risk genes primarily affecting ovarian cancer risk.
• STK11: Associated with sex cord tumors with annular tubules, a rare ovarian cancer.

Colorectal Cancer

Key genes for colorectal cancer risk include:

• MLH1, MSH2, MSH6, PMS2, and EPCAM: Lynch syndrome genes causing 40-80% lifetime risk of colorectal cancer.
• APC: Associated with familial adenomatous polyposis and near 100% risk of colorectal cancer without intervention.
• MUTYH: Biallelic mutations cause MUTYH-associated polyposis with high colorectal cancer risk.
• STK11, PTEN, and BMPR1A/SMAD4: Associated with hamartomatous polyposis syndromes and increased colorectal cancer risk.
• POLD1, POLE: Associated with polymerase proofreading-associated polyposis.

Pancreatic Cancer

Genes linked to pancreatic cancer include:

• BRCA1, BRCA2, and PALB2: Associated with increased pancreatic cancer risk.
• MLH1, MSH2, MSH6, PMS2, and EPCAM: Lynch syndrome genes with modest pancreatic cancer risk.
• ATM: Associated with moderate pancreatic cancer risk.
• STK11: Peutz-Jeghers syndrome with substantial pancreatic cancer risk.
• CDKN2A: Associated with familial atypical multiple mole melanoma syndrome and increased pancreatic cancer risk.

Prostate Cancer

Key genes for prostate cancer risk include:

• BRCA1 and BRCA2: BRCA2, in particular, confers significant prostate cancer risk.
• HOXB13: Specifically associated with hereditary prostate cancer.
• ATM and MLH1, MSH2, MSH6, PMS2: Associated with modest increases in prostate cancer risk.

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Red Flags That Suggest Hereditary Cancer Risk

Several personal and family history factors can suggest an increased likelihood of having a hereditary cancer syndrome. 

These "red flags" often indicate the need for comprehensive genetic testing:

Personal History Red Flags

• Breast cancer at any age
• Ovarian cancer at any age
• Colorectal or rectal cancer at any age
• Metastatic or high-risk prostate cancer
• Pancreatic cancer at any age
• Uterine cancer diagnosed at younger ages

Family History Red Flags

• Breast cancer diagnosed at age 50 or younger
• Multiple relatives with the same type of cancer (e.g., two or more breast cancers in one relative at any age)
• Three or more breast cancers in relatives on the same side of the family
• Ovarian cancer at any age
• Pancreatic cancer or metastatic/high-risk prostate cancer in a first-degree relative
• Colorectal, rectal, or uterine cancer diagnosed before age 50 in a first-degree relative
• Known gene mutation in a family member
• Ashkenazi Jewish ancestry with a family history of cancer
• Triple-negative breast cancer at any age

The presence of these red flags doesn't guarantee a hereditary cancer syndrome, but they significantly increase the likelihood and warrant consideration of genetic testing.

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Benefits of Comprehensive Cancer Genetic Testing

• Risk Assessment: Understanding individual genetic risk helps tailor screening and prevention strategies.
• Family Risk Clarification: Identifying a hereditary mutation allows family members to be tested for the same specific mutation.
• Targeted Screening: Individuals with positive results can begin enhanced screening at appropriate ages.
• Risk-Reducing Options: Knowledge of specific gene mutations opens the door to preventive measures that may reduce cancer risk.
• Therapeutic Implications: Some genetic mutations may influence treatment choices if cancer develops.

The Testing Process

The cancer genetic testing process typically includes:

1. Pre-test considerations and education: Understanding  benefits, limitations, and potential implications of testing.

2. Sample collection: Usually a small blood sample or saliva sample.

3. Laboratory analysis: Examination of selected genes for mutations.

4. Results interpretation: Classifying any identified variants according to their clinical significance.

5. Post-test counseling: Explaining results and their implications for medical management.

6. Family follow-up: If a mutation is found, counseling about implications for blood relatives.

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Conclusion

Comprehensive cancer genetic testing has transformed our ability to identify individuals at increased risk for hereditary cancers. By analyzing multiple genes associated with various cancer types, these tests provide a more complete picture of genetic risk than was previously possible.

The genes included in these panels are carefully selected based on their association with cancer risk, scientific evidence's strength, and positive results' clinical actionability. This ensures that testing provides meaningful information that can guide cancer screening, risk reduction, and treatment decisions.

For individuals with personal or family histories suggestive of hereditary cancer, comprehensive genetic testing offers the opportunity to understand their risks and take proactive steps toward cancer prevention and early detection.