Beyond BRCA: Other Hereditary Cancer Syndromes

When we think about hereditary cancer, BRCA1 and BRCA2 gene mutations often come to mind first. These genes have received significant attention for their role in hereditary breast and ovarian cancer. However, they represent just the tip of the iceberg when it comes to hereditary cancer syndromes.

Approximately 5-10% of all cancers are hereditary, meaning genetic mutations cause them to be passed down from parent to child. While BRCA mutations account for many hereditary breast and ovarian cancers, mutations in numerous other genes can increase cancer risk. Understanding these lesser-known hereditary cancer syndromes is crucial for proper risk assessment, early detection, and prevention strategies.

In this article, we'll explore three significant hereditary cancer syndromes beyond BRCA—Lynch Syndrome, PALB2-associated cancer syndrome, and Li-Fraumeni Syndrome (caused by TP53 mutations)—and examine how genetic testing can help identify these conditions, and in what circumstances testing is most appropriate.

‍

Lynch Syndrome: The Most Common Hereditary Colorectal Cancer Syndrome

Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is the most common hereditary colorectal cancer syndrome, responsible for approximately 3-5% of all colorectal cancers. It's caused by mutations in genes responsible for DNA mismatch repair—MLH1, MSH2, MSH6, PMS2, and EPCAM.

Cancer Risks in Lynch Syndrome

People with Lynch Syndrome have significantly elevated risks for several types of cancer compared to the general population:

• Colorectal cancer: 40-70% lifetime risk (compared to about 4% in the general population)
• Endometrial (uterine) cancer: 25-60% lifetime risk in women (compared to about 3% in the general population)
• Ovarian cancer: 4-24% lifetime risk
• Stomach cancer: 5-13% lifetime risk
• Small intestine cancer: 3-6% lifetime risk
• Hepatobiliary tract cancer: 1-4% lifetime risk
• Urinary tract cancer: 5-25% lifetime risk
• Brain/central nervous system tumors: 1-3% lifetime risk
• Sebaceous skin tumors: 1-9% lifetime risk

The risk varies depending on which specific gene is mutated. For example, MLH1 and MSH2 mutations typically carry higher cancer risks than MSH6 or PMS2 mutations.

Warning Signs of Lynch Syndrome

Several clinical indicators in a personal or family history might suggest Lynch Syndrome:

• Colorectal or endometrial cancer diagnosed before age 50
• Multiple Lynch-associated cancers in one individual
• Multiple relatives with Lynch-associated cancers, especially across generations
• Tumors showing microsatellite instability (MSI) or loss of mismatch repair (MMR) proteins on immunohistochemistry testing
• Family history meeting the Amsterdam II criteria or revised Bethesda guidelines.

‍Frequency of Lynch Syndrome

Lynch Syndrome is estimated to affect approximately 1 in 300 to 1 in 400 individuals in the general population. However, this may be an underestimate as many individuals with Lynch Syndrome remain undiagnosed.

Screening Recommendations for Lynch Syndrome

For individuals with Lynch Syndrome, the following screening recommendations typically apply:

• Colonoscopy every 1-2 years, beginning at age 20-25 (or 2-5 years before the earliest colorectal cancer diagnosis in the family, whichever comes first)
• Annual endometrial sampling and transvaginal ultrasound for women, beginning at age 30-35
• Upper endoscopy with gastric biopsy every 3-5 years beginning at age 30-35
• Annual urinalysis beginning at age 30-35
• Consideration of prophylactic hysterectomy and bilateral salpingo-oophorectomy for women who have completed childbearing

Early detection through regular screening has been shown to reduce cancer mortality in Lynch Syndrome carriers significantly.

‍

PALB2: The "New BRCA" in Hereditary Breast Cancer

PALB2 (Partner and Localizer of BRCA2) has emerged as an essential gene in hereditary breast cancer risk. Sometimes referred to as "the new BRCA," PALB2 mutations are now considered the third most common cause of hereditary breast cancer after BRCA1 and BRCA2.

Cancer Risks Associated with PALB2 Mutations

Individuals with PALB2 mutations face increased cancer risks:

• Breast cancer: Women with PALB2 mutations have a 33-58% lifetime risk of developing breast cancer, comparable to the risk associated with BRCA2 mutations
• Male breast cancer: Men with PALB2 mutations have an increased risk, though the exact percentage is still being studied
• Pancreatic cancer: 2-3% lifetime risk, roughly 5-10 times higher than the general population
• Ovarian cancer: Some studies suggest a modestly increased risk, though the data is still evolving

Warning Signs of PALB2 Mutations

‍Clinical features in an individual or a family that might suggest PALB2 mutations include:

• Breast cancer diagnosed at a young age (under 50)
• Multiple cases of breast cancer in the family, especially across generations
• Male breast cancer in the family
• A mix of breast and pancreatic cancers in the family
• Negative testing for BRCA1/2 mutations despite a strong family history of breast cancer

‍Frequency of PALB2 Mutations

PALB2 mutations are found in approximately 1-2% of individuals with hereditary breast cancer who test negative for BRCA1/2 mutations. In the general population, the frequency is estimated to be between 1 in 1,000 and 1 in 5,000 individuals.

Screening Recommendations for PALB2 Mutation Carriers

For individuals with PALB2 mutations, the following screening recommendations are typically advised:

• Annual breast MRI starting at age 30
• Annual mammogram starting at age 30 (alternating with breast MRI every six months)
• Clinical breast exam every 6-12 months
• Consideration of risk-reducing mastectomy based on family history and other risk factors
• Consideration of pancreatic cancer screening in families with a history of pancreatic cancer

‍

Li-Fraumeni Syndrome: TP53 and Multi-Organ Cancer Risk

Li-Fraumeni Syndrome (LFS) is a rare but particularly devastating hereditary cancer syndrome caused by mutations in the TP53 gene. TP53 is often called the "guardian of the genome" because it helps prevent cells with damaged DNA from dividing.

Cancer Risks in Li-Fraumeni Syndrome

LFS dramatically increases the risk of developing multiple types of cancer, often at young ages:

• Breast cancer: Up to 85% lifetime risk in women (often occurring before age 45)
• Soft tissue sarcomas: Approximately 25% lifetime risk
• Osteosarcoma (bone cancer): Approximately 13% lifetime risk
• Brain tumors: Approximately 14% lifetime risk
• Adrenocortical carcinoma: Approximately 10% lifetime risk
• Leukemia and lymphoma: Approximately a 4-5% lifetime risk
• Lung, colorectal, stomach, and other cancers: Also elevated risks

What makes Li-Fraumeni Syndrome particularly challenging is the broad spectrum of affected organs and the early age of onset for many of these cancers.

Warning Signs of Li-Fraumeni Syndrome

Clinical features that might suggest Li-Fraumeni Syndrome include:

• Cancer diagnosis at an unusually young age (especially breast cancer before age 30)
• Multiple primary cancers in a single individual
• Rare cancers such as adrenocortical carcinoma, choroid plexus carcinoma, or childhood sarcomas
• Family history of numerous cancer types consistent with LFS
• Multiple family members with cancer diagnoses before age 45
• Meeting the "Chompret criteria" or "classic Li-Fraumeni criteria" for clinical diagnosis

Frequency of Li-Fraumeni Syndrome

Li-Fraumeni Syndrome is relatively rare, with an estimated prevalence of about 1 in 5,000 to 1 in 20,000 individuals. However, recent evidence suggests it may be more common than previously thought, as milder forms are being identified through more widespread genetic testing.

Screening Recommendations for Li-Fraumeni Syndrome

‍Due to the high risk and broad spectrum of cancers, screening for Li-Fraumeni Syndrome is comprehensive:

• Annual complete physical examination
• Annual brain MRI (or more frequently if symptoms arise)
• Annual whole-body MRI scan
• Yearly breast MRI and mammogram for women beginning at age 20
• Colonoscopy every 2-5 years starting in early adulthood
• Regular dermatologic examination
• Consideration of abdominal ultrasound and blood tests

This intensive surveillance approach, sometimes called the "Toronto Protocol," has shown promising results in detecting cancers at earlier, more treatable stages.

‍

Other Important Hereditary Cancer Syndromes

While Lynch Syndrome, PALB2-associated cancers, and Li-Fraumeni Syndrome represent significant hereditary cancer syndromes, several others warrant attention. 

‍

‍Cowden Syndrome (PTEN Mutations)

Cowden Syndrome is characterized by multiple hamartomas (benign tumor-like growths) and an increased risk of breast, thyroid, endometrial, colorectal, and kidney cancers. Mutations in the PTEN gene cause it, affecting approximately 1 in 200,000 individuals.

‍

Peutz-Jeghers Syndrome (STK11 Mutations)

This syndrome, caused by mutations in the STK11 gene, is characterized by intestinal polyps, pigmented spots on the lips and inside the mouth, and an increased risk of gastrointestinal, breast, ovarian, cervical, and other cancers.

‍

Hereditary Diffuse Gastric Cancer (CDH1 Mutations)

Mutations in the CDH1 gene significantly increase the risk of diffuse gastric cancer and lobular breast cancer. Women with CDH1 mutations have a 42% lifetime risk of developing breast cancer and a 60-80% risk of developing diffuse gastric cancer.

‍

CHEK2 Mutations

CHEK2 mutations are associated with a moderate increase in breast cancer risk (approximately double the general population risk) and possibly increased risks of colon, prostate, and other cancers.

‍

ATM Mutations

ATM mutations are associated with a moderate increase in breast cancer risk (approximately 2-4 times the general population risk) and possibly increased risks of pancreatic, prostate, and other cancers.

‍

Recognizing the Signs of Hereditary Cancer Syndromes

‍Specific patterns in your personal or family history might suggest a hereditary cancer syndrome:

• Cancer diagnosed at an unusually young age (typically before age 50)
• Multiple cases of the same type of cancer in closely related family members
• Multiple primary cancers in a single individual
• Clusters of cancers known to be associated with a specific syndrome
• Rare cancers (such as male breast cancer, adrenocortical carcinoma, or ovarian cancer in women under 40)
• Cancer affecting paired organs (both breasts, both kidneys)
• Cancer in individuals known to be from ethnic backgrounds with founder mutations (such as Ashkenazi Jewish ancestry)

If you notice these patterns in your family, consider discussing genetic counseling with your healthcare provider.

‍

The Role of Genetic Testing

‍Genetic testing can identify mutations that cause hereditary cancer syndromes, allowing for personalized risk assessment and management strategies. The process typically involves:

1. Genetic education: Gaining understanding of your personal and family cancer history, the benefits and limitations of testing, and what the results might mean for you and your family
2. Genetic testing: A blood or saliva sample is analyzed for mutations in cancer-associated genes
3. Results interpretation: A genetic counselor helps you understand what your results mean for your cancer risk
4. Risk management: Recommendations for screening, preventive measures, or treatment options based on your genetic test results

Modern genetic testing often employs panel testing, which analyzes multiple cancer-associated genes simultaneously. This increases the likelihood of identifying hereditary cancer syndromes beyond the most common ones.

‍

Prevention and Management Strategies

• Enhanced surveillance: More frequent or specialized screening tests can help detect cancer at its earliest, most treatable stages
• Risk-reducing medications: Certain medications may help reduce cancer risk in some hereditary syndromes
• Risk-reducing surgery: Removing at-risk organs before cancer develops (such as in mastectomy for high breast cancer risk) can significantly reduce cancer risk
• Lifestyle modifications: Maintaining a healthy weight, regular physical activity, limiting alcohol consumption, and avoiding tobacco may help reduce cancer risk even in those with genetic predispositions

‍

Conclusion

While BRCA1 and BRCA2 mutations are well-known contributors to hereditary cancer risk, Lynch Syndrome, PALB2-associated cancers, Li-Fraumeni Syndrome, and other hereditary cancer syndromes collectively affect thousands of families. Understanding these conditions, recognizing their warning signs, and considering genetic testing when appropriate can lead to early detection and potentially life-saving interventions.

If you have concerns about your family's cancer history, consider speaking with a healthcare provider about a genetic risk assessment. Knowledge is power—and in hereditary cancer syndromes, it could be the power that saves lives

‍