This article explores the most common hereditary cancer syndromes, their associated genetic mutations, clinical features, and management approaches.

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1. Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

Key genes involved:

• BRCA1 and BRCA2: Mutations in these genes account for the majority of HBOC cases
• Other associated genes: PALB2, RAD51C, RAD51D, and BRIP1

Associated cancers:

• Breast cancer (both males and females)
• Ovarian cancer
• Pancreatic cancer
• Prostate cancer (in men)

Hallmark features:

• Early-onset breast or ovarian cancer, often before age 50
• Family history of breast and/or ovarian cancer across multiple generations
• Occurrence of bilateral breast cancer or male breast cancer in the family

Management strategies:

1. Enhanced screening: Regular mammograms and breast MRIs starting earlier than standard guidelines.
2. Risk-reducing surgeries: Preventive mastectomy or salpingo-oophorectomy.
3. Chemoprevention: Use of medications such as tamoxifen.
4. Family genetic counselling: Encouraging testing for at-risk relatives.

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2. Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer, HNPCC)

Key genes involved:

• MLH1, MSH2, MSH6, PMS2, and EPCAM. Associated Cancers
• Colorectal cancer
• Endometrial (uterine) cancer
• Ovarian, stomach, small intestine, hepatobiliary, and urinary tract cancers

Hallmark features:

• Early onset colorectal cancer, typically before age 50
• Multiple primary cancers in a single individual
• Strong family history of Lynch-associated cancers

Management strategies:

1. Colonoscopy surveillance: Starting at age 20-25 or earlier based on family history.
2. Prophylactic surgeries: Hysterectomy and oophorectomy after childbearing in women.
3. Preventive medication: Aspirin may reduce colorectal cancer risk.
4. Genetic testing: For family members at risk.

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3. Familial Adenomatous Polyposis (FAP)

Key gene involved:

• APC

Associated cancers:

• Colorectal cancer (nearly 100% lifetime risk if untreated)
• Duodenal, thyroid, and liver cancers

Hallmark features:

1. Development of hundreds to thousands of adenomatous polyps in the colon and rectum, often during adolescence.
2. High risk of cancer by early adulthood.

Management strategies:

1. Regular surveillance: Colonoscopy or sigmoidoscopy starting in adolescence.
2. Surgical interventions: Colectomy is often recommended in early adulthood.
3. Extracolonic cancer screening: Regular endoscopy to monitor for duodenal polyps.
4. Family genetic testing: Testing for siblings and offspring.

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4. Li-Fraumeni Syndrome

Key gene involved:

• TP53

Associated cancers:

• Soft tissue sarcomas
• Osteosarcomas
• Breast cancer
• Brain tumours
• Adrenocortical carcinoma

Hallmark features:

1. Early-onset of various cancers, often in childhood or young adulthood.
2. Multiple primary cancers in an individual.
3. Strong family history of diverse cancers.

Management strategies:

1. Comprehensive screening: Whole-body MRI and other imaging modalities.
2. Avoid radiation therapy: Minimise exposure due to increased risk of radiation-induced cancers.
3. Family genetic counselling: Testing and monitoring for relatives.

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5. Cowden Syndrome

Key gene involved:

• PTEN

Associated cancers:

• Breast cancer
• Thyroid cancer (typically follicular type)
• Endometrial cancer
• Renal cell carcinoma
• Colorectal cancer

Hallmark features:

• Presence of hamartomas (benign growths) in multiple organ systems
• Distinctive skin findings such as trichilemmomas and papillomatous papules
• Macrocephaly (large head size)

Management strategies:

1. Tailored cancer screening: Regular breast, thyroid, and endometrial screenings.
2. Family counselling and testing: Identify at-risk relatives.

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6. Peutz-Jeghers Syndrome (PJS)

Key gene involved:

• STK11 (LKB1)

Associated cancers:

• Gastrointestinal cancers (stomach, small intestine, colon, and pancreas)
• Breast cancer
• Ovarian and testicular cancers

Hallmark features:

• Pigmented spots on the lips, mouth, and fingers (mucocutaneous pigmentation)
• Hamartomatous polyps in the gastrointestinal tract

Management strategies:

1. Endoscopic surveillance: Regular GI tract monitoring.
2. Routine cancer screening: Based on family history and associated risks.
3. Family counselling: Testing for relatives at risk.

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7. Von Hippel-Lindau Syndrome (VHL)

Key gene involved:

• VHL

Associated cancers:

• Renal cell carcinoma
• Pheochromocytomas
• Hemangioblastomas of the brain, spinal cord, and retina
• Pancreatic neuroendocrine tumours

Hallmark features:

• Tumours or cysts affecting multiple organs
• Early onset of associated conditions

Management strategies:

1. Regular imaging: Monitor the brain, spine, and abdomen.
2. Screening for pheochromocytomas: Measure blood pressure and catecholamine levels.
3. Genetic testing and counselling: Encourage testing among family members.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr. Archi Rungta is a BDS graduate from Government Dental College and Hospital, Mumbai.