Hereditary Cancer Syndromes

Introduction & Red Flags - Syndrome Spotting 101

• Hereditary Cancer Syndromes (HCS): Inherited genetic predisposition to developing cancer.
• Primarily Autosomal Dominant (AD) inheritance pattern.
• Caused by germline mutations in critical cancer genes (tumor suppressors, oncogenes, DNA repair).
• Red Flags:
  • Multiple primary cancers in one person.
  • Cancer in ≥2 close relatives (same lineage).
  • Early cancer onset (e.g., breast/colon < 50 yrs).
  • Bilateral/multifocal disease (e.g., bilateral retinoblastoma).
  • Rare cancers (e.g., male breast cancer).
  • Specific tumor patterns (e.g., MTC & pheo in MEN2).

⭐ Most HCS exhibit Autosomal Dominant inheritance.

BRCA & Li-Fraumeni - The Breast/Ovary Axis

• BRCA1 & BRCA2 (Autosomal Dominant - AD): Tumor suppressor genes.
  • Associated Cancers: Breast (esp. Triple Negative with BRCA1), Ovarian (serous), Prostate, Pancreatic, Melanoma.
  • Management:
    • Screening: Annual breast MRI from age 25.
    • Prophylaxis: Risk-Reducing Salpingo-Oophorectomy (RRSO) by age 35-40 (BRCA1), 40-45 (BRCA2). Risk-reducing mastectomy.
• Li-Fraumeni Syndrome (LFS) (AD): Germline TP53 mutation.
  • Core Cancers (📌 SBLA): Sarcoma, Breast (often early onset, premenopausal), Leukemia/Lymphoma, Adrenocortical carcinoma. Also brain tumors.
  • Management: Rigorous surveillance (e.g., whole-body MRI). Crucially, avoid radiation therapy due to ↑ risk of secondary cancers.

⭐ Women with BRCA1 mutation have a lifetime risk of developing breast cancer of approximately 65-72% and ovarian cancer of 39-44% by age 80.

Lynch & FAP - Colon's Genetic Foes

• Lynch Syndrome (HNPCC)
  • Autosomal Dominant (AD).
  • Defect in DNA Mismatch Repair (MMR) genes: MLH1, MSH2, MSH6, PMS2. 📌 "Lynch Mobs Miss Matches".
  • Amsterdam II / Revised Bethesda Guidelines for diagnosis.
  • ↑ risk: Colorectal (CRC, often R-sided), endometrial, ovarian, stomach.
  • Microsatellite Instability-High (MSI-H).
• Familial Adenomatous Polyposis (FAP)
  • Autosomal Dominant (AD).
  • APC gene mutation (tumor suppressor).
  • Hundreds to thousands of colonic adenomatous polyps.
  • Near 100% CRC risk by age 40 if untreated.
  • Variants: Gardner (osteomas, desmoids, CHRPE), Turcot (CNS tumors like medulloblastoma).

⭐ Prophylactic colectomy, often total proctocolectomy with IPAA, is standard for FAP by early adulthood (e.g., age 20-25) due to ~100% CRC risk.

MEN & Other Notables - MENagerie of Syndromes

• MEN 1 (Wermer Syndrome): Gene: MEN1 (tumor suppressor). 📌 3 P's:
  • Parathyroid hyperplasia (most common, >90%)
  • Pancreatic neuroendocrine tumors (e.g., gastrinoma, insulinoma)
  • Pituitary adenoma (e.g., prolactinoma)
• MEN 2A (Sipple Syndrome): Gene: RET (proto-oncogene).
  • Medullary Thyroid Carcinoma (MTC) (penetrance ~100%)
  • Pheochromocytoma (~50%, often bilateral)
  • Primary Hyperparathyroidism (~20-30%)
• MEN 2B: Gene: RET (distinct mutations).
  • MTC (earlier onset, more aggressive)
  • Pheochromocytoma
  • Mucosal neuromas (lips, tongue), Marfanoid habitus, Intestinal ganglioneuromatosis
• Von Hippel-Lindau (VHL) Disease: Gene: VHL (tumor suppressor).
  • Hemangioblastomas (CNS, retina)
  • Clear cell Renal Cell Carcinoma (often bilateral, multiple)
  • Pheochromocytoma, Pancreatic cysts/NETs

⭐ In MEN 2 syndromes (RET mutations), Medullary Thyroid Carcinoma (MTC) is the index tumor; prophylactic thyroidectomy based on RET mutation risk stratification is recommended. oka

High‑Yield Points - ⚡ Biggest Takeaways

• Li-Fraumeni (TP53): High risk for sarcomas, breast, brain, adrenocortical cancers.
• HBOC (BRCA1/2): ↑ Breast, ovarian, prostate, pancreatic cancer risk; prophylactic surgery (mastectomy, oophorectomy) is key.
• Lynch Syndrome (MMR genes): ↑ Colorectal, endometrial, ovarian, stomach cancer risk. Screen early.
• FAP (APC gene): Thousands of colonic polyps, near 100% CRC risk; prophylactic colectomy mandatory.
• MEN1 (MEN1 gene): Parathyroid hyperplasia, Pancreatic NETs, Pituitary adenomas (3Ps).
• MEN2 (RET gene): Medullary Thyroid Cancer (MTC), Pheochromocytoma. Prophylactic thyroidectomy for MTC.
• VHL (VHL gene): Hemangioblastomas (CNS/retina), Renal Cell Carcinoma, Pheochromocytomas.