Cancer Inheritance: Understanding Genetic Risk & Family History

Cancer risk reflects interplay of genetic susceptibility and environmental exposures.

Hereditary Cancer Syndromes (~5–10% of cancers)

Autosomal dominant mutations in high-penetrance genes:

• HBOC: BRCA1/2 → breast, ovarian, prostate, pancreatic.
• Lynch: MLH1, MSH2, MSH6, PMS2, EPCAM → colorectal, endometrial, ovarian, gastric.
• FAP/MAP: APC/MUTYH → colorectal polyposis.
• Li-Fraumeni: TP53 → sarcomas, breast, brain, adrenocortical.
• Others: CDH1 (diffuse gastric), STK11 (Peutz-Jeghers), VHL, MEN1/2.

Familial Clustering (Common Cancers)

Breast, colorectal, prostate, pancreatic — 2–3× risk with 1 FDR affected. Polygenic + shared environment.

Genetic Testing Indications

• Early onset (<50), multiple primaries, rare cancers, known family mutation, ancestry (Ashkenazi Jewish — 1/40 BRCA founder).

Management if Mutation Positive

• Enhanced screening (MRI, earlier colonoscopy).
• Risk-reducing surgery (mastectomy, BSO, colectomy).
• Chemoprevention (tamoxifen, aspirin).
• Cascade testing of relatives.

Key Takeaway

Most cancers are sporadic. Strong family history or early onset warrants genetic counseling/testing. Identification enables life-saving prevention.