Inherited cancer syndromes (autosomal dominant, recessive and familiar)

1. Concept

Cancer arises from genetic predisposition + environmental factors. Inherited syndromes carry a germline mutation → high lifetime risk, earlier onset, multiple/bilateral tumors, strong family history. The same genes also drive sporadic cancers.

2. Autosomal dominant syndromes

Inherit one mutant tumor-suppressor allele; a somatic second hit later in life triggers cancer (Knudson two-hit).

Gene	Syndrome	Tumors
RB1	Familial retinoblastoma	Bilateral retinoblastoma (small round-cell retinal tumor); secondary osteosarcoma
APC	Familial adenomatous polyposis (FAP)	Hundreds of colonic polyps → colorectal carcinoma by age 15–20
TP53	Li-Fraumeni	Sarcomas, breast, leukemia, brain, adrenocortical carcinoma (~50× risk by 50)
BRCA1/2, PTEN	HBOC / Cowden	Breast, ovarian; PTEN → hamartomas

• HNPCC / Lynch (MMR genes MLH1, MSH2, MSH6, PMS2) → MSI → colon + endometrial ± ovarian.

3. Autosomal recessive syndromes

Both alleles mutated; usually defective DNA repair.

• Xeroderma pigmentosum (NER defect) → UV thymine dimers uncorrected → skin cancers (BCC, SCC, melanoma).
• Ataxia-telangiectasia (ATM, HR repair defect) → cerebellar ataxia, telangiectasias, radiosensitivity; ↑ breast cancer, lymphoma/leukemia.

4. Familial cancers

• High cancer frequency in families without a defined inheritance pattern; likely multifactorial.
• Features: early onset, ≥2 affected relatives, multiple/bilateral tumors. Examples: colon, breast, ovary, brain.

💡 High-yield: AD (two-hit tumor suppressors): RB1 (retinoblastoma), APC (FAP), TP53 (Li-Fraumeni), BRCA1/2; Lynch (MMR → MSI, colon+endometrial). AR (DNA repair): xeroderma pigmentosum (NER → skin cancer), ataxia-telangiectasia (ATM). Familial = clustering, multifactorial, early/bilateral.