STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

Tumor Suppressors & DNA Repair

The brakes and the mechanics: lose both copies of a brake, or the repair crew, and mutations pile up.

FOCUS ON
Use the two-hit model. Inherited syndromes start with one bad copy in every cell, so tumors come early, bilateral and multiple. Know p53 and Rb at the G1/S checkpoint, the syndrome for each gene, and the four DNA repair systems.
GENE
NORMAL ROLE
INHERITED SYNDROME
SPORADIC TUMORS
TP53
17p · "guardian"
Senses DNA damage → p21 halts G1/S → repair or apoptosis (BAX)
Li-Fraumeni: sarcomas, early breast cancer, leukemia, adrenocortical carcinoma, brain tumors
Most commonly mutated gene in human cancer
RB
13q14
Hypophosphorylated Rb holds E2F; cyclin D/CDK4 phosphorylates it to allow S phase
Familial retinoblastoma (bilateral, early) + osteosarcoma
Unilateral retinoblastoma in older child
APC
5q21
Degrades β-catenin (Wnt pathway)
Familial adenomatous polyposis (hundreds of polyps)
First hit in most sporadic colon cancers
BRCA1 · BRCA2
17q · 13q
Homologous recombination repair of double-strand breaks
Hereditary breast/ovarian cancer (BRCA1); breast incl. male, pancreas, prostate (BRCA2)
PARP inhibitors (olaparib)
NF1 · NF2
17q · 22q
Neurofibromin = RAS GTPase-activating protein · merlin = cytoskeletal link
NF1: neurofibromas, café-au-lait, Lisch nodules · NF2: bilateral vestibular schwannomas, meningiomas
—
VHL
3p
Targets HIF-1α for degradation
von Hippel-Lindau: hemangioblastomas, bilateral clear cell RCC, pheochromocytoma
Sporadic clear cell RCC
WT1 · PTEN
11p13 · 10q
Kidney/gonad development · inhibits PI3K/AKT
Wilms tumor (WAGR, Denys-Drash) · Cowden: hamartomas, breast, thyroid, endometrial cancer
PTEN: prostate, endometrial
CDKN2A (p16) · SMAD4 · STK11
Inhibits CDK4 · TGF-β signaling · cell polarity kinase
Familial melanoma · juvenile polyposis · Peutz-Jeghers
Pancreatic carcinoma (p16, SMAD4/DPC4)
Mismatch repair
MLH1, MSH2, MSH6, PMS2
Fixes base mispairs after replication
Lynch syndrome: right-sided colon, endometrial, ovarian cancers
Microsatellite instability (MSI-high)
Nucleotide excision repair
Removes bulky lesions (UV pyrimidine dimers)
Xeroderma pigmentosum: skin cancers in childhood, photosensitivity
—
Other repair defects
Base excision · double-strand break sensing · helicases
MUTYH polyposis · ataxia-telangiectasia (ATM) · Fanconi anemia · Bloom syndrome
Radiation and chemo sensitivity

Mechanism — the G1/S checkpoint and two hits

DNA damageDetected
→
p53 ↑→ p21
→
CDK4 blockedRb stays bound to E2F
→
ArrestRepair or apoptosis
Inherited 1st hitEvery cell
→
Somatic 2nd hitLoss of heterozygosity
→
TumorEarly, bilateral, multiple

HPV short-circuits the brake: E6 degrades p53 and E7 inactivates Rb.

DNA repair systems

SYSTEM
FIXES
DEFECT
Mismatch repair
Mispaired bases after replication
Lynch syndrome (MSI)
Nucleotide excision
Bulky adducts, pyrimidine dimers
Xeroderma pigmentosum
Base excision
Single damaged bases
MUTYH-associated polyposis
Homologous recombination
Double-strand breaks (sister template)
BRCA1/2, Fanconi, Bloom, A-T
Non-homologous end joining
Double-strand breaks (no template)
Some SCID forms; radiosensitivity

How it's tested

COMMON CONFUSIONFAP gives hundreds of polyps. Lynch gives few polyps but early, right-sided cancers with MSI. Both are autosomal dominant.
THE TRAPA child treated for bilateral retinoblastoma later develops a bone tumor. This is germline RB loss causing osteosarcoma, not a radiation side effect alone.
YOUR APPROACHSyndrome → gene → normal job. Germline cases mean early, bilateral or multiple tumors and a family history.

If you see… think…

Bilateral retinoblastoma in infancy, osteosarcoma later → germline RB
Family with sarcomas, young breast cancer, adrenal carcinoma, brain tumors → Li-Fraumeni (TP53)
Hundreds of colon polyps by age 20 → FAP (APC)
Colon cancer at 42, mother with endometrial cancer → Lynch (mismatch repair)
Bilateral clear-cell RCC + cerebellar hemangioblastoma → VHL
Bilateral vestibular schwannomas → NF2
Café-au-lait spots, neurofibromas, Lisch nodules → NF1 (RAS GAP)
Child with freckling and skin cancers after minimal sun → xeroderma pigmentosum
BRCA-mutated ovarian cancer → PARP inhibitor
Mucocutaneous freckles + hamartomatous GI polyps → Peutz-Jeghers (STK11)