Oncogenes & Tumor Suppressors

THE CLINICAL PHOTOS

What These Genes Look Like

Retinoblastoma, neurofibromatosis, renal cell carcinoma, and breast cancer. Tap any photo to enlarge.

Retinoblastoma: leukocoria

NF1: cafe-au-lait spots

CML: BCR-ABL smear

The Core Concept

Cancer genetics comes down to two types of broken genes:

Oncogenes = gain of function. One mutant allele is enough. The gas pedal gets stuck ON.
Tumor suppressors = loss of function. Both alleles must be lost (two-hit hypothesis). The brake pedal is removed.

Methylation is the #1 way to silence genetic material. It requires energy. As you age, your energy for methylation drops, which is why your ability to suppress oncogenes declines with age. Cancer is a disease of aging.

★ The enhancer analogy: An enhancer jumps up and says "hey, he needs seven million cells today, not the regular two million." It enhances how many copies get made. When an oncogene is activated, it is like an enhancer stuck in the ON position.

INTERACTIVE

Gain vs Loss Sorting Game

Tap a gene chip, then tap the correct bucket to place it. Oncogenes gain a function. Tumor suppressors lose one.

Tap a gene chip below, then tap the correct bucket to place it.

Oncogene (Gain of Function)

Tumor Suppressor (Loss of Function)

THE CONCEPTS

High-Yield Cancer Genetics

The associations that show up on every board exam. Tap to learn each one.

Two-Hit Hypothesis (Knudson)

Tumor suppressors require both alleles to be knocked out. Inherited (familial) cancers get the first hit from a germline mutation at birth. They only need one more somatic hit. Sporadic cancers need both hits to happen somatically, which takes longer.

This is why inherited retinoblastoma presents bilateral and early (both eyes, childhood), while sporadic retinoblastoma presents unilateral and later (one eye, older child).

NF1 vs NF2

NF1: Chromosome 17 (17 has a "1" in it). Peripheral neurofibromatosis. Cafe-au-lait spots, Lisch nodules, axillary freckling, optic gliomas.

NF2: Chromosome 22 (22 has two "2"s in it). Central neurofibromatosis. Bilateral acoustic neuromas (vestibular schwannomas). Think: "2 ears, 2 tumors, chromosome 22."

The "Liar" Omas

These end in "-oma" but are malignant despite the benign-sounding suffix:

Hepatoma (hepatocellular carcinoma)
Melanoma
Lymphoma
Mesothelioma
Seminoma
Teratoma (can be malignant)

Metastasis Targets

The six places cancer loves to go: Brain, bone, lung, liver, adrenal, pericardium. Metastatic disease is far more common than primary cancers at these sites.

⚠️

Board Trap: VHL Location

VHL is on the short arm of chromosome 3. It causes renal cell carcinoma, hemangioblastomas (cerebellum, retina, spinal cord), and pheochromocytoma. VHL normally degrades HIF (hypoxia-inducible factor). Without VHL, HIF stays active and drives VEGF production, which is why these tumors are so vascular.

ELIMINATION GAME

Name That Mutation

A clinical vignette. Eight possible genes. Eliminate until one stands. Tap to eliminate.

Elimination Round

A 2-year-old boy presents with leukocoria (white pupillary reflex) in the left eye. His father had bilateral eye tumors removed at age 3. Genetic testing reveals a germline mutation. Which gene is responsible?

Tap cards to eliminate them. The correct gene will be the last one standing.

RAS

Oncogene. Gain-of-function. Not eye tumors.

BCR-ABL

Philadelphia chromosome. CML. Hematologic.

RB1

Tumor suppressor. Chromosome 13q14.

APC

Familial adenomatous polyposis. Colon.

HER2/neu

Oncogene. Breast cancer amplification.

BRCA1

DNA repair. Breast and ovarian cancer.

VHL

Renal cell carcinoma. Chromosome 3p.

p53

Guardian of genome. Li-Fraumeni syndrome.

BOARD-STYLE WALKTHROUGH

Clinical Vignettes

25 original board-style questions. Shuffled, never-repeat. Post-answer clue highlights show you what to look for next time.