How neoplasia is tested on Step 1
Questions name a gene and ask for its function or its tumor, name a carcinogen and ask for its cancer, or describe a tumor and ask about its spread, grade, or stage.
Cancer is accumulated DNA damage that turns on growth (oncogenes), turns off brakes (tumor suppressors), disables repair, and evades death β selected over many cell divisions.
Benign vs malignant
Behavior, not size, separates benign from malignant tumors. Naming usually signals which: "-oma" is benign (adenoma, leiomyoma), "carcinoma" is malignant epithelium, and "sarcoma" is malignant mesenchyme.
Oncogenes and tumor suppressor genes
Normal growth depends on accelerators (proto-oncogenes) and brakes (tumor suppressors). Cancer needs mutations in both.
| Gene | Type | Associated cancers |
|---|---|---|
| KRAS | Oncogene (GTPase) | Pancreatic, colon, lung adenocarcinoma |
| HER2 (ERBB2) | Oncogene (receptor tyrosine kinase) | Breast, gastric β target of trastuzumab |
| BCR-ABL t(9;22) | Oncogene (tyrosine kinase) | Chronic myeloid leukemia β target of imatinib |
| c-MYC t(8;14) | Oncogene (transcription factor) | Burkitt lymphoma |
| TP53 | Tumor suppressor (G1/S checkpoint) | Most cancers; Li-Fraumeni syndrome |
| RB1 | Tumor suppressor (holds E2F) | Retinoblastoma, osteosarcoma |
| APC | Tumor suppressor (Wnt/Ξ²-catenin) | Familial adenomatous polyposis, colorectal cancer |
| BRCA1/2 | Tumor suppressor (DNA repair) | Breast, ovarian, prostate, pancreatic |
A few genes, like BCL2, act by blocking apoptosis rather than driving proliferation.
Carcinogens and oncogenic infections
Chemicals, radiation, and microbes cause cancer by damaging DNA or by driving chronic proliferation.
| Agent | Cancer |
|---|---|
| Aflatoxin (Aspergillus on grains, nuts) | Hepatocellular carcinoma |
| Asbestos | Bronchogenic carcinoma (most common), mesothelioma |
| Aromatic amines, cigarette smoke, cyclophosphamide | Urothelial (bladder) carcinoma |
| Vinyl chloride, arsenic | Hepatic angiosarcoma |
| Nitrosamines (smoked foods) | Gastric carcinoma |
| Ionizing radiation | Leukemia, papillary thyroid carcinoma |
| HPV 16/18 | Cervical, anal, oropharyngeal carcinoma (E6 inactivates p53, E7 inactivates RB) |
| EBV | Burkitt and Hodgkin lymphoma, nasopharyngeal carcinoma |
| HBV, HCV | Hepatocellular carcinoma |
| H. pylori | Gastric adenocarcinoma, MALT lymphoma |
Smoking causes more cancer types than any other single carcinogen β lung, oral, larynx, esophagus, pancreas, kidney, bladder, and cervix.
Invasion and metastasis
To metastasize, a carcinoma cell must detach (loss of E-cadherin), degrade the basement membrane (metalloproteinases, e.g. collagenase IV), migrate through the stroma, enter vessels, survive in the circulation, and grow at a distant site.
- Lymphatic spread: typical of carcinomas β first to regional nodes.
- Hematogenous spread: typical of sarcomas, and of renal cell carcinoma, hepatocellular carcinoma, follicular thyroid carcinoma, and choriocarcinoma.
- Seeding of body cavities: ovarian carcinoma across the peritoneum.
- Common destinations: liver and lung (most common overall), bone, and brain.
Grade vs stage
Two different questions: how abnormal are the cells, and how far has the tumor spread?
A 6-month-old has bilateral retinoblastoma. Her father had retinoblastoma as a child and later developed osteosarcoma. What is the inheritance mechanism, and why are the tumors bilateral?
- RB1 is a tumor suppressor gene; both alleles must be inactivated for a tumor to form.
- The child inherited one mutated RB1 allele from her father in every cell (germline first hit).
- Only one additional somatic hit is needed in any retinal cell, so multiple tumors arise early, often in both eyes.
Answer. Familial retinoblastoma β a germline loss-of-function RB1 mutation (two-hit hypothesis). Survivors are also at increased risk for osteosarcoma.