Carcinogens & Tumor Markers

How carcinogens cause cancer

Initiation then promotion. Chemical carcinogenesis is a two-step process. Initiation is a permanent DNA mutation caused by a mutagenic carcinogen. Promotion is proliferation of the mutated clone, driven by agents (hormones, chronic irritation, phorbol esters) that are not mutagens themselves; a promoter produces tumors only when it acts after an initiator.

Direct-acting vs procarcinogens. Direct-acting carcinogens, such as alkylating agents (busulfan, melphalan), need no activation. Most chemical carcinogens are procarcinogens that cytochrome P450 enzymes convert into reactive electrophiles that form DNA adducts. Examples: aflatoxin B1 and the polycyclic aromatic hydrocarbons of tobacco smoke (benzo[a]pyrene). Inherited variation in these P450 enzymes partly explains why exposed people differ in cancer risk.

Radiation. Ionizing radiation causes DNA strand breaks and predisposes to leukemia and papillary thyroid carcinoma (especially after childhood exposure). UV light (UVB) creates pyrimidine dimers, causing basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin.

Chemical carcinogens by target organ

Aflatoxin → hepatocellular carcinoma. Aflatoxin B1 is made by Aspergillus growing on improperly stored grains, peanuts, and corn. It leaves a signature TP53 mutation at codon 249 (a G→T transversion) and synergizes strongly with hepatitis B. Classic vignette: HBV carrier + moldy grain + liver mass + high AFP.

Vinyl chloride, arsenic, Thorotrast → hepatic angiosarcoma. Same organ, different tumor: angiosarcoma is a malignant endothelial tumor, not the hepatocellular carcinoma caused by aflatoxin or hepatitis viruses. Vinyl chloride exposure comes from PVC plastic manufacturing; Thorotrast is an obsolete thorium-based radiographic contrast agent. Arsenic also causes squamous cell carcinoma of the skin and lung cancer.

Aromatic amines → bladder. β-Naphthylamine, benzidine, and aniline dyes cause urothelial (transitional cell) carcinoma of the bladder. Exposure occurs in the dye, rubber, and textile industries and through cigarette smoke, the leading risk factor for bladder cancer.

Asbestos → lung and pleura. Occupational exposure in shipbuilding, roofing, and insulation work. Bronchogenic carcinoma is the most common asbestos-related cancer; mesothelioma is the most specific. Exposure markers are ferruginous (asbestos) bodies, golden-brown beaded rods that stain with Prussian blue, and calcified pleural plaques. Smoking multiplies the lung cancer risk.

Oncogenic viruses and other infections

HPV 16 and 18. High-risk types integrate into host DNA and express two oncoproteins: E6 degrades p53 (losing the arrest/apoptosis brake) and E7 inhibits Rb (freeing E2F). The result is unchecked cycling, dysplasia, and squamous cell carcinoma of the cervix, anus, vulva, penis, and oropharynx. Low-risk types 6 and 11 cause benign condylomata acuminata. Memory aid: E6 hits p53 ("Six-P"), E7 hits Rb ("seveN").

Bacteria and parasites. These act mainly through chronic inflammation and regenerative proliferation.

• H. pylori: gastric adenocarcinoma and gastric MALT lymphoma; the MALT lymphoma can regress after antibiotic eradication of the organism.
• Schistosoma haematobium: chronic bladder inflammation with squamous metaplasia → squamous cell carcinoma of the bladder.
• Clonorchis sinensis (liver fluke from undercooked fish): cholangiocarcinoma.

Serum tumor markers

Monitor, rarely screen. Tumor markers are too nonspecific to screen for or diagnose cancer. Their main role is tracking response to treatment and detecting recurrence: a marker should fall after resection, and a later rise suggests relapse. PSA is the notable screening exception, and even it is controversial because it also rises in BPH and prostatitis. Cancer is confirmed by biopsy.

Pure seminoma does not make AFP: a testicular tumor with a high AFP contains a nonseminomatous (yolk sac) component.