Cancer aetiology

CANCER AETIOLOGY

intrinsic aetiology = cancer syndromes due to inherited genetic lesions (2-5%). For 16 of the 27 cancers studied by deCODE genetics in Iceland, the results indicate that relatives of patients are at a significantly higher risk for cancer. For some cancers this increased risk even extended out to distant -- 3rd to 5th degree relatives. Relatives of individuals with gastric cancers , colorectal cancers , or endothelial cancer were more likely to develop one of these cancers, although not necessarily in the same site as did their relative. Gastric cancers , lung cancers and colorectal cancers were also seen more frequently in the mates of patients, confirming lifestyle or environmental factors contribute to increased risk.
extrinsic aetiology = genetic lesions acquired during post-zygotic life (95-98%). Age-specific cancer rates show large historical increases that indict environmental risk factors. But these environmental factors did not necessarily act by increasing oncomutation rates. Mathematical analyses suggest selective effects on pre-existing oncomutants. The widely held hypothesis that environmental chemicals induce a substantial fraction of human point mutations has not been supported by observation. Direct measurement of the kinds and numbers of point mutations in human tissues have, in fact, found no clear relationship with exposure to environmental agents, save for sunlight in the skin. Alternative hypotheses that point mutations arise primarily as errors during turnover of undamaged DNA and that environmental conditions select rather than induce oncomutants seem to better explain the facts of environmental carcinogenesis in humans.

physical aetiology (1%) : ionizing radiations

diagnostic radiations (modern devices expose to 1-2 mGy and cause < 1% of all breast carcinomas )
therapeutic radiations (1% of cancer mortality)
environmental radiations (3% of cancer mortality)

UV rays in sunlight (1%)
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chemical aetiology : naturally occurring and synthetic carcinogens

food (30-35% of cancer mortality) : the hypothesis that "overnutrition" increases the risk of bowel cancer is supported by studies within the populations of the developed world, where overconsumption of energy, low levels of physical activity, high body mass index, and abdominal obesity are strong independent risk factors for colorectal carcinoma , much as they are for insulin resistance and cardiovascular disease. A similar link to obesity has been established for esophageal adenocarcinoma , once the rarest form of cancer of the esophagus but now advancing rapidly throughout North America and Western Europe.

food additives (1%)

Web resources

Cancer & diet

tobacco smoking (30-32% of cancer mortality)
industrial activities (1-4% of cancer mortality)
ethanol (3-4% of cancer mortality)
environmental pollution (2% of cancer mortality)

chronic infections (8% in developed countries, 25% in developing countries; reproductive and sex habits are responsible for 7% of cancer mortality)

		benign hyperplasia	malignant neoplasms
oncogenic viruses	HHV-4 / EBV	oral hairy leukoplakia , immunoproliferative syndrome or lymphoproliferative disease in immunocompromised inviduals	Burkitt lymphoma , nasopharyngeal carcinoma , Hodgkin's lymphoma (HL), B-cell chronic lymphocytic leukemia (B-CLL) in immunocompromised patients
	HHV-8 / KSHV		Kaposi's sarcoma
	HBV	liver focal hyperplasia	hepatocellular carcinoma (HCC)
	HPV-5 HPV-8 HPV-14 HPV-17 HPV-20	cutaneous plaques and papillomas in patients with epidermodysplasia verruciformis	squamous cell carcinoma (SCC) in immunocompromised patients
	HPV-6 HPV-10 HPV-11 HPV-16 HPV-18 HPV-31 HPV-33 HPV-35 HPV-39 HPV-40 HPV-42 HPV-43 HPV-44 HPV-45 HPV-51 HPV-52 HPV-56 HPV-58 HPV-59 HPV-61	cervical intraepithelial neoplasia (CIN), neoplasms of vulva and penis and perianal intraepithelial neoplasia (PIN)	50% of cervical carcinomas (95% from the 5 species in bold characters; pooled OR for cervical carcinoma associated with the presence of any HPV = 158.2) vulvar carcinoma penile intraepithelial neoplasia (PIN) anal cancer
	HPV-6 HPV-11	condyloma acuminatum Heck focal epithelial hyperplasia	verrucous carcinoma of vulva and penis, Buschke-Löwenstein giant condyloma
	HTLV-1	attenuated leukemia	ATL
	HHMMTV		breast cancers
oncogenic Bacteria	Helicobacter pylori	gastric dysplasia	distal gastric adenocarcinoma
oncogenic Metazoa	Opisthorchis viverrini	cholangitis	cholangiocarcinoma

Web resouces

Retrovirus as carcinogens and pathogens : expectations and reality by Peter Duesberg
Latent viruses and mutated oncogenes : no evidence for pathogenicity by Peter Duesberg

unknown (5%)

disruption of circadian rhythms - either through constant light exposure or by pinealectomy - accelerates breast epithelial stem-cell proliferation, induces mammary-gland development and increases the formation of spontaneous mammary tumours in rodents and accelerates cancer progression in tumour-bearing animals and in cancer patients. The activity of the immune system, usually represented by the number of lymphocytes, peaks in the late evening and is lowest in the early morning : disruption in this circadian rhythm could therefore lead to immune suppression, which could disrupt cancer immunosurveillance and promote tumour development. Immune product such as cytokines can also act to modulate the activity of the SCN clock and the HPA and HPG axes, providing an immune-regulatory, circadian-paced feedback loop. Mice with disruptions in the core circadian gene Per2 display salivary gland hyperplasia and develop lymphoma (spontaneously and after exposure to g-radiation).
chronic inflammation (20% of sporadic cancers) : activation of NF-kB , a hallmark of inflammatory responses that is frequently detected in tumours, constitutes a missing link between inflammation and cancer. The Mdr2-knockout mouse strain spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma (HCC), a prototype of inflammation-associated cancer : the inflammatory process triggers hepatocyte NF-kB through upregulation of TNF-a in adjacent endothelial and inflammatory cells. Switching off NF-kB in mice from birth to 7 months of age, using a hepatocyte-specific inducible IkB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kB inhibition through anti-TNFa treatment or induction of IkB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to HCC^ref