General predisposition (heredity) and environment can be viewed as the two ends of a spectrum of predisposing influence. At the extreme are those neoplasms developing because of a strong hereditary component and those related to heavy exposure to environmental carcinogens, but in between are the great majority resulting from varying proportions of heredity and environment.
GENETIC FACTORS AND CARCINOGENESIS Genetic hypothesis:
The understanding of this hypothesis begins with retroviruses. Retroviruses are RNA viruses which possess Reverse Transcripts that allows reverse transcription of viral RNA into virus- specific DNA. This DNA transcript may then be incorporated into a malignant cell. But the entire viral RNA is not necessary for this transformation, only a single gene will suffice. This gene is called an oncogene or V-onc (viral oncogene).
It was then found that within the genome of normal cells of almost all species (including humans) there were genes which were closely homologous to V-oncs. These genes were termed as Proto-oncogenes or c-oncs (cellular oncogenes).
(The homology between V-oncs and c-ons, and other evidence strongly suggests that c-ons were captured and perhaps modified during evolution by actively transforming retroviruses.) These c- oncs under certain circumstances can be induced to evoke cancers. The potential mechanisms by which this occurs are:
1. direct over-expression of the c-onc;
2. inhibition of cellular regulatory genes, thereby promoting over -expression of the c-oncs;
3. alteration (mutation) in the c-onc.
The mutations are usually point mutations. They may be- a. random accidents; b. induced by environment carcinogens.
However, it is unlikely that oncogenesis is related to a single mutational event. It probably involves two or more genetic changes -one is necessary for replicative activity and escape from growth controls; the other confers the cancerous phenotypic characteristics.
This probably explains why cells already bearing a hereditary mutation as in Down’s syndrome are particularly susceptible to oncogenesis.
It is also still not clear how the activated oncogenes bring about the phenotypic alterations characteristic of cancer cells.
Epigenetic aberrant differentiation hypothesis:
Normally all cells in an individual possess the identical genome but the phenotype differs depending upon the `turning’ on and off of genes. Thus nerve cells differ from liver cells differ from liver cells which differ from adrenal cells- each having their own function though the genome is the same.
It is believed that aberrant differentiation leading to carcinogenesis involves depression of genes, so that the cancer cells shows embryonic characteristics and is capable of active replication. This probably accounts for the production of embryonic antigens by certain tumours.
Unifying theory of carcinogenesis:
There still rages a controversy between the genetic and epigenetic hypothesis. But it is possible to formulate a unifying hypothesis for the mode of action of all known carcinogenic influences by relating them to their ability to induce mutations in cells, and in the absence of environmental influences, spontaneous mutations may activate cellular oncogenes or create new oncogenes.
Host factors in carcinogenesis: 1. Age.
2. Immunocompetence 3. Heredity 4. Clinical disorders.
5. Race 6. Sex
The frequency of cancer increases as age increases. However, certain cancers are common in the paediatric age -group like leukaemia, lymphomas, tumours of the central nervous system, soft tissue sarcomas and bone sarcomas. Certain tumours like prostatic carcinoma are seen most almost exclusively in old age.
The exact reason why cancer increases with increased age is not known but the probable reasons are-
a. as age increases, competence of immune system decreases,
b. as age increases, the tendency to mutations also increases;
c. as age increases, mechanisms capable of repairing DNA mutations may slow down.
There is evidence to show that tumour-specific antigens are present in malignancy and in some instances they elicit an immune response. Hence patients with a competent immune system carry a better prognosis.
Certain cancers, and precancerous conditions have a distinct hereditary pattern. However, in most cancers, well defined familial influences can be identified in only a few instances.
The incidence of Ca is increased in various hereditary DNA – repair deficiency syndromes /chromosomal instability syndromes, e.g. in Xeroderma pigmentosa, the individual sustains cumulative radiation-induced mutations in the epidermal cells, on exposure to sunlight. The enzymes needed to repair these mutations are missing due to hereditary factors. These mutations then predispose the individual to skin cancer.
Hereditary cancerous and precancerous disorders: ——————————————————————— Disorder Predominant tumours ——————————————————————— Autosomal dominant inheritance Retinoblastoma Retinoblastoma, sarcomas-orbital following radiation) and at remote sites.
Neurofibromatosis Neurogenic sarcoma, acoustic neuroma, pheochromocytoma
Familia polyposis coli Colonic cancer, adenomatous polyps Gardener’s syndrome Colonic cancer, adenomatous polyps Peutz-Jeghers syndrome Controversial whether predisposes to colonic cancer Hereditary multiple Tumours of the pituitary gland. Para endocrine neoplasia thyroid gland, and pancreatic islet syndrome Type I (MEN I) cells
Multiple endocrine neo Variant MEN II -plasia syndrome
-Type III (MEN III)
Cutaneous malignant melanoma Cutaneous malignant melanoma,other cancers
Von Hipper-Lindau disease Hemangioblastoma of cerebellum, hypernephroma and pheochromocytoma
Wilms’ tumour Wilms’ tumour
Cancer-family syndromes Adenocarcinomas (primarily of the colon and endometrium)
Breast cancer in association Breast cancer, ovarian carcinoma, with other malignant neo- leukemia and brain tumour.
Autosomal recessive inheritance Chromosome instability syndromes
Xeroderma pigmentosum Basal and squamous cell carcinoma of skin, malignant melanoma Fanconi’s anemia Leukaemia and lymphoma
Bloom’s syndrome Acute leukaemia
Ataxia telangiectasia Acute leukaemia, lymphoma and possibly gastric cancer.
Turcot’s syndrome Colonic polyps, cancer and brain tumours.
————————————————————————- Other precancerous states are-
Tuberous sclerosis, Cowden’s multiple hamartoma syndrome, Albinism, Epidermodysplasia verruciformis, Polydysplastic epidermolysis bullosa, Dyskeratosis congenita, Late onset immunologic deficiency and X-linked agammaglobulinemia
4. Clinical disorders: Certain clinical disorders are potentiality malignant.
For examples- a. Chronic atrophic gastritis -Gastric carcinoma (Pernicious anaemia)
b. Chronic ulcerative colitis – Colorectal carcinoma Adenoma of colon.
c. Leukoplakia buccal cavity – Squamous cell carcinoma -genitals.
d. Chronic skin fistula -Squamous cell carcinoma
e. Cirrhosis of liver -Hepatocellular carcinoma
In general, benign neoplasms do not become malignant. Those that do, like the adenoma of the colon, are the exceptions and not the rule.
Though certain cancers are predominantly seen in certain races, the causes may be environmental influences’rather than a `racial predisposition’.
For example- a. Gastric carcinoma is much more common in Japan than in the U.S.A. while Ca breast is much more common in the U.S.A. than in Japan.
b. White races are more susceptible to skin cancer.
6. Sex: The role of `environmental influences’ again is important, rather than a sexual predisposition.
a. The incidence of Ca lung is much higher in males than in females. But now, the incidence of lung cancer in females is on the rise due to increased number of women taking up smoking.
b. Cancer of breast is very rare in males.
c. Cancer of bladder is rare in females.
As discussed earlier, all environmental carcinogens probably exert their effects by altering the genetic code either by inducing mutations or by affecting the cell regulatory mechanisms.
Environmental carcinogens can be broadly classified as:
Less than 30 Percent of cancers are radiation induced. Nearly all tissues are susceptible to development of cancers following radiations, but their sensitivity varies. The most sensitive tissues are bone marrow, breast and thyroid.
a. Chronic exposure to deep X-rays leads to increase in incidence of leukaemia among radiologists.
b. Atomic bomb blasts in Hiroshima and Nagasaki have led to increase in incidence of leukaemia in those regions.
c. Use of radioactive substances like radium in the dials of watches leads to development of osteogenic sarcoma of bones through radium deposition in the bones after 15-25 years of exposure.
d. Use of radioactive iodine- 131 in the treatment of goitre leads to development of thyroid cancer in later life.
e. Miners of radioactive elements like radium show a ten-fold increase in incidence of lung cancer.
f. Exposure to UV light (sunlight) especially in white skin individuals leads to increase in incidence of most skin cancers.
g. Therapeutic radiation of-
i. benign giant cell tumours leads to osteogenic sarcoma
ii. ankylosing spondylitis leads to leukaemia and
iii. thymic enlargement in children leads to thyroid cancer.
Two points are worthy of note-
i. Radiations induced malignancies appear only after a long latent period of some years.
ii. At low dosage levels, the radiation induced injury is amenable to repairs. Thus, tumours may or may not appear when fractional doses as in radiotherapy are received by the cell. This depends upon the dosage, the length of the intervals, the capacity of the cells to repair in the interval and what is most important is the individual’s susceptibility. Since susceptibility varies widely, it is very difficult to establish `safe’ tolerable levels of radiation exposure so that the radio- therapy given for the treatment of cancer is `safe. Therefore, the decision whether to give radiotherapy, and if so, then in what regime, is a crucial one as it can change the course of the disease in either direction.
2. Chemical: —————————————————————— Chemical agent Malignancy
a. Arsenic (used in farming – Lung, skin, liver and horticulture)
b. Asbestos – Mesothelioma of lung, bronchogenic carcinoma c. Benzene – Leukaemia
d. Benzidine – Bladder
e. Chromium – Lung compounds
f. Mustard gas – Lung
g. Polycyclic hydro- – Lung skin carbons.
h. Vinyl chloride – Angiosarcoma of (used in plastics) liver
i.Beta-naphthylamine -Urinary bladder
j. Aflatoxin B1 (contamination of farm products, grains, peanuts) – Liver
k. Carbon tetrachloride -Liver
l. Cadmium oxide -Lung, prostrate
m. Chromates -Lung
n. Betel nut (arecanut) -Oral cavity
o. Thorium dioxide -Liver
p.Tobacco smoke – Larynx,lung, bronchus
q. Iron ore (haematite) -Lung
r. Wood dust -Adenocarcinoma of nasal cavity, and sinuses.
s. Isopropyl oils -Larynx, nasal cavity (inhaled)
t. Alcohol -Oral cavity, oesophagus, stomach, liver, larynx.
u. Alkylating agents -Cancer of bladder in young children cyclophosphamide treated earlier for acute leukaemia melphalan ——————————————————————-
Some chemical carcinogens are direct-reacting and require no chemical transformation to induce carcinogenicity. Other carcinogens are indirect reacting (procarcinogens) and become active (ultimate carcinogens ) after metabolic conversion. Certain agents have hardly any carcinogenicity of their own, but they augment the activity of other carcinogens-these are called promoters.
3. Viral: The relation between viral oncogenes and cellular oncogenes has been discussed earlier. Viruses may act on proto-oncogenes to initiate carcinogenesis. Though viruses have been proved to be the causative agents of malignancy in animals, their role in carcinogenesis in humans is probable and not yet proved beyond doubt.
1. RNA viruses-
a) Human T-cell leukaemia virus (HTLV-1)
b. Mammary tumour virus
II. DNA viruses a. Human papillom virus (HPV)
b. Herpes viruses
Herpes simplex virus-2 (HSV-2)
c. Hepatitis B virus
4. Physical a. Chronic irritation of sharp tooth or ill-fitting denture
b. Chronic inflammation c. Trauma
A.Type of neoplasia 1. a.T-cell leukaemia Lymphoma b.Breast carcinoma II. a. Squamous cell cancer in hereditary epidermo-dysplasia verruciformis b. Vulval and cervical carcinoma African Burkitt’s lymphoma Naso-pharyngeal carcinoma Kaposi’s sarcoma c. Hepato-cellular carcinoma
4. a. Cancer of buccal cavity. b. Epidermoid carcinoma in the skin near a chronically draining sinus of osteomyelitis. c. H/o trauma to breast is positive in many cases of cancer of breast. May enhance metastatic spread.
A. Strength of evidence 1. a. Almost certain b. Weak II. a. Almost certain b. Uncertain c. Probable
4. a. Weak b. Probable
Dietary factors serve more as promoters of carcinogenesis rather than initiators. For example- Increased intake of fat correlates with increase in incidence of cancer of breast. Cancer of colon. Certain dietary guidelines suggested are:- a. Decrease in intake of fat.
b. Increase in intake of fruits (especially citrus fruits), vegetables (especially carotene rich vegetables) and whole cereal grain.
These provide vitamin A, vitamin C and fibre.
c. Decrease in consumption of salt cured smoked food.
d. Decrease in consumption of alcohol.
It has been shown in animals that administration of high doses of vitamin A inhibits carcinogenesis. However, the validity of this is human remains debatable
They probably serve as promoters.
Oestrogen given to –
a. Pregnant women – Uterine vaginal carcinoma in offspring
b. Premenopausal – Liver adenoma.
c. Menopausal – Endometrial & post meno carcinoma pausal women
Studies have revealed that certain psychological patters are present in individuals who develop cancer. There is usually a major emotional trauma, a marked tendency to hold resentment and a tendency to repression. It is also known that prolonged mental stress is one of the factors that contributes to the development of cancer.