We identify mutations in the germline of patients with heritable cancer. However, in most cancers, a normal cell become malignant cell by a series of mutations that arise in somatic cells. They do not arise in germline cells. Usually mutations occur in several genes to give rise to neoplasia. How many mutations cause a cancer? What specific genes are affected?

Advances in molecular and cellular biology and epidemiologic analyses of human and experimental cancers are providing hypotheses in cancer causation. These are the evidences:

1. Malignant tumours are clonal in nature

2. Some cancers show a Mendelian pattern of inheritance

3. DNA from malignant cells can transform normal cells to a malignant phenotype.

4. Most tumours contain somatic mutations in oncogenes and/or tumour suppressor genes.

5. Recurring sites of chromosomal change are observed in cancers at the site of genes involved in cellular growth control.

6. Most carcinogens are mutagens.

7. Defects in DNA repair systems increase the probability of cancer.

Five to ten accumulated mutations are believed to be necessary to transform a cell from normal to a malignant phenotype. At each step the mutated cell may gain a slight growth advantage.  The best studied example is colon cancer. An analysis of DNA from tissues extending from normal epithelium to adenoma to carcinoma have identified some of the genes mutated along the path.

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