Oncogenes and Cancer

English Version

Cancer is caused by alterations in oncogenes, tumor suppressor genes, and microRNA genes. These alterations are usually somatic events, although germ line mutations can predispose a person to heritable or familial cancer. A single genetic change is rarely sufficient for the development of a malignant tumor. Most evidence points to a multistep process of sequential alterations in several, often many, oncogenes, tumor suppressor genes, or microRNA genes in cancer cells.

Tumors often possess cytogenetically different clones that arise from the initial transformed cell through secondary or tertiary genetic alterations. This heterogeneity contributes to differences in clinical behavior and responses to treatment of tumors of the same diagnostic type. Apart from the initial clone and subclones, tumors can also contain progenitor cancer cells, all of which constitute a spectrum of cells with different genetic alterations and states of differentiation. These populations can differ in sensitivity to chemotherapy, radiotherapy, and other treatments, making clinical management difficult. For these reasons, the initiating steps in the development of cancer are of considerable clinical importance and are a priority in the development of rational cancer treatment.

An example of this concept is chronic myelogenous leukemia, which is initiated by a reciprocal t(9;22) chromosomal translocation that fuses the ABL protooncogene to the BCR gene. The fusion gene encodes an oncogenic ABL fusion protein with enhanced tyrosine kinase activity. All leukemic cells carry this chromosomal alteration, which is why inhibition of the excessive tyrosine kinase activity of the fusion protein by imatinib induces complete remission in most patients when relapse occurs, the leukemic cells usually carry mutations in ABL that render them resistant to the drug.

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