Oncogenes and tumour suppressor genes
As well as chromosomal abnormalities, other genetic changes occur in myeloma which can influence the development and progression of the disease. These involve genetic alterations or mutations that permanently change the sequence of the DNA within a cell. Sometimes a mutation can cause a gene to function improperly, resulting in the encoded protein being non-functional or being produced at an abnormal rate.
Many of the genetic mutations in myeloma, like many cancers, involve regulatory genes called proto-oncogenes and tumour suppressor genes. Proto-oncogenes encode proteins that stimulate cell growth and survival. Mutated proto-oncogenes can promote uncontrolled cell growth that may lead to cancer. Tumour suppressor genes encode proteins that inhibit cell growth. Mutations in these genes can remove normal regulatory signals that stop cell growth at the appropriate point in the cell cycle.
Mutations involving several oncogenes and tumour suppressor genes have been implicated in the development of myeloma. Some of these are shown in Table 3.
Table 3: Oncogenes and tumour suppressor genes involved in myeloma
| Oncogene / tumour suppressor gene | Action |
|---|---|
| Ras | Ras is a proto-oncogene involved in the conduction of signals needed for cell growth. Ras mutations are seen in a significant proportion of myeloma cells cultured in the laboratory for investigation. K-Ras is the most frequently mutated form of this gene followed by N-Ras. The p21/Ras signalling transduction pathway is critical for cell growth and differentiation. This signalling pathway is involved in the production of the cytokine interleukin-6 (IL-6), a powerful growth and survival factor for myeloma cells. Ras mutations can lead to the growth and survival of myeloma cells independent of IL-6. |
| TP53 | TP53 is a tumour suppressor gene that regulates expression of p53, an important regulator of the cell cycle. Mutation of this gene, associated with del(17p), is an indicator of poor prognosis. |
| Bcl-2 | Bcl-2 genes regulate cell survival and play an important role in regulating programmed cell death (apoptosis) Myeloma cells express high levels of the Bcl-2 protein which plays an role as a survival factor. Mutations in these genes can cause deregulation of apoptosis, allowing for the growth and survival of myeloma cells. |
| p15 and p16 | The p15 and p16 genes encode for the production of proteins that inhibit cell growth. The p15 and p16 proteins belong to a class of proteins known as cyclin-dependent kinase (CDK) inhibitors. CDKs induce key functions in the cell cycle such as DNA replication and mitosis and CDK inhibitors act as tumour suppressors by acting as a brake on the cell cycle. Mutations in p15 or p16 can lead to uncontrolled cell division. |
| c–Myc | cMyc is a proto-oncogene which encodes the c-Myc protein which functions in the regulation of the cell cycle. It is normally present in actively growing cells and stimulates cell growth. About 40% of myeloma patients have deregulated expression of the c-Myc proto-oncogene, causing elevated levels of the c-Myc protein and, consequently, uncontrolled growth of myeloma cells. |
| Rb-1 | Like p53, the tumour suppressor gene Rb-1 directly inhibits cell cycle progression. The tumour suppressor gene Rb-1, located on chromosome 13q, is deleted in almost 50% of myeloma patients, allowing cells to grow uncontrollably. |