Genetic Mutations in Cancer

Oncogenes and Cancer

• A deletion on chromosome 5 can fuse part of the ALK gene with part of another gene called EML4, creating a fusion gene in a subset of lung cancers.
• HER2 amplification and overexpression in breast cancers can be treated with antibodies or drugs that block HER2 activity, leading to cessation of tumor growth and tumor regression.
• RAS mutations are the most common type of abnormality involving proto-oncogenes in human tumors, occurring in 15-20% of cases.
• RAS genes (HRAS, KRAS, NRAS) are commonly activated by point mutations, trapping RAS in its active state and forcing the cell into a continuously proliferating state.
• Transcription factors like MYC can activate the transcription of other genes, and its amplification or translocation can contribute to cancer development.

Tumor Suppressor Genes

• Tumor suppressor genes apply brakes to cell proliferation, and their mutation can lead to uncontrolled cell growth.
• The Retinoblastoma (RB) gene regulates the G1/S checkpoint and is located on chromosome 13.
• Mutations in DNA repair genes can lead to an increase in mutations in other genes, including proto-oncogenes and tumor suppressor genes.

Molecular Defects in Cancer

• Gene amplification can increase the expression of oncogenes.
• Deletions can lead to the loss of tumor suppressor genes.
• Most human cancers have molecular defects that affect one or more components of growth factor signaling pathways.

Growth Factors and Receptors

• Normal cells require stimulation by growth factors to proliferate, but cancer cells can acquire the ability to synthesize their own growth factors, creating an autocrine loop.
• Oncogenes can encode growth factor receptors, such as receptor tyrosine kinases, which can be activated by point mutations, gene rearrangements, or gene amplifications.
• Examples of growth factor receptors involved in cancer include ERBB1 (EGFR) and ERBB2 (HER2).

Retinoblastoma and TP53

• Retinoblastoma is a childhood tumor that can occur sporadically or be inherited as an autosomal dominant trait.
• The two-hit hypothesis explains the development of retinoblastoma, requiring two mutations (hits) to inactivate both normal alleles of the RB locus.
• TP53, located on chromosome 17p, is a tumor suppressor gene that is mutated in over 70% of human cancers and plays a crucial role in DNA repair, cell division, and cell death by apoptosis.

Other Tumor Suppressor Genes

• APC (Adenomatous polyposis coli) is a tumor suppressor gene that functions by downregulating growth-promoting signaling pathways and is associated with familial adenomatous polyposis.
• APC loss of function can contribute to the development of colon cancer.
• DNA repair genes ensure accurate copying of genetic information during cell division, and their mutation can lead to an increase in cancer-causing mutations.