Chapter 6: The Genetics of Cancer PDF

Cancer: Cancer as a Genetic Disease: Cancer is now understood as a genetic disease, meaning it involves changes in the genes of cells. - Genomic Alterations: These changes in genes can range from small changes in the DNA sequence (like single-nucleotide substitutions) to larger-scale changes in chro...

Cancer: Cancer as a Genetic Disease: Cancer is now understood as a genetic disease, meaning it involves changes in the genes of cells. - Genomic Alterations: These changes in genes can range from small changes in the DNA sequence (like single-nucleotide substitutions) to larger-scale changes in chromosomes, such as rearrangements, amplifications, or deletions. - Somatic Mutations: Most cancer-causing mutations occur in somatic cells, which are the non-reproductive cells in our body. Only a small percentage of cancers are caused by inherited mutations (germ-line mutations). - Multiple Mutations: Unlike many genetic diseases that can result from a single gene mutation, cancer typically develops from the accumulation of many mutations in different genes over time. - Effects on Cellular Functions: These mutations affect various cellular functions like repairing damaged DNA, controlling cell division, triggering cell death (apoptosis), guiding cell differentiation, influencing cell movement (migration), and regulating cell-to-cell communication. Cancer: Cancer is not a single disease but rather a complex group of diseases, possibly up to a hundred, each behaving differently based on their cellular origin and genetic alterations. Despite the diversity, all cancers share two fundamental properties: 1. Abnormal cell growth and division (proliferation). 2. Defects in the normal controls that prevent cells from spreading and forming metastases (metastasis). - Molecular Level: These properties arise from mutations or inappropriate expression of genes that control cell growth and metastasis. - Benign vs. Malignant Tumors: Benign tumors result from uncontrolled cell growth but can often be removed without serious harm. Malignant tumors, however, have cells that can break away, spread, and form secondary tumors (metastases), making them difficult to treat and potentially life-threatening. - Complexity of Malignancy: Malignant tumors can contain billions of cells and may invade and grow in multiple parts of the body, posing significant challenges for treatment and management. Cancer cells in both primary and secondary tumors are clonal Clonal: All cells within a tumor originate from a single cell that contained a number of mutations. = All cancer cells within a tumor come from one common ancestral cell - Specific Mutations: Cancer cells accumulate specific genetic mutations that cause them to behave abnormally. - Diagnostic Relevance: Knowing that cancer cells are clonal aids in diagnosing and treating cancer effectively. - Evidence from Chromosomal Changes: Reciprocal Chromosomal Translocations are common in cancers like leukemia and lymphomas. - Burkitt Lymphoma: Patients with Burkitt lymphoma show shows reciprocal translocations between chromosome 8 and chromosomes 2, 14, or 22 All lymphoma cells within a patient have identical translocation breakpoints. - X-Chromosome Inactivation: - X-chromosome inactivation pattern in cancer cells confirms their clonal origin. - Normal Mosaic State: Female humans are mosaic with inactivated paternal and maternal X chromosomes in different cells. - Early Development Process: X-chromosome inactivation occurs randomly in cells during early development. - Consistent Inactivation: All cancer cells within a tumor from one female patient have the same inactive X chromosome. = occurs early in development and is random, and can also play a role. In females, all cancer cells within a tumor, including primary and metastatic tumors, have the same inactivated X chromosome. Cancer Stem Cell Hypothesis: Proposed concept related to cancer cell origins, suggesting the presence of cancer stem cells (CSCs). - Cell Proliferation: Tumors consist of cells with varying proliferation rates; some cells proliferate, while others do not. Cancer Stem Cells (CSCs): Cells within tumors that proliferate and give rise to various cell types in the tumor, akin to normal stem cells. - Stem Cell Characteristics: CSCs share traits with normal stem cells, such as self-renewal ability and undifferentiated state. - Self-Renewal Process: Stem cells divide asymmetrically, generating one differentiated cell and one stem cell during self-renewal. - Tumor Composition: Tumors are heterogeneous, containing non-proliferating cells and CSCs responsible for tumor growth. - Contrast to Stochastic Model: The CSC hypothesis opposes the stochastic model, which suggests all tumor cells have tumor-forming potential. - Identification: CSCs identified in brain, breast, colon, ovary, pancreas, and prostate cancers. - Proportion in Tumors: The fraction of CSCs in tumors varies; some tumors may have a small fraction (e.g.,