In-depth Notes on Cancer Genetics and Cell Regulation

Learning Outcomes

• Define cancer and identify the common characteristics of cancers, including uncontrolled cell growth, the potential to invade surrounding tissues, and the ability to metastasize to distant sites in the body. Cancer is not just one disease but consists of over 100 different types, each defined by the originating cell type, location in the body, and the behavior of the tumor (benign or malignant).

• Explain the link between mutagenesis and cancer by detailing how genetic mutations can occur due to exposure to environmental factors such as chemicals (carcinogens), radiation, and viruses, as well as lifestyle choices (e.g., tobacco use, diet, alcohol consumption) and hereditary predispositions that increase the likelihood of developing cancer. Epidemiological studies highlight the importance of both intrinsic genetic factors and external influences in the genesis of pediatric and adult cancers.

• Summarize the major events in the development of cancer, which typically unfold through several stages:

  • Initiation: The first genetic mutation occurs in a somatic cell, potentially due to DNA damage from carcinogens or the error-prone nature of DNA replication. This mutation may be harmless initially but can set the stage for further mutations.

  • Promotion: This stage is characterized by the selective proliferation of mutated cells often promoted by growth factors, hormones, or inflammation. External factors, such as chronic irritation or inflammation, can perpetuate cell division, creating a pool of cells harboring mutations.

  • Progression: Accumulation of additional mutations leads to malignant transformation and the establishment of invasive tumors. During this phase, cells may acquire properties that enable them to invade surrounding tissues and metastasize to distant sites throughout the body, leading to more advanced disease.

• Differentiate between low- and high-penetrance alleles associated with cancer, emphasizing that common, low-penetrance alleles may contribute slightly to cancer risk, while rare, high-penetrance alleles, such as those found in BRCA1 and BRCA2 genes, can significantly increase the risk particularly in individuals with family histories of breast and ovarian cancer. Understanding these genetics is crucial for risk assessment and personalized medicine.

• Explain the role of cyclins and CDKs in regulating the cell cycle, focusing on their functions in key checkpoints, notably G1/S and G2/M checkpoints. Dysregulation of these proteins can lead to unchecked cellular division, exemplifying a hallmark of cancer in which normal regulatory mechanisms are bypassed, resulting in sustained proliferation, evasion of apoptosis, and, ultimately, tumor growth.

• Compare and contrast proto-oncogenes, oncogenes, and tumor suppressor genes:

  • Proto-oncogenes: These genes typically promote normal cell division and functioning. When mutated, they can become oncogenes that drive excessive cell growth and division. For example, mutations in the KRAS gene lead to constitutive signaling that promotes cellular proliferation and survival irrespective of external growth signals.

  • Tumor Suppressor Genes (TSGs): These genes are responsible for limiting cell division and promoting apoptosis. Mutations in TSGs like RB and TP53 can disable these critical checkpoints in the cell cycle, leading to unregulated growth, and are implicated in a large number of cancers.

• Explain viral oncogenesis, differentiating between DNA and RNA oncoviruses:

  • DNA Oncoviruses: These viral particles can disrupt normal cellular functions by expressing proteins that interfere with tumor suppressor genes. For instance, Human Papillomavirus (HPV) is known to cause cervical cancer through its E6 and E7 proteins that degrade p53 and RB proteins, respectively, leading to uncontrolled cell division.

  • RNA Oncoviruses: These viruses may introduce their own oncogenes into the host genome or alter the expression of cellular genes. The Rous Sarcoma Virus (RSV) serves as a classical model of how RNA viruses can induce cancer through the incorporation of viral oncogenes that drive cell transformation and proliferation.

• Summarize the role of the Ras protein in cell proliferation, discussing its critical function in growth factor signaling pathways. Ras acts as a molecular switch that governs various cell signaling pathways, including those that promote cell division. Mutations in the Ras gene lead to its constitutive activation, which can result in unchecked cellular proliferation and contribute to tumorigenesis in several cancers.

• Explain the details of the RB and TP53 genes as tumor suppressors:

  • RB Gene: This gene encodes the retinoblastoma protein (pRB), which is crucial for regulating the transition from G1 to S phase of the cell cycle. Mutations in the RB gene prevent it from performing its functions, thus allowing uncontrolled progression through the cell cycle and facilitating cancer development.

  • TP53 Gene (p53): The TP53 gene encodes the p53 protein, a key regulator of the cellular response to DNA damage and stress. It can halt the cell cycle, repair damaged DNA, or initiate apoptosis if the damage is beyond repair. Loss of p53 function is prevalent in several cancers and reinforces malignancy through mechanisms that destabilize genomic integrity, further contributing to tumorigenesis.