Cancer Genetics
Hallmarks of Cancer
Evading Apoptosis: Cancer cells develop mechanisms to evade programmed cell death, allowing them to survive longer than normal cells. They can express anti-apoptotic proteins and downregulate pro-apoptotic signals.
Self-Sufficiency in Growth Signals: Unlike normal cells that depend on external growth signals, cancer cells can produce their own growth factors or activate signaling pathways inappropriately, enabling them to grow independently.
Insensitivity to Anti-Growth Signals: Cancer cells ignore signals from the surrounding environment that typically suppress cell division and growth, thereby acquiring a growth advantage.
Sustained Angiogenesis: Tumors can induce the formation of new blood vessels (angiogenesis) through the secretion of vascular endothelial growth factor (VEGF), ensuring a continuous supply of oxygen and nutrients essential for tumor expansion.
Tissue Invasion & Metastasis: Cancer cells can deteriorate the extracellular matrix and invade neighboring tissues. They can also metastasize, spreading to distant organs through the bloodstream or lymphatic system, forming secondary tumors.
Limitless Replicative Potential: Cancer cells sustain their ability to divide indefinitely, often through the maintenance of telomeres via telomerase activation, unlike normal somatic cells that have a finite number of divisions.
Objectives of This Lecture
Define key terms: neoplasm, carcinogenesis, carcinogens, tumorigenesis, tumor suppressor, proto-oncogene, oncogene, DNA repair genes.
Differentiate between benign and malignant tumors, including their growth patterns and potential health implications.
Describe the types of tumors, such as carcinomas, sarcomas, and lymphomas, and discuss potential causes of neoplasm formation, including environmental and genetic factors.
Explain Knudson's two-hit model of carcinogenesis and how it applies to the understanding of genetic predispositions to cancer.
Discuss key signaling pathways involved in tumorigenesis, including their interactions with the three main categories of cancer genes: tumor-suppressor genes, proto-oncogenes, and DNA repair genes.
Describe methods for identifying cancer-causing genes, including modern genomic approaches.
What is Cancer?
Cancer is characterized by uncontrolled cell growth leading to the formation of neoplasms, which are abnormal masses of tissue that can be benign (non-cancerous) or malignant (cancerous).
Neoplasms
Neoplasia: Refers to new and abnormal growth of tissue, which can be either benign or malignant.
Neoplasm: A mass of cells that undergoes uncontrolled proliferation; it is often referred to as a tumor or cancer. Neoplasms have the potential to disrupt local tissue function and invade neighboring structures.
Benign vs. Malignant Neoplasms
Benign Tumors: These tumors grow as a compact mass, remain localized to the site of origin, and do not invade surrounding tissues or metastasize. Although they can cause symptoms based on their location and size, they are generally not life-threatening.
Malignant Tumors: These tumors are characterized by invasive growth, where cancer cells invade nearby tissues and can spread to other parts of the body through the bloodstream or lymphatic system. They can lead to significant health risks and require aggressive treatment.
Importance of Cancer Genetics
Cancer is a major health issue worldwide, accounting for nearly 25% of all deaths. It is projected that approximately 50% of the population will be diagnosed with invasive cancer at some point in their lives, with a noted increase in incidence associated with aging.
Tumor Classification
Tumors are classified based on the tissue type of origin:
Carcinoma: Malignancies derived from epithelial cells, which line the surfaces and cavities of the body.
Sarcoma: Cancers arising from connective tissues such as bones, cartilage, and muscle.
Lymphoma: Malignancies originating in lymphatic tissues, affecting the immune system.
Glioma: Cancers derived from glial cells in the central nervous system.
Leukemia: Cancers that affect the blood and bone marrow, leading to the overproduction of abnormal white blood cells.
Carcinogenesis
Carcinogenesis is the process of cancer development, influenced by several factors:
Environmental alterations: Factors such as exposure to radiation and carcinogenic chemicals.
Genetic alterations: Inherited or acquired mutations in genes that control cell growth and division.
Carcinogens: Substances that can induce cancer, either through direct DNA damage or by promoting cellular changes that lead to tumor formation. Exposure to carcinogens can result in somatic mutations (which are not inheritable) or cancer-predisposing mutations in germline cells (which can be passed to future generations).
Knudson’s Hypothesis
Knudson's Two-Hit Model proposes that both alleles of a tumor suppressor gene must be mutated for a tumor to develop:
Sporadic Case: Involves two random mutations in the same cell, leading to cancer.
Familial Case: In this scenario, an individual inherits one mutated allele from a parent and is at a higher risk of acquiring a second mutation in the other allele, often leading to earlier onset of the disease.
Cancer Genes
Cancer genes can be categorized into three main types:
Tumor-Suppressor Genes: These inhibit cell proliferation and promote apoptosis; mutations can lead to uncontrolled growth, e.g., RB1, APC, p53.
Proto-Oncogenes: These promote cell growth and division. Mutations can convert them into oncogenes, leading to increased proliferation, e.g., c-myc.
DNA Repair Genes: These are responsible for maintaining genomic integrity. Defects in these genes can lead to genomic instability and cancer, e.g., BRCA1.
Tumor-Suppressor Genes (TSGs)
TSGs play a vital role in preventing tumor formation. Typically, they are recessive at the cellular level; hence, mutations leading to cancer are often inherited in a dominant manner, increasing disease prevalence in heterozygous individuals. For example, the RB1 gene encodes the retinoblastoma protein (pRb), which is crucial for regulating the cell cycle and preventing uncontrolled cellular proliferation.
Oncogenes
Oncogenes are formed from mutated proto-oncogenes and promote growth and proliferation in cells. They are generally dominant, and their activation typically results from gain-of-function mutations. For instance, RAS is a prominent oncogene that is frequently mutated in various types of cancer.
DNA Repair Genes
Deficiencies in DNA repair mechanisms can lead to genomic instability, which is a hallmark of cancer. Key genes involved in DNA repair processes include BRCA1, associated with breast and ovarian cancer, and ATM, which plays a role in the repair of double-strand DNA breaks.
Identifying Inherited Cancer-Causing Genes
Methods used to identify genes that contribute to familial cancers include:
Linkage analysis: Assessing inheritance patterns in families.
Polymorphic markers: Comparing normal and cancerous cells to identify genetic variances.
Genome-wide association studies (GWAS): Large-scale studies that look for statistical associations between specific genetic variants and cancer risk.
Genome-Wide Association Studies (GWAS)
GWAS are powerful tools that compare allele frequencies in cases of cancer versus controls, typically focusing on single nucleotide polymorphisms (SNPs) with the help of microarray technologies. These studies have been instrumental in identifying genetic variants that contribute to cancer susceptibility and are critical for advancing our understanding of cancer genetics.