11.2 Cancer genetics and molecular basis of cancer
4 min read•august 16, 2024
Cancer genetics unravels the molecular basis of uncontrolled cell growth. This topic explores the hallmarks of cancer, including sustained proliferation and evasion of growth suppressors, which drive tumor development and progression.
and tumor suppressors play crucial roles in cancer formation. The section delves into how genetic and epigenetic alterations in these genes contribute to cancer development, setting the stage for targeted therapies and personalized medicine approaches.
Hallmarks of Cancer
Fundamental Characteristics of Cancer Cells
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- Cancer characterized by six hallmarks leading to uncontrolled cell growth and spread
- Sustained proliferative signaling allows continuous cell division
- Overexpression or mutation of growth factor receptors (EGFR)
- Hyperactivation of downstream signaling pathways (RAS-RAF-MAPK)
- Evasion of growth suppressors circumvents normal
- Inactivation of p53 and Rb
- Disruption of contact inhibition mechanisms (loss of NF2/Merlin)
- Resistance to cell death promotes cancer cell survival
- Upregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL)
- Downregulation of pro-apoptotic factors (Bax, Bad)
Enabling Characteristics for Tumor Growth
- Replicative immortality allows unlimited cell divisions
- Activation of telomerase enzyme maintains telomere length
- Alternative lengthening of telomeres (ALT) in some cancers
- supports tumor growth through new blood vessel formation
- Increased expression of pro-angiogenic factors (VEGF, FGF)
- Downregulation of angiogenesis inhibitors (thrombospondin-1)
- and metastasis enable cancer spread to distant sites
- Dysregulation of cell adhesion molecules (E-cadherin loss)
- Activation of matrix metalloproteinases (MMP-2, MMP-9)
- Epithelial-mesenchymal transition (EMT) promotes cell motility
Oncogenes and Tumor Suppressors
Oncogene Activation and Function
- Oncogenes promote excessive cell growth when activated through genetic alterations
- (BRAF V600E in melanoma)
- Gene amplifications (MYCN in neuroblastoma)
- Chromosomal translocations (BCR-ABL in chronic myeloid leukemia)
- Common oncogenes encode proteins involved in various cellular processes
- RAS family (KRAS, HRAS, NRAS) activates multiple signaling pathways
- MYC regulates transcription of growth-promoting genes
- HER2/neu amplification leads to increased cell proliferation ()
- Oncogenes typically act in a dominant manner requiring only one mutated allele
Tumor Suppressor Gene Inactivation
- Tumor suppressor genes inhibit cell proliferation and promote genome stability
- Loss or inactivation of tumor suppressors contributes to cancer development
- Key tumor suppressor genes regulate various cellular functions
- p53 controls cell cycle arrest and in response to DNA damage
- BRCA1/2 participate in DNA repair and maintain genomic integrity
- APC regulates cell adhesion and Wnt signaling pathway
- Two-hit hypothesis explains tumor suppressor gene inactivation
- Both alleles must be inactivated for cancer to develop
- Often involves combination of inherited and somatic mutations
- Tumor suppressor genes generally act in a recessive manner
Genetic and Epigenetic Alterations in Cancer
Genetic Alterations in Cancer Cells
- Point mutations alter single nucleotides affecting protein function
- Missense mutations (p53 R175H in various cancers)
- Nonsense mutations (APC in colorectal cancer)
- Chromosomal translocations create fusion genes or alter gene regulation
- Philadelphia chromosome t(9;22) in chronic myeloid leukemia
- EWS-FLI1 fusion in Ewing sarcoma
- Gene amplifications increase copy number of oncogenes
- ERBB2 (HER2) amplification in breast cancer
- MYCN amplification in neuroblastoma
- Chromosomal instability (CIN) leads to aneuploidy and large-scale rearrangements
- Contributes to tumor heterogeneity and progression
- Common in solid tumors (colorectal, lung, breast cancers)
- Microsatellite instability (MSI) results from defective DNA mismatch repair
- Accumulation of mutations in repetitive DNA sequences
- Characteristic of hereditary nonpolyposis colorectal cancer (HNPCC)
Epigenetic Alterations in Cancer
- DNA methylation changes affect gene expression without altering sequence
- Global DNA hypomethylation leads to genomic instability
- Hypermethylation of CpG islands silences tumor suppressor genes (BRCA1, MLH1)
- Histone modifications alter chromatin structure and gene expression
- Histone acetylation generally activates gene expression
- Histone methylation can either activate or repress genes depending on the site
- Non-coding RNAs regulate gene expression at post-transcriptional level
- MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors
- Long non-coding RNAs (lncRNAs) involved in various cancer-related processes
Targeted Therapies for Cancer
Kinase Inhibitors and Monoclonal Antibodies
- Kinase inhibitors block specific enzymes involved in cancer cell signaling
- Imatinib targets BCR-ABL fusion protein in chronic myeloid leukemia
- Vemurafenib inhibits mutant BRAF V600E in melanoma
- Monoclonal antibodies target specific proteins on cancer cell surfaces
- Trastuzumab binds HER2 in HER2-positive breast cancer
- Rituximab targets CD20 in B-cell lymphomas
Emerging Targeted Therapies
- PARP inhibitors exploit synthetic lethality in DNA repair-deficient cancers
- Olaparib for BRCA-mutated ovarian and breast cancers
- Niraparib for platinum-sensitive ovarian cancer maintenance therapy
- Immunotherapies harness the immune system to fight cancer
- Checkpoint inhibitors (pembrolizumab, nivolumab) block PD-1/PD-L1 interaction
- CAR-T cell therapy engineers T cells to target specific cancer antigens
- Personalized medicine approaches tailor treatments to individual patients
- Genomic profiling identifies actionable mutations
- Liquid biopsies monitor treatment response and disease progression
- Combination therapies target multiple pathways to improve efficacy
- BRAF and MEK inhibitors in melanoma (dabrafenib + trametinib)
- Immunotherapy combinations (ipilimumab + nivolumab) in various cancers
Key Terms to Review (18)
Angiogenesis: Angiogenesis is the process through which new blood vessels form from pre-existing vessels, playing a crucial role in growth and development. This process is vital for supplying nutrients and oxygen to tissues, and it becomes particularly significant in the context of cancer, as tumors require a blood supply to grow and spread. Understanding angiogenesis helps reveal how cancer cells manipulate this process to facilitate their own survival and proliferation.
Apoptosis: Apoptosis is a programmed cell death mechanism that occurs in multicellular organisms, allowing for the orderly and controlled elimination of cells. This process is crucial for maintaining tissue homeostasis, development, and responding to cellular stress or damage, linking it closely to DNA repair mechanisms, cellular organelles, and the genetics of cancer.
Breast cancer: Breast cancer is a malignant tumor that develops from the cells of the breast tissue, and it can occur in both men and women, though it is far more common in women. Understanding the genetics and molecular mechanisms behind breast cancer is crucial, as mutations in specific genes like BRCA1 and BRCA2 significantly increase an individual's risk of developing the disease. Research into these genetic factors provides insights into potential targeted therapies and preventative measures.
Cell cycle regulation: Cell cycle regulation refers to the mechanisms and processes that control the progression of a cell through the various stages of the cell cycle, including growth, DNA replication, and division. This regulation is crucial for maintaining genomic stability, preventing uncontrolled cell division, and ensuring proper tissue development and function.
Crispr-cas9: CRISPR-Cas9 is a revolutionary gene-editing technology that enables precise modifications to DNA within organisms, utilizing a guide RNA to direct the Cas9 enzyme to specific genomic locations. This tool has transformed the fields of genetics and molecular biology, allowing for advances in functional genomics, therapeutic interventions, and agricultural applications.
Cytokines: Cytokines are small proteins that are crucial in cell signaling, especially in the immune system. They are secreted by various cells and act as communication molecules that regulate immunity, inflammation, and hematopoiesis. In the context of cancer, cytokines play significant roles in tumor development and progression by influencing the behavior of immune cells and cancer cells.
Deletions: Deletions refer to the loss of a segment of DNA from a chromosome, which can lead to the absence of one or more genes. This can significantly impact cellular function and contribute to the development of various diseases, including cancer, by disrupting normal gene expression and protein production.
Growth factors: Growth factors are naturally occurring proteins that stimulate the growth, proliferation, and differentiation of cells. They play a vital role in various biological processes, including tissue repair, embryonic development, and the regulation of immune responses. In the context of cancer, growth factors can become dysregulated, contributing to uncontrolled cell division and tumor development.
Hereditary breast and ovarian cancer syndrome: Hereditary breast and ovarian cancer syndrome refers to an inherited genetic condition that significantly increases the risk of developing breast and ovarian cancers, primarily linked to mutations in the BRCA1 and BRCA2 genes. This syndrome highlights the role of genetics in cancer susceptibility, emphasizing the importance of genetic testing, family history, and preventive measures in managing cancer risk.
Invasion: In the context of cancer, invasion refers to the process by which cancer cells spread from their original (primary) site to nearby tissues and organs. This characteristic is crucial because it distinguishes malignant tumors from benign ones, as malignant tumors have the ability to invade surrounding structures and establish secondary growths, known as metastases. Understanding this process helps in deciphering the aggressive nature of certain cancers and highlights the importance of early detection and intervention.
Li-Fraumeni Syndrome: Li-Fraumeni Syndrome is a hereditary cancer predisposition disorder caused by mutations in the TP53 gene, leading to an increased risk of various cancers at a young age. This syndrome is associated with a wide spectrum of cancers, including sarcomas, breast cancer, brain tumors, and adrenal cortical carcinoma, highlighting the critical role of TP53 in tumor suppression and cancer development.
Lung cancer: Lung cancer is a type of cancer that originates in the lungs, leading to uncontrolled cell growth and tumor formation. This disease is primarily linked to genetic mutations and environmental factors, such as smoking and exposure to carcinogens. Understanding lung cancer involves exploring its genetic underpinnings, how it develops at the molecular level, and the mechanisms that drive its progression.
Next-generation sequencing: Next-generation sequencing (NGS) is a revolutionary DNA sequencing technology that allows for the rapid sequencing of entire genomes or targeted regions of DNA, drastically increasing the speed and reducing the cost compared to traditional methods. This technology has transformed genomic research and diagnostics by enabling high-throughput sequencing, which has become essential for applications like genome assembly, cancer genetics, and personalized medicine.
Oncogenes: Oncogenes are mutated forms of normal genes, known as proto-oncogenes, that have the potential to cause cancer by promoting uncontrolled cell growth and division. These genetic alterations can occur due to various factors, including mutations, gene amplifications, or chromosomal rearrangements, leading to the activation of pathways that drive tumorigenesis. Understanding oncogenes is crucial in molecular biology as they illuminate the mechanisms behind cancer development and progression.
Pi3k/akt pathway: The pi3k/akt pathway is a crucial signaling pathway that regulates various cellular processes, including growth, survival, and metabolism. This pathway is often activated by growth factors and plays a significant role in cancer development, as its dysregulation can lead to uncontrolled cell proliferation and survival.
Point mutations: Point mutations are small-scale changes in the DNA sequence that involve the alteration of a single nucleotide base pair. These mutations can lead to changes in protein structure and function, potentially contributing to various diseases, including cancer. Understanding point mutations is crucial for grasping the molecular basis of cancer genetics, as they can affect oncogenes and tumor suppressor genes, leading to uncontrolled cell growth and malignancy.
Ras signaling pathway: The ras signaling pathway is a critical cellular communication network that transmits signals from cell surface receptors to the nucleus, ultimately influencing cell growth, differentiation, and survival. This pathway plays a significant role in cancer biology as mutations in the ras gene can lead to uncontrolled cell proliferation and tumorigenesis, highlighting its importance in understanding cancer genetics and the molecular basis of cancer.
Tumor suppressor genes: Tumor suppressor genes are segments of DNA that produce proteins responsible for regulating cell growth and preventing uncontrolled cell division. When these genes are mutated or inactivated, they lose their ability to control cell proliferation, which can lead to the development of cancer. Understanding the role of tumor suppressor genes is critical for grasping how genetic factors contribute to cancer development and progression.