Molecular Biology of Cancer BC.504 Lecture Notes PDF

# Molecular Biology of Cancer BC.504 ## Presented by: Dr. Amany H. Adam, Ph.D. Lecturer of Biochemistry, Faculty of Science, Damanhour University. # Cancer Epidemiology - Cancer incidence and mortality are rapidly growing world-wide. ## Distribution of Cases & Deaths for the 10 Most Common Ca...

# Molecular Biology of Cancer BC.504 ## Presented by: Dr. Amany H. Adam, Ph.D. Lecturer of Biochemistry, Faculty of Science, Damanhour University. # Cancer Epidemiology - Cancer incidence and mortality are rapidly growing world-wide. ## Distribution of Cases & Deaths for the 10 Most Common Cancers in 2018 | Incidence: Both Sexes | Mortality: Both Sexes | | ------------------------ | ------------------------ | | Other 36.6% | Other 29.3% | | Lung 11.6% | Lung 18.4% | | Breast 11.6% | Colorectum 9.2% | | Colorectum 10.2% | Stomach 8.2% | | Prostate 7.1% | Liver 8.2% | | Leukaemia 3.2% | Prostate 3.8% | | Cervix Uteri 3.3% | Pancreas 4.5% | | Bladder 3.0% | Esophagus 5.3% | | Thyroid 3.1% | Breast 6.6% | | Cervix Uteri 3.2% | **9.6 million deaths** | | Esophagus 3.2% | | | Liver 4.7% | | | Stomach 5.7% | | | **18.1 million new cases** | | **Source: GLOBOCAN 2018.** ## Distribution of Cases & Deaths for the Top 10 Most Common Cancers in 2020 | Incidence: Both Sexes | Mortality: Both Sexes | | :----------------------- | :----------------------- | | Other cancer 36.9% | Other cancer 29.2% | | Female breast 11.7% | Lung 18.0% | | Lung 11.4% | Colorectum 9.4% | | Colorectum 10.0% | Liver 8.3% | | Prostate 7.3% | Stomach 7.7% | | Leukaemia 3.1% | Female breast 6.9% | | Cervix uteri 3.4% | | | Prostate 3.8% | **9.9 million deaths** | | Pancreas 4.7% | | | Esophagus 5.5% | | | Bladder 3.0% | | | Thyroid 3.0% | | | Cervix uteri 3.1% | | | Liver 4.7% | | | Esophagus 3.1% | | | Stomach 5.6% | | | **19.3 million new cases** | | **Source: GLOBOCAN 2021.** ## Distribution of Cases & Deaths for the Top 10 Most Common Cancers in 2018 for Males | Incidence: Males | Mortality: Males | | :----------------------- | :----------------------- | | Other 30.6% | Other 23.0% | | Lung 14.5% | Lung 22.0% | | Prostate 13.5% | Liver 10.2% | | Non-Hodgkin Lymphoma 2.7% | Stomach 9.5% | | Bladder 2.8% | Prostate 6.7% | | Colorectum 10.9% | Colorectum 9.0% | | Leukaemia 2.6% | Esophagus 6.6% | | Kidney 2.7% | Leukaemia 3.3% | | Non-Hodgkin Lymphoma 3.0% | Pancreas 4.2% | | Esophagus 4.2% | **5.4 million deaths** | | Bladder 4.5% | | | Stomach 7.2% | | | Liver 6.3% | | | **9.5 million new cases** | | **Source: GLOBOCAN 2018.** ## Distribution of Cases & Deaths for the Top 10 Most Common Cancers in 2020 for Males | Incidence: Males | Mortality: Males | | :----------------------- | :----------------------- | | Other cancer 30.7% | Other cancer 22.9% | | Lung 14.3% | Lung 21.5% | | Prostate 14.1% | Liver 10.5% | | Non-Hodgkin lymphoma 2.7% | Stomach 9.1% | | Bladder 2.9% | Colorectum 9.3% | | Colorectum 10.6% | Prostate 6.8% | | Leukaemia 2.7% | Esophagus 6.8% | | Kidney 2.7% | Leukaemia 3.2% | | Non-Hodgkin lymphoma 3.0% | Pancreas 4.5% | | Esophagus 4.2% | **5.5 million deaths** | | Bladder 4.4% | | | Liver 6.3% | | | Stomach 7.1% | | | **10.1 million new cases** | | **Source: GLOBOCAN 2021.** ## Distribution of Cases & Deaths for the Top 10 Most Common Cancers in 2020 for Females | Incidence: Females | Mortality: Females | | :----------------------- | :----------------------- | | Other cancer 28.9% | Other cancer 25.4% | | Breast 24.5% | Breast 15.5% | | Colorectum 9.4% | Lung 13.7% | | Lung 8.4% | Colorectum 9.5% | | Non-Hodgkin lymphoma 2.6% | Cervix uteri 5.7% | | Liver 3.0% | Stomach 7.7% | | Ovary 3.4% | Liver 6.0% | | Stomach 4.0% | Leukaemia 3.0% | | Corpus uteri 4.5% | Esophagus 3.8% | | Thyroid 4.9% | Ovary 4.7% | | Cervix uteri 6.5% | Pancreas 4.9% | | **9.2 million new cases** | **4.4 million deaths** | **Source: GLOBOCAN 2021.** ## Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, United States, 2023 ### Estimated New Cases | Male | % | Female | % | | :--- |:---:| :--- | :---: | | Prostate | 29 | Breast | 31| | Lung & bronchus | 12 | Lung & bronchus | 13 | | Colon & rectum | 8 | Colon & rectum | 8 | | Urinary bladder | 6 | Uterine corpus | 7 | | Melanoma of the skin | 6 | Melanoma of the skin | 4 | | Kidney & renal pelvis | 5 | Non-Hodgkin lymphoma | 4 | | Non-Hodgkin lymphoma | 4 | Thyroid | 3 | | Oral cavity & pharynx | 4 | Pancreas | 3 | | Leukemia | 4 | Kidney & renal pelvis | 3 | | Pancreas | 3 | Leukemia | 3 | | **All Sites** | **100** | **All Sites** | **100** | ### Estimated Deaths | Male | % | Female | % | | :--- |:---:| :--- | :---: | | Lung & bronchus | 21 | Lung & bronchus | 21 | | Prostate | 11 | Breast | 15 | | Colon & rectum | 9 | Colon & rectum | 8 | | Pancreas | 8 | Pancreas | 8 | | Liver & intrahepatic bile duct | 6 | Ovary | 5 | | Leukemia | 4 | Uterine corpus | 5 | | Esophagus | 4 | Liver & intrahepatic bile duct | 4 | | Urinary bladder | 4 | Leukemia | 3 | | Non-Hodgkin lymphoma | 4 | Non-Hodgkin lymphoma | 3 | | Brain & other nervous system | 3 | Brain & other nervous system | 3 | | **All Sites** | **100** | **All Sites** | **100** | ** Source: GLOBOCAN 2023.** # TABLE 5: The Most Frequent Cancers in Egypt Estimated Using the Results of the National Population-Based Registry Program of Egypt 2008-2011. ## Males * | Site | % | Crude Rate | ASR | | :--- |:---:| :---:| :---: | | Liver | 33.63 | 39.5 | 61.8 | | Bladder | 10.71 | 12.6 | 21.1 | | Lung | 5.69 | 6.7 | 10.4 | | Non-Hodgkin lymphoma | 5.48 | 6.4 | 8.8 | | Brain | 5.48 | 6.4 | 8.8 | | Prostate | 4.27 | 5.0 | 9.3 | | Breast | 32.04 | 35.8 | 48.8 | ## Females | Site | % | Crude Rate | ASR | | :--- |:---:| :---:| :---: | | Liver | 23.81 | 27.5 | 43.6 | | Breast | 15.41 | 17.8 | 24.3 | | Brain | 6.94 | 8.0 | 13.5 | | Non-Hodgkin lymphoma | 5.29 | 6.1 | 8.5 | | Bladder | 4.64 | 5.4 | 7.5 | | Lung | 4.22 | 4.9 | 7.5 | ## Both Sexes | Site | % | Crude Rate | ASR | | :--- |:---:| :---:| :---: | | Liver | 23.81 | 27.5 | 43.6 | | Breast | 15.41 | 17.8 | 24.3 | | Brain | 6.94 | 8.0 | 13.5 | | Thyroid | 3.28 | 3.7 | 6.1 | | Non-Hodgkin lymphoma | 5.29 | 6.1 | 8.5 | | Bladder| 4.64 | 5.4 | 7.5 | | Lung | 4.22 | 4.9 | 7.5 | *Includes trachea, bronchus, and lung tumors. *Includes brain and nervous system tumors. ## FIGURE 7: Estimated Number of Cases in Egypt (2013-2050) - Male cases are represented by a blue line. - Female casesare represented by a red line. - The graph is labeled with cases on the left and year on the bottom. - The year on the graph starts at 2013 and increases by two years until 2049. ## FIGURE UNTITLED: Estimated Number of Cases in Egypt (2013-2050) - Cases are represented by various colors. - The graph is labeled with cases on the left and year on the bottom. - The year on the graph starts at 2013 and increases by two years until 2050. - The color key is as follows: - Increased cases due to change in population structure is represented by red. - Increased cases due to population growth is represented by yellow. - Baseline cases (number of cases in 2013) is represented by lightblue. # Cancer Incidence in Egypt - In 2020, the incidence rate of total cancer cases in Egypt has increased by 4.5% with (134,632 cases). # Number of New Cancer Cases in 2018 vs. 2020 in Egypt ## Number of New Cases in 2018, Both Sexes, All Ages | Type | # | % | | :--- |:---:| :---:| | Other cancers | 55 274 | 42.9% | | Liver | 25 399 | 19.7% | | Breast | 23 081 | 17.9% | | Bladder | 9 239 | 7.2% | | Non-Hodgkin lymphoma | 9 854 | 7.6% | | Lung | 6 045 | 4.7% | **Total: 128 892** ## Number of New Cases in 2020, Both Sexes, All Ages | Type | # | % | | :--- |:---:| :---:| | Other cancers | 60201 | 44.7% | | Liver | 27895 | 20.7% | | Breast | 22038 | 16.4% | | Bladder | 10655 | 7.9% | | Non-Hodgkin lymphoma | 7305 | 5.4% | | Lung | 6538 | 4.9% | **Total: 134632** # Number of New Cancer Cases in 2020 in Egypt (Both Males & Females) ## Number of New Cancer Cases in 2020. Both Sexes, All Ages. | Type | # | % | | :--- |:---:| :---:| | Other cancers | 26474 | 39.8% | | Liver | 18 145 | 27.3% | | Breast | 22038 | 32.4% | | Bladder | 8410 | 12.6% | | Non-Hodgkin lymphoma | 3895 | 5.9% | | Lung | 4851 | 7.3% | | Prostate | 4767 | 7.2% | **Total: 66 542** ## Number of New Cancer Cases in 2020. Both Sexes, All Ages | Type | # | % | | :--- |:---:| :---:| | Other cancers | 34 100| 5% | | Liver | 9750 | 14.3% | | Breast | 22038 | 32.4% | | Colorectum | 2782 | 4.1% | | Ovary | 2787 | 4.1% | **Total: 68 090** # There is a need to understand the disease and translate our knowledge into effective therapies. # What Is Cancer? - Cancer is a group of diseases characterized by unregulated cell growth and the invasion and spread of cells from the site of origin, or primary site, to other sites in the body. - Over 100 types of cancer have been classified. # Benign vs. Malignant ## Benign - An abnormal growth that does not invade surrounding tissue or spread to other parts of the body. - Have a slow growth rate. - Most cells in benign tumors are normal. - Cells are not cancerous. - Do not invade the tissues around them. - Do not spread to other parts of the body - Easy to remove. - Have less chance to recur. - Secrete hormones including benign pheochromocytomas. - Can be treated with surgery. ## Malignant - An abnormal growth that can invade and destroy nearby tissue and that may spread (metastasize) to other parts of the body. - Have a fast growth rate. - Cells abnormal DNA and chromosomes, which make the nucleus larger and darker. - Cells are cancerous. - Invade the tissues around them. - Spread to the other parts of the body either through the bloodstream or lymphatic tissue. - Difficult to remove. - More likely to recur. - Secrete substances, which cause fatigue and weight loss. - Treated with chemotherapy, radiation therapy, or immunotherapy treatments. ## Tumor Classification: Benign vs Malignant - A tumor is an abnormal mass in the body that grows due to cells reproducing too much or not dying when they are supposed to. - Tumors are classified as benign or malignant based on multiple characteristics they display. ### Benign Tumors - Grow slowly and have distinct borders. - Do not invade surrounding tissue. - Do not invade other parts of the body. ### Malignant (Cancerous) Tumors - Can grow quickly and have irregular borders. - Often invade surrounding tissue. - Can spread to other parts of the body through a process called metastasis. # The Tissue of origin Gives the Distinguishing Characteristics of the Cancer - Carcinomas are cancers that originate in epithelial cells and represent approximately 85% of cancers. - Sarcomas are cancers derived from mesoderm cells (e.g. bone, muscle). - Adenocarcinomas are cancers of glandular tissue (e.g., breast). - Carcinoma - this type of cancer originates from the epithelial layer of cells that form the lining of external parts of the body or the internal linings of organs within the body. - Myeloma - these originate in the plasma cells of bone marrow. - Sarcoma - these cancers originate in connective and supportive tissues including muscles, bones, cartilage, and fat. - Lymphoma - these are cancers of the lymphatic system. - Mixed type - these have two or more components of the cancer. - Leukaemia - this is a group of cancers that are grouped within blood cancers. ## Cancers by Cell/Tissue Type | Type | Description | | :--- |:---:| | Carcinomas | Epithelial cells (skin, body cavities, organs) | | Sarcomas | Bones and soft tissues | | Myelomas | Plasma cells (manufacture antibodies) | | Leukemias | Blood cells (originates in bone marrow) | | Lymphomas | Immune system (lymph nodes, spleen, stomach, testicles) | | Mixed types | Derive from multiple cell/tissue types | ## Type of Tissue, and the Associated Benign and Malignant Cancers | Type of tissue | Benign | Malignant | | :--- |:---:| :---:| | Epithelial tissue | papilloma | carcinoma | | lining epithelium | | | | glands & lobules | adenoma | adenocarcinoma | | Connective tissue & muscle tissue | | | | dense connective tissue | fibroma | fibrosarcoma | | cartilage | chondroma | chondrosarcoma | | bone | osteoma | osteosarcoma | | smooth muscle | leiomyoma | leiomyosarcoma | | skeletal muscle | rhabdomyoma | rhabdomyosarcoma | | Neuronal tissue | | | | glial tissue | glioma | glioblastoma | | meninges | meningioma | meningial sarcoma | ## Carcinoma Type and Description | Type | Description | | :--- |:---:| | Adenocarcinoma | Carcinoma featuring microscopic glandular-related tissue cytology, tissue architecture and/or gland-related molecular products, e.g., mucin | | Squamous cell carcinoma | Carcinoma with observable features and characteristics indicative of squamous differentiation (intercellular bridges, keratinization, squamous pearls) | | Adenosquamous carcinoma | Mixed tumor containing both adenocarcinoma and squamous cell carcinoma, wherein each of these cell types comprise at least 10% of the tumor volume | | Anaplastic carcinoma | Heterogeneous group of high-grade carcinomas that feature cells lacking distinct histological or cytological evidence of any of the more specifically differentiated neoplasms. These tumors are referred to as anaplastic or undifferentiated carcinomas | | Large cell carcinoma | Composed of large, monotonous rounded or overtly polygonal-shaped cells with abundant cytoplasm | | Small cell carcinoma | Cells are usually round and are less than approximately 3 times the diameter of a resting lymphocyte and little evident cytoplasm. Occasionally, small cell malignancies may themselves have significant components of slightly polygonal and/or spindle-shaped cells | # Cancer Classification Based on Tissue Type ## Cancer Types | Cancer Type | Subtypes | | :--- |:---:| | Carcinomas | Adenocarcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma | | Leukaemias| Lymphoma, myeloma | | Sarcomas | Bone sarcoma, soft tissue sarcoma | | Cancers of brain and spinal cord | | ## SARCOMA Types | Type | Description | | :--- |:---:| | Angiosarcoma | Malignant neoplasm in the vessel walls | | Osteosarcoma | Tumor in a bone | | Ewing’s sarcoma | Bone | | Chondrosarcoma | Cartilage | | Gastrointestinal stromal tumor | Mesenchymal neoplasms of the gastrointestinal tract | | Liposarcoma | Fat cells | | Fibrosarcoma | Fibrous connective tissue | | Hemangioendothelioma | Vascular neoplasms | # The Tissue of Origin Gives the Distinguishing Characteristics of the Cancer - Cancers of different origins have distinct features. - The major factor that causes cancer in each target tissue is different; ultraviolet (UV) radiation from the sun can easily target the skin, while inhalation of cigarette smoke can target the lungs. - In addition, there are differences in the molecular mechanisms involved in carcinogenesis within each cell type and the pattern of spread of cells from the primary site. # How Cancer Arises? - Cancer is a multi-gene, multi-step disease originating from a single abnormal cell (clonal origin). - Changes in DNA sequences result in the cell progressing slowly to the mildly aberrant stage - Successive rounds of mutation & natural selection lead to a mass of abnormal cells called tumors. - Some cells in the tumor undergo further rounds of mutations leading to the formation of malignant cells which cause metastasis. # Insights Into Cancer - Initiation and progression of cancer depends on both external factors in the environment (tobacco, chemicals, radiation, and infectious organisms) and factors within the cell (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). - These factors can act together or in sequence, resulting in abnormal cell behaviour and excessive proliferation. - As a result, cell masses grow and expand, affecting surrounding normal tissues (such as in the brain), and can also spread to other locations in the body (metastasis). - However, it is important to remember that most common cancers take months and years for these DNA mutations to accumulate and result in a detectable cancer. # Molecular Basis of Cancer - The evolution from a normal cell to metastatic cancer cell requires multiple genetic and epigenetic changes - There are at least three mechanisms that allow these changes to be transferred to the progeny of a malignant cell: an inherited mutation, a somatic mutation, & methylation of the cell’s DNA. - These genetic events typically affect at least four pathways; however, the order in which the genes are affected is not critical. # Malignant Transformation Multi-Step of HCC - The images diagram the progression from a normal liver to HCC. - There are four steps to the progression: - Normal liver - Chronic hepatitis - Cirrhosis - Hepatocellular carcinoma (with cirrhosis) - The process is triggered by Hepatitis C, Hepatitis B, Ethanol, or NASH. - Epigenetic alterations and genetic alterations occur during the progression. - Dysplastic nodules and liver cirrhosis occur during the progression. - HCC occurs at the end of the process. # Multistep Genetic Model for Colorectal Adenocarcinoma Sequence - An image of the normal epithelium and the steps leading to its progression to carcinoma, with specific genes noted. - A mutation in the APC tumor suppressor gene is generally considered to be the initiation event. - This is followed by the sequential accumulation of other epigenetic and genetic changes that eventually result in the progression from a normal cell to a metastatic tumor. # Hallmarks of Cancer Cell - It has been suggested that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth: (1) self-sufficiency in growth signals, (2) insensitivity to antigrowth signals, (3) evasion of apoptosis, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) tissue invasion and metastasis. - These six capabilities are shared in common by all types of human tumors. - Although virtually all cancers must acquire the same six hallmark capabilities, their means will vary both mechanistically and chronologically across tumor types. ## The Eight Hallmarks of Cancer - As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. - The eight hallmarks currently comprise (1) the acquired capabilities for sustaining proliferative signaling, (2) evading growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing/accessing vasculature, (6) activating invasion and metastasis, (7) reprogramming cellular metabolism, and (8) avoiding immune destruction. - In the most recent elaboration of this concept, deregulating cellular metabolism and avoiding immune destruction were segregated as “emerging hallmarks,” but now, eleven years later (from 2011), it is evident that they, much like the original six, can be considered core hallmarks of cancer, and are included as such in the current depiction. ## The Hallmarks of Cancer, Circa 2022 - There are 10 marks of cancer, including the original six and four emerging ones. ### Hallmarks, The Original Six - Sustaining proliferative signaling - Evading growth suppressors - Resisting cell death - Enabling replicative immortality - Inducing or accessing vasculature - Activating invasion & metastasis ### The Four Emerged Hallmarks - Deregulating cellular metabolism - Avoiding immune destruction - Unlocking phenotypic plasticity - Nonmutational epigenetic reprogramming # Risk Factors for Development of Cancer ## Intrinsic Risk Factors - Random errors in DNA replication ### Categories - [Unmodifiable] ## Non-Intrinsic Risk Factors - Endogenous risk factors - Biologic aging - Genetic susceptibility - DNA repair machinery - Hormones - Growth factors - Inflammation - etc. - Exogenous risk factors - Radiation - Chemical carcinogens - Tumor causing viruses - Bad lifestyles such as smoking, luck of exercise, nutrient imbalance - etc. ### Categories - [Partially modifiable] - [Modifiable]