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CancerEpidemiologyLecture1.pptxIntroduction to Cancer Epidemiology and Carcinogenesis
PUBH 6550/8550
Chronic Disease Epidemiology
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Cancer is a term describing malignant diseases. Cancer should not be thought of as a single disease but rather a group of diseases which may have many characteristics in common but not necessarily the same causative agents, etiology or molecular profiles. In general, cancer defines diseases that have the capacity to invade surrounding normal tissue, metastasize (spread to distant sites) and kill the host in which it originates.
Objectives
What is the definition of cancer?
Benign vs. Malignant
Most common cancer types in men and women
Learn how to obtain cancer-related data using Internet sources
Understand cancer staging
Understand the basics of how carcinogenesis occurs
Describe inherited cancer syndromes
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Causation and Cancer
Examples of Identified Causes and Future Efforts in Cancer Prevention
Tobacco use and lung cancer
Infectious agents (e.g., HPV) and cervical cancer
Ionizing radiation and leukemia
Designation of a risk factor as “causal” has been the starting point for initiating cancer prevention programs based on reducing exposure to the risk factor
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The concept of causation has long had a central role in the application of epidemiologic evidence for controlling cancer. Designation of a risk factor as “causal” has been the starting point for initiating cancer prevention programs based on reducing exposure to the risk factor. Though the concept of causation remains a matter of continuing discussion, use of the term in public health implies that the evidence supporting causality of association has reached a critical threshold of certainty and that reduced exposure can be expected to be followed by reduced disease occurrence. In other words, if there is “enough” evidence supporting a particular risk factor (or a preventive or prognostic factor), it seems to be considered ‘causal’. Keep in mind, though, that risk factor is the most proper term.
What is cancer?
Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death.
Characteristics: Abnormality, Uncontrollability, invasiveness
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According to the American Cancer Society (ACS), cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Although cancer is often referred to as a single condition, it actually consists of more than 100 different diseases. These diseases are characterized by uncontrolled growth and spread of abnormal cells. Cancer can arise in many sites and behave differently depending on its organ of origin. Breast cancer, for example, has different characteristics than lung cancer. It is important to understand that cancer originating in one body organ takes its characteristics with it even if it spreads to another part of the body. For example, metastatic breast cancer in the lungs continues to behave like breast cancer when viewed under a microscope, and it continues to look like a cancer that originated in the breast.
Characteristics of Cancer
Abnormality
Cells are the structural units of all living things. Each of us has trillions of cells, as does a growing tree. Cells make it possible for us to carry out all kinds of functions of life: the beating of the heart, breathing, digesting food, thinking, walking, and so on. However, all of these functions can only be carried out by normal healthy cells. Some cells stop functioning or behaving as they should, serving no useful purpose in the body at all, and become cancerous cells.
Uncontrollability
The most fundamental characteristic of cells is their ability to reproduce themselves. They do this simply by dividing. One cell becomes two, the two become four, and so on. The division of normal and healthy cells occurs in a regulated and systematic fashion. In most parts of the body, the cells continually divide and form new cells to supply the material for growth or to replace worn-out or injured cells. For example, when you cut your finger, certain cells divide rapidly until the tissue is healed and the skin is repaired. They will then go back to their normal rate of division. In contrast, cancer cells divide in a haphazard manner. The result is that they typically pile up into a non-structured mass or tumor.
Invasiveness
Sometimes tumors do not stay harmlessly in one place. They destroy the part of the body in which they originate and then spread to other parts where they start new growth and cause more destruction. This characteristic distinguishes cancer from benign growths, which remain in the part of the body in which they start. Although benign tumors may grow quite large and press on neighboring structures, they do not spread to other parts of the body. Frequently, they are completely enclosed in a protective capsule of tissue and they typically do not pose danger to human life like malignant tumors (cancer) do.
Who is at risk of developing cancer?
Anyone can develop cancer, but the risk increases with age. About 76% of all cancers are diagnosed at age 55 and older.
In the U.S., men have about a 1 in 2 lifetime risk of developing cancer; for women, the risk of developing cancer is about 1 in 3.
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Statistics
Dr. Brian Fink
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Dr. Brian Fink
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Dr. Brian Fink
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Statistics
In 2019 in the U.S., there will be an estimated 1,762,450 new cancer cases and 606,880 cancer deaths.
https://cancerstatisticscenter.cancer.org/#/
Interactive Cancer Statistics Center
Has cancers ranked by incidence and death rates.
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In 2004, the American Cancer Society estimated 1,368,030 new cancer cases will be diagnosed in the United States, including 59,410 in Ohio.
563,700 cancer deaths will occur in the United States, including 24,480 in Ohio.
The average annual age-adjusted death rate for cancer per 100,000 persons in Ohio is greater than the national average. Ohio: 212.4 National: 199.8
NCI State Cancer Profiles
http://statecancerprofiles.cancer.gov/
This site provides customized views for cancer statistics nationwide, statewide, and countywide.
Outstanding resource, complete with its own tutorials.
A little slow in terms of being totally current.
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This resource can be very useful not only for school-related work but for your career. It is a great tool for accessing data whenever you wish.
Measuring Cancer in the U.S.
Surveillance, Epidemiology, and End Results (SEER): http://seer.cancer.gov
North American Association of Central Cancer Registries: http://www.naaccr.org
National Center for Health Statistics (mortality data): http://www.cdc.gov/nchs
US Population Estimates (Census Data):
http://eire.census.gov/popest/data/counties.php
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Here are additional useful, well-known and trusted websites to obtain cancer statistics for the United States.
Definitions: Benign vs. Malignant
Benign vs. Malignant Tumors
| Benign | Malignant | |
| Architecture | Retained | Lost |
| Differentiation | Retained | Lost |
| Growth | Slow or static | Rapid |
| Mode of growth | Encapsulated | Invasive |
| Systemic Spread | None | Metastases |
| Prognosis | No recurrence, site dependent | May recur |
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Benign tumors are tumors that cannot spread by invasion or metastasis; hence, they only grow locally. Benign tumors remain localized to the tissue in which they arise; they may grow large but will not spread to other parts of the body. If they grow into openings such as the trachea (wind pipe) or a major blood vessel, they can be fatal. But if found early, they can be cured by surgical removal, or in some cases by radiation therapy.
Malignant tumors are tumors that are capable of spreading by invasion and metastasis. By definition, the term "cancer" applies only to malignant tumors. Malignant tumors are a more serious matter. Some of their cells might break off, invading and destroying surrounding tissue or traveling through the blood or lymph streams to distant parts of the body, where new tumors might form. From these new tumors, malignant cells could break off again and establish even more colonies.
This process of invasion and spread is called "metastasis." Common sites for metastases, or secondary tumors, include the lymph glands, bones, lungs, liver and brain.
Definitions
Neoplasia: excessive and abnormal tissue growth
uncoordinated with (autonomous of) normal tissue
may persist in the absence of normal growth stimuli
2. Neoplastic transformation: permanent and
heritable changes leading to uncontrolled
proliferation and growth
3. Tumor: enlarged mass of tumor
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Neoplasia - A relatively autonomous growth of tissue; the growth of which exceeds and is uncoordinated with that of normal tissue and persists in some manner after cessation of the inducing stimulus.
An important mediator of neoplastic growth is blood supply. To grow beyond 1 to 2 mm in diameter a neoplasm must become vascularized.
1. Neovascularization has a dual effect on neoplastic cells. It supplies nutrients and oxygen and newly formed endothelial cells stimulate neoplastic cell growth by secreting polypeptide growth factors, such as IL-1, PDGF and insulin-like growth factor.
2. Angiogenesis is a necessary biological correlate of malignancy. Some research has demonstrated a correlation between the extent of angiogenesis and the probability of metastasis.
3. Neoplasms contain factors capable of affecting the entire series of events needed to form new capillaries. Two of the most important are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). These 2 factors are commonly elevated in a wide variety of different types of neoplasms. Elevated levels can be detected in the serum and urine of a significant number of cancer patients.
4. These factors are produced by neoplastic cells or be derived from inflammatory cells that infiltrate the neoplasms.
5. Neoplastic cells can also induce antiangiogenic molecules. Neoplastic growth is thus controlled by the balance between angiogenic and antiangiogenic stimuli.
6. Most human neoplasms are not angiogenic early in their life history. It has been hypothesized that mutations/decreased expression of critical tumor suppressor genes may act as a molecular switch since some tumor suppressor gene protein products are inhibitors of angiogenesis.
Dr. Brian Fink
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Cancer Progression and Tumor Subtypes
Histologic Progression
Hyperplasia: Increase in cell number, no change in appearance or organization
Metaplasia: Reversible change from one adult cell type to another
Dysplasia: Disordered growth and maturation, altered size, shape, and organization of cells. Reversible.
Anaplasia: Dedifferentiation and loss of organization
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Hyperplasia refers to an abnormal increase in the number of cells, which are in a normal component of that tissue and are arranged in a normal fashion with subsequent enlargement of the affected part. One example is thyroid hyperplasia, an enlargement of the thyroid gland caused by an abnormal rapid growth of the epithelial cells lining the follicles. Another example is: Guitar strumming leads to hyperplasia of the cells on the thumb (a callus is formed). The callus on the thumb is a hyperplastic growth.
Metaplasia refers to the replacement of one mature cell type with another mature cell type, for example, squamous metaplasia of the respiratory columnar epithelium - as evidenced by the metaplastic cough of a smoker.
Dysplasia refers to the replacement of one mature cell type with a less mature cell type, for example, dysplasia of the cervix epithelium.
Hyperplasia, metaplasia, and dysplasia are reversible because they are results of a stimulus. Neoplasia is irreversible because it is autonomous.
Hyperplasia
The enlargement of an organ or tissue caused by an increase in the reproduction rate of its cells, often as an initial stage in the development of cancer.
Dr. Brian Fink
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Metaplasia
A change of cells to a form that does not normally occur in the tissue in which it is found.
Example: occurs in smokers. In non-smokers, part of the surface of their airway is made up of a type of columnar epithelium where the cells look like columns under the microscope.
However, in people who smoke for a long time, the toxins act as a stimuli for these cells to be replaced by a different type. The surface turns into a squamous epithelium. Squamous cells are cells that look like single pancakes under the microscope; they are really flat.
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Dysplasia
The presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer.
Cervical dysplasia is a condition in which healthy cells on the cervix undergo some abnormal changes.
The abnormal cells are not cancerous, but can develop into cancer if it is not caught early and treated.
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Anaplasia
A condition of cells in which they have poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells.
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Normal Prostate Gland
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In this benign gland, the luminal contour shows tufts and papillary infoldings. The tall secretory epithelial cells have pale clear cytoplasm and uniform round or oval nuclei. Prominent nucleoli are not seen. Many basal cells can be identified.
Basal Cell Hyperplasia of Prostate
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Basal cell hyperplasia is usually seen in the transition zone and as you can tell, it is identified by an increase in cell number. Occasionally, it may be encountered in needle biopsies (which sample peripheral zone). Usually there is no change in appearance or organization. The transition zone of the prostate is the innermost part of the prostate gland and surrounds the urethra where it passes through the organ. The transition zone, along with the central zone, begins to enlarge as men pass age 40. Because of the immediate proximity, to the urethra, the enlargement of this part of the gland can cause difficulty in urination or ejaculation. The transition zone makes up about 5% of the glandular volume and is the site of about 10% of prostate cancers.
Continuum of Progression
Distinction between benign and malignant cancers is not always clear-cut
Carcinoma in-situ: tumor with histologic characteristics of malignancy, but confined to the epithelium, basement membrane intact
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Cancer that involves only the place in which it began and that has not spread. Carcinoma in situ is an early-stage tumor.
For example, squamous cell carcinoma in situ (Bowen's disease) is an early cancer of the skin. It develops from squamous cells which are flat, scale-like cells in the outer layer of the skin (the epithelium). The term "in situ" (borrowed from the Romans) means "in the natural or normal place" and, in the case of cancer, it means that the tumor cells are still confined to the site where they originated and they have neither invaded neighboring tissues nor metastasized afar. The tumor is curable.
Ductal Carcinoma in situ of the Breast
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Ductal carcinoma in situ (DCIS) of the breast. The ducts connect the lobules to the nipple. The ducts are an extremely common place for in situ carcinoma to occur. In the breast, DCIS occurs far more frequently than in the lobules (milk producing glands- LCIS).
Continuum of Progression
Carcinogenesis is a multi-step process that occurs over time
Stages of carcinogenic progression may be associated with well-defined gross or microscopic lesions
- Colon polyps -- adenocarcinomas
Morphologically-defined precursor lesions are undefined and/or inaccessible for most cancers
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Adenocarcinoma: A malignant tumor originating in glandular tissue.
Cancer Staging
In Situ – Tumor at the earliest stage when it has not penetrated or invaded surrounding tissue. An in situ lesion can only be diagnosed by microscopic examination.
Localized – Tumor has not spread beyond the original (primary) organ.
Regional – Tumor has spread beyond the primary organ to organs, tissues, or lymph nodes surrounding the primary organ.
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Cancer staging systems describe how far cancer has spread anatomically and attempt to put patients with similar prognosis and treatment in the same staging group. Since prognosis and treatment depend quite a bit on the stage, you can see how important it is to know what stage you have! At the same time other factors, including your general health, your own preference, and the results of biochemical tests on your cancer cells will contribute to determining the prognosis and treatment. So while the stage is important it is not everything.
The concept of stage is applicable to almost all cancers except for most forms of leukemia. Since leukemias involve all of the blood, they are not anatomically localized like other cancers, so the concept of staging doesn't make as much sense for them. A few forms of leukemia do have staging systems which reflect various measures of how advanced the disease is. For most solid tumors, there are two related cancer staging systems, the Overall Stage Grouping, and the TNM system (Tumor, Nodes, Metastasis).
Cancer Staging
Distant – Tumor has spread to other parts of the body beyond adjacent tissues, or metastasized, either through the blood system or lymph nodes.
Unstaged/Unknown – Insufficient information is available to determine the stage or extent of the disease at diagnosis.
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Cancer staging systems describe how far cancer has spread anatomically and attempt to put patients with similar prognosis and treatment in the same staging group. Since prognosis and treatment depend quite a bit on the stage, you can see how important it is to know what stage you have! At the same time other factors, including your general health, your own preference, and the results of biochemical tests on your cancer cells will contribute to determining the prognosis and treatment. So while the stage is important it is not everything.
The concept of stage is applicable to almost all cancers except for most forms of leukemia. Since leukemias involve all of the blood, they are not anatomically localized like other cancers, so the concept of staging doesn't make as much sense for them. A few forms of leukemia do have staging systems which reflect various measures of how advanced the disease is. For most solid tumors, there are two related cancer staging systems, the Overall Stage Grouping, and the TNM system (Tumor, Nodes, Metastasis).
Cancer Staging
Staging describes the extent or severity of an individual’s cancer based on the extent of the original (primary) tumor and the extent of spread in the body.
Staging helps the doctor plan a person’s treatment.
The stage can be used to estimate the person’s prognosis
Knowing the stage is important in identifying research studies that may be suitable for a particular patient.
http://www.cancer.gov/cancertopics/factsheet/Detection/staging
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Staging is based on knowledge of the way cancer develops. Cancer cells divide and grow without control or order to form a mass of tissue, called a growth or tumor. As the tumor grows, it can invade nearby organs and tissues. Cancer cells can also break away from the tumor and enter the bloodstream or lymphatic system. By moving through the bloodstream or lymphatic system, cancer can spread from the primary site to form new tumors in other organs. The spread of cancer is called metastasis.
Check out the following site for more information on the TNM system: http://www.cancer.gov/cancertopics/factsheet/Detection/staging.
Cancer Subtypes
Histogenic subtypes: by cell type of origin (broad)
Topology: by organ
Morphology / histology: by cell type within organ (specific)
Behavior: cellular (tumor grade) and clinical (tumor stage)
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Cancer Types
Most cancers (>90%) arise from "epithelial" tissues, such as the inside lining of the colon, breast, lung or prostate. These are referred to as carcinomas and usually affect older people.
Sarcomas are tumors that arise from "mesenchymal" tissues such as bone, muscle, connective tissue, cartilage and fat.
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Most cancers (>90%) arise from "epithelial" tissues, such as the inside lining of the colon, breast, lung or prostate. These are referred to as carcinomas and usually affect older people. Sarcomas are tumors that arise from "mesenchymal" tissues such as bone, muscle, connective tissue, cartilage and fat. Sarcomas occur in young people as well as in adults and comprise less than 1% of all cancers. Sarcomas are named by the tissue of origin; for example, "osteosarcoma" arises from bone, "liposarcoma" arises from fat and "chondrosarcoma" arises from cartilage.
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Carcinomas
Major categories of epithelium
Covering and lining membranes
Glands
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A carcinoma is any malignant cancer that arises from epithelial cells. Carcinomas invade surrounding tissues and organs and may metastasize to lymph nodes and distal sites. Carcinoma in situ (CIS) is a pre-malignant condition, in which cytological signs of malignancy are present, but there is no histological evidence of invasion through the epithelial basement membrane.
Carcinoma, like all neoplasia, is classified by its histopathological appearance. Adenocarcinoma and squamous cell carcinoma, two common descriptive terms for tumors, reflect the fact that these cells may have glandular or squamous cell appearances respectively. Severely anaplastic tumors might be so undifferentiated that they do not have a distinct histological appearance (undifferentiated carcinoma).
Sometimes a tumor is referred to by the presumptive organ of the primary (eg carcinoma of the prostate) or the putative cell of origin (hepatocellular carcinoma, renal cell carcinoma).
Carcinomas
Covering and lining membranes
Contiguous cells connected by junctions
Separated from connective tissue by basement membrane
Normal cell functions: protection, secretion, absorption, transport
Skin, GI tract, GU tract (kidneys, tubules, pelvis), endothelium (blood vessels), mesothelium (body cavities)
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Carcinomas
2. Glands
Exocrine: ducts to epithelial surface
Mammary glands, prostate, sweat glands, liver (bile), pancreas (digestive enzymes)
Endocrine: no ducts
Thyroid, adrenal, liver (glycogen, albumin), pancreas (insulin)
Parenchyma: epithelial component
Stroma: connective tissue component
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Histologic Subtypes of Carcinomas
Epidermoid: squamous cell, transitional cell carcinoma
Adenocarcinoma: form secretory or gland-like structures
Site-specific: hepatocarcinoma, renal cell carcinoma
Undifferentiated (anaplastic): small (oat) cell carcinoma of lung, medullary carcinoma of breast
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An epidermoid carcinoma is a cancer that begins in squamous cells (thin, flat cells that look like fish scales). Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the lining of the respiratory and digestive tracts. Also called squamous cell carcinoma.
Although commonly associated with lung cancer, adenocarcinoma is a type of cancer that develops in cells lining glandular types of internal organs, such as the lungs, breasts, colon, prostate, stomach, pancreas, and cervix. Another type of adenocarcinoma, mucinous adenocarcinoma, accounts for only 10-15% of all adenocarcinomas and is particular to aggressive carcinomas that are comprised of at least sixty percent mucus. In other words, it is a cancer that begins in cells that line certain internal organs and that have gland-like (secretory) properties.
Why are carcinomas so common?
Derived from basal layer or stem cells
Undifferentiated cells that normally give rise to differentiated (mature) epithelial cells, can still proliferate
2. Often in contact with the external environment
- Opportunity for exposure
Epithelial cells are often metabolically active
- May activate environmental carcinogens
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We have so many epithelial cells that it makes sense that most cancers arise from them. In a way, it is purely a numbers game.
Need layer that renews itself so cells proliferate.
#2 examples are the skin, intestinal tract, and bladder.
Sarcomas
Dense: cartilage, bone, ligaments, tendons, fasciae
Loose: fibroblasts, adipocytes, perivascular cells
Basement membranes, glandular stroma, extracellular matrix
Muscle: smooth, heart, skeletal
Sometimes treated as a separate tissue type
Low proliferative capacity
Less environmental exposure than epithelium
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A sarcoma is a cancer of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Sarcomas are fairly rare and have a low proliferative capacity (don’t spread very well).
An example is Kaposi sarcoma: a sarcoma of spindle cells mixed with angiomatous tissue. Usually classed as an angioblastic tumour. A fairly frequent disease associated with HIV infection or long term immunosuppresion.
Hemolymphatic Cancers
Blood and lymphoid cells
Myeloid cells
Granulocytes
Monocytes
Erythroid cells (red blood cells)
Megakaryotic cells (platelets)
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Hodgkin’s and Non-Hodgkin’s lymphoma are the main examples.
Hemolymphatic Cancers
2. Lymphoid Cells
B cells, T cells: Non-Hodgkin’s lymphoma, lymphoid leukemias
Plasma cells: multiple myeloma
Reed-Sternberg cells: Hodgkin’s lymphoma (now considered B-cell derived)
Cells often retain ability to proliferate
Highly exposed
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Carcinogenesis
Multistep Carcinogenesis
Cancers are derived from a single cell
- Monoclonal origin
For a single cell to become a tumor, it must gain a selective advantage over other cells in the surrounding environment
- Clonal expansion
To gain a selective advantage and become malignant, the cell must overcome multiple barriers
- Multistep carcinogenesis, clonal evolution
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Example: lymphomas evolve with somatic mutations to more sever lymphomas. The cell has to acquire changes that allow it to proliferate and perhaps be invasive so it will outgrow other cells.
Selective advantage allows cell to proliferate.
Neoplastic phenotype
Acquired characteristics of neoplastic clone
Deregulated growth
Overcome need for growth stimuli
Override cell cycle control mechanisms
Overcome or prevent differentiation
Mature phenotype loses capacity to proliferate (senescence), exception would be lymphocytes
Unlimited replicative potential
Local invasion/metastasis
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Deregulated growth: normally a cell is tightly controlled by growth stimuli, this cell ignores or overrides these mechanisms.
Overcome/prevent differentiation: normally, as a cell matures, they develop the mature phenotype (like top skin cells) and decline in proliferation.
Exception: if lymphocytes encounter their antigen and they proliferate and proliferate
Local invasion: overcome normal controls from surrounding cells
Neoplastic phenotype
2. Deregulated survival
Cells ignore apoptotic stimuli
- Apoptosis: active process of cell “suicide” (programmed cell death)
External stimuli: loss of cell-cell junctions, cell-mediated immunity
Internal stimuli: DNA damage, hypoxia, telomere erosion
Cells avoid apoptotic triggers
Influence surrounding cells and extracellular matrix (ECM) to support tumor growth
Angiogenesis
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As cells mature, they get senescent (do NOT divide). Apoptosis requires energy, stimuli that causes the cell to release enzymes that make it die.
External stimuli can trigger apoptosis. Example: cytotoxic T cells kill cells it does not recognize.
Internal stimuli: telomeres prevent unraveling of DNA, as cell divides and divides, the telomeres get shorter and cannot prevent DNA unraveling and damage.
Hypoxia: if tumor does not have blood supply, its cells can die.
Angiogenesis: tumor stimulates cells to make blood vessels for blood, oxygen, and nutrients. Tumor cells influence surrounding tissues to support it.
Neoplastic phenotype
3. Hypermutable phenotype
Background (normal) rate of somatic mutations at 3 per cell over a person’s lifetime
Likelihood of acquiring carcinogenic mutations increased beyond expectations – as much as 100 times higher
Believed by many (but not all) to be a necessary step in all carcinogenic mechanisms, others believe it is a consequence of transformation
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It is hard to develop a somatic (cell) mutation, some cancer cells mutate a lot. Requires somatic mutations at very high rates and it may be a cause or consequence of neoplasia.
Neoplastic phenotype
How is the phenotype achieved?
Individual-level genetic factors
High-penetrance genes (familial cancers)
Low-penetrance genes (gene x environment)
Penetrance: proportion of allele carriers that express the phenotype (all or none)
Phenotype: observable characteristics
Phenocopy: environmentally-determined phenotype that mimics a genetic trait
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Penetrance: proportion of people with an abnormal allele that express a certain phenotype
High penetrance: lots of people express the phenotype associated with the genotype. It makes sense that inherited conditions would have a high penetrance, as family members inheriting a gene from other family members would be more likely to express the phenotype.
Neoplastic phenotype
Mutation: variant allele (gene) found in ≤ 1% of the population
Polymorphism: variant allele that occurs in > 1% of the population
High penetrance cancer genes are mutations, strong link to rare phenotype
Known low-penetrance genes associated with cancer are polymorphisms, identification of rare low-penetrance mutations unlikely
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Neoplastic phenotype
How is the phenotype achieved?
2. Acquired (cell-level) genetic factors
Somatic mutations
Epigenetic causes of altered gene expression
Epigenetic: heritable changes in gene function that are unrelated to changes in DNA sequence (mutations)
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A cell in the carcinogenic pathway is proliferating and passes its mutations to its progeny. Epigenetic changes are in gene function and expression related to other things that can also be inherited by progeny. Example: methylation status is passed to progeny cells. Methyl group are often added to promoter sequences on DNA, thus silencing their expression. Methylation, like all epigenetic events, simply alters the expression and function. It does NOT alter the sequence of DNA. Think of methylation and other epigenetic events as on/off expression or function switches only.
Neoplastic phenotype
How is the phenotype achieved?
Carcinogenic pathway events
High-penetrance genes (familial cancers)
Somatic mutations
Epigenetic causes of altered function
2. Off-pathway events (carcinogenesis modifiers)
Low-penetrance genes + environment
Exogenous and endogenous factors
Inflammation, systemic growth factors, hormones, input from surrounding cells, ECM
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Anything happening to that individual cell and its genes
Inflammation creates lots of reactive oxygen species (ROS).
Genes Involved in Carcinogenesis
Basic functional categories of genes involved
Oncogenes
Tumor suppressor genes
DNA repair genes
Alternate categories also valid
Individual genes may fit multiple categories
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Proto-oncogenes are perfectly normal as they help in growth promotion. It is their mutation to oncogenes that makes them dangerous in terms of carcinogenesis.
Perhaps the best tumor suppressor gene known is p53, which is frequently found to be mutated in various forms of cancers.
These are the genes most often involved with carcinogenesis. DNA repair genes that are mutated are analogous to have a bunch of broken tools in your toolbox. Now, you have trouble fixing problems and the problems persist and get worse. Two inherited forms of colorectal cancer are caused in part by mutations in DNA mismatch repair genes.
Genes Involved in Carcinogenesis
1. Oncogenes
Proto-oncogene: normal function to promote proliferation only in response to appropriate stimuli
Oncogene: gain of function mutations cause “constitutive expression” and inappropriate growth
Dominant effect: only one mutant allele needed to affect phenotype
Rare in familial syndromes (often lethal)
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Proto-oncogene: pro-growth but only with growth factors
Constitutive expression: stays turned on all the time, grows inappropriately
Dominant: get the phenotype with only one mutant
Rare: because it is usually lethal so you are not born
Genes Involved in Carcinogenesis
2. Tumor suppressor genes
Normal function: prevent cell growth in absence of appropriate stimuli
Loss of function mutations stimulate inappropriate growth
Recessive effect: both alleles must be inactivated
Often associated with hereditary cancers
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Inherit one abnormal allele from each parent
Genes Involved in Carcinogenesis
Loss of Heterozygosity (LOH)
One allele of tumor suppressor is non-functional
Typically a hereditary mutation
Loss of second (wild type or normal) allele leads to loss of function
Classically observed as a large deletion, may also be other somatic mutations
Epigenetic silencing may be very common
LOH suggests tumor suppressor locus
Mendelian dominant pattern of inheritance when inherited mutation is inactivating
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Lose a gene region, lose tumor suppressor function.
Epigenetic silencing: abnormal methylation, another somatic mutation from a base pair change
Mendelian: appears dominant because you only need one bad allele of the tumor suppressor gene, you still need to lose the good gene to get the cancer though
Genes Involved in Carcinogenesis
3. DNA repair genes
DNA is constantly damaged
Normal cellular metabolism (e.g. oxidation)
Spontaneous processes (e.g. cytosine deamination to form thymine or uracil)
Replication errors
Environmental mutagens (least common?)
Multiple complex pathways of DNA repair may be triggered depending on type of damage
Components may operate in multiple pathways, and pathways may overlap functionally
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Normal cell metabolism produces reactive oxygen species (ROS) that damage DNA.
Genes Involved in Carcinogenesis
Alternate categorization
Oncogenes
Tumor suppressor genes
Gatekeeper genes: classical tumor suppressors, pathway events
Caretaker genes: DNA repair, apoptosis
Off-pathway events, loss of function modifies (accelerates) carcinogenesis
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Genes Involved in Carcinogenesis
Genes may fall into multiple categories
- TP53 (p53): mutated in 50% of cancers
Cell cycle control (tumor suppressor)
Mutant gene product may inhibit wild-type p53 protein (oncogene)
Role in DNA repair
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Some mutations help GAIN function (oncogene). However, oncogenes, as their name implies, refer to tumors (onco). Thus, these mutations of proto-oncogenes to oncogenes allow carcinogenesis to progress.
Inherited Cancer Syndromes
Inherited Cancer Syndromes
Familial (vs. sporadic) cancers
Substantial risk of cancer in relatives from several generations (familial aggregation)
Mendelian mode of inheritance
- Single gene vs. polygenic trait
Early age of onset if hereditary
Multiple or bilateral cancers common among family members
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Why would an inherited mutation cause early or multiple cancers? Every cell in your body has step 1 mutation in the carcinogenesis pathway, so the rate you develop cancer is faster since more cells are now at risk due to this inherited mutation. Familial cancers help identify tumor suppressor genes.
Inherited Cancer Syndromes
Discovery of familial cancers
Familial aggregation observed
Unlikely unless highly penetrant and/or outcome very rare or distinct
2. Segregation analysis confirms Mendelian mode of inheritance
3. Linkage analysis confirms association between disease locus and marker
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If you inherit the gene, you’ll likely get the phenotype.
Inherited Cancer Syndromes
Familial Retinoblastoma (Rb)
Autosomal dominant
- Offspring of patients have 50% probability
Bilateral retinoblastomas prior to 1 year
Increased other cancers (osteosarcoma) in survivors
Approximately 40% of retinoblastomas familial
- 1/20,000 births develop Rb (3% of pediatric malignancies)
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Autosomal: looks dominant since half of your kids will get it.
Autosomal dominant: anything but sex chromosomes.
Familial retinoblastoma is hereditary, is passed from parent to child, and is bilateral (affects both eyes). Familial retinoblastoma represents 10% of cases. It is associated with a long-term predisposition to other types of cancer. The second type of retinoblastoma, responsible for 70% of all new cases, is unilateral (only one eye is affected). It represents the non-heritable form of the disease, and carries no increased risk of a second tumor. Ninety percent of all retinoblastoma cases are diagnosed within the first three years of the child's life. On average, children with familial retinoblastoma typically are diagnosed at four months of age. When there is no family connection, the cancer is usually diagnosed when the child is approximately one to two years of age.
Inherited Cancer Syndromes
Familial retinoblastoma (Rb)
LOH in inherited and sporadic
Sporadic are unilateral and older
Knudson’s 2-hit model: inherited cases required one mutation, sporadic required 2 hits
Rb is a tumor suppressor
Required for cell cycle control, loss of function allows proliferation in absence of growth factors
Inhibits the transcriptional activator E2F (which initiates cell cycle progression from G1 to S)
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Familial retinoblastoma occurs when the fetus inherits from one of its parents a chromosome (number 13) that has its RB locus deleted (or otherwise mutated). The normal Rb protein prevents mitosis. E2F attaches to promoter sites and starts cell cycle progression from Rb protein. If Rb not there to bind to E2F, E2F does all this.
Knudson’s 2-hit Theory
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In essence, inheriting one variant allele (in other words, a mutation – First Hit), the risk of having a second, non-hereditary mutation (Second Hit) is much higher than if you did not inherit a mutation.
Inherited Cancer Syndromes
Li-Fraumeni Syndrome (p53)
Autosomal dominant
Childhood soft tissue sarcomas, early onset breast cancer, brain tumors, leukemias, lung cancer, others
50% probability of cancer by age 45, 90% by age 65
Phenotype less distinct than Rb
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Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. Individuals with LFS are at increased risk for developing multiple primary cancers.
Two forms of Li-Fraumeni syndrome are recognized: classic Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL).
Classic LFS is defined by the following criteria:
A proband with a sarcoma diagnosed before 45 years of age AND
A first-degree relative with any cancer under 45 years of age AND
A first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age
Proband: An individual or member of a family being studied in a genetic investigation (index case).
Inherited Cancer Syndromes
Li-Fraumeni Syndrome (p53)
p53 identified as a tumor suppressor in sporadic cancers first
- New evidence gain of function (oncogenic) mutations: mutated protein may inhibit wild-type
LOH very common, somatic mutations in 50% of cancers
Transcriptional activator with key roles in DNA repair, cell cycle control, apoptosis
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Inherited Cancer Syndromes
Familial adenomatous polyposis (FAP)
Up to several thousand colorectal adenomas (polyps) beginning in adolescence
Most get colon adenocarcinomas by age 40 (develops from benign tumors)
1/10,000 births
≤ 2% of colorectal cancers
Also other GI tumors, osteomas, epidermoid cysts, hepatoblastomas, desmoid tumors
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Familial adenomatous polyposis, often called FAP, is an inherited colorectal cancer syndrome. This cancer usually develops in the lower part of the digestive system, including the large intestine (colon) and rectum. People with the classic type of familial adenomatous polyposis may begin to develop multiple noncancerous (benign) polyps (growths) in the colon as early as their teenage years. The average age at which an individual develops colon cancer in classic familial adenomatous polyposis is about 39 years. Some people have a variant of the disorder, called attenuated familial adenomatous polyposis, in which polyp growth is delayed. The average age of colorectal cancer onset for attenuated familial adenomatous polyposis is about 55 years.
Inherited Cancer Syndromes
Familial adenomatous polyps (FAP)
Apc gene mutations
Phenotype varies with specific mutations
Somatic mutations common in sporadic polyps, also esophageal carcinoma
Sporadic mutations are seen in benign lesions prior to malignancy
May affect cell-cell interactions, cytoskeleton, other
- Binds beta-catenin
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In people with classic familial adenomatous polyposis, the number of polyps increases with age and can include hundreds to thousands of polyps. Unless the colon is removed, these polyps will become malignant (cancerous). Also of particular significance are noncancerous growths called desmoid tumors. These fibrous tumors usually occur in the tissue covering the intestines and may be initiated by abdominal surgery. With classic familial adenomatous polyposis and its attenuated variant, other benign and malignant tumors are sometimes found in other places in the body, especially the duodenum (a section of the small intestine), stomach, bones, skin, and other tissues. People who have many of these other growths in addition to colon polyps are sometimes referred to as having Gardner syndrome.
Familial adenomatous polyposis affects about 1 in 30,000 people, with 800 to 1,000 new cases detected each year.
Inherited Cancer Syndromes
Hereditary non-polyposis colon cancer (HNPCC)
Autosomal dominant
Early onset colorectal cancer, ≤ 2% of cases
Multiple primary tumors
Endothelial cancer, urinary tract cancers, stomach, biliary system
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Hereditary nonpolyposis colorectal cancer, often called HNPCC or Lynch syndrome, is a type of inherited cancer of the digestive tract, particularly the colon (large intestine) and rectum. People with hereditary nonpolyposis colorectal cancer have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with this disorder also have a greatly increased risk of endometrial and ovarian cancer. Even though the disorder is described using the term nonpolyposis, people with hereditary nonpolyposis colorectal cancer may have occasional noncancerous growths called colon polyps. These colon polyps occur at an earlier age than do colon polyps in the general population. Although the polyps do not occur in greater numbers than in the general population, they are more prone to become cancerous.
Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer.
Inherited Cancer Syndromes
Hereditary non-polyposis colon cancer (HNPCC)
Tumors show microsatellite instability
Dinucleotide repeats (CACACACA) in non-coding DNA prone to replication errors (slippage)
Single-base substitutions, small deletions/insertions
Mutations in mismatch repair enzymes involved in identification and repair
MSH2, MLH1 most often involved
Also PMS1, PMS2, MSH6
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In various di or tri-nucleotide repeats get replicated and are prone to slippage errors, you lose bases, mismatch repair system fixes the errors
Summary: Inherited Syndromes
Those syndromes are extremely rare, thus they have little influence on population level risks
Understanding syndromes has led to identification of key genes and processes associated with carcinogenesis
Somatic mutations and polymorphisms may be important in sporadic cancers
May provide keys to understanding tissue-specific aspects of carcinogenic pathway components
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