INTRODUCTION TO ONCOLOGY Flashcards
What is Cancer?
• At the most fundamental level, cancer is a disease
caused by changes in genes or DNA.
• Cancer occurs when there is a genetic mutation that leads
to proliferation of a colony of malignant cells.
• Cancer is a term for over 100 diseases in which abnormal
cells divide without control and can invade other tissues.
• Cancer is characterized by abnormalities in cell growth
(uncontrolled proliferation and reduced differentiation),
local tissue invasion, and metastases
4 characteristics of cancer
Uncontrolled Proliferation
• Cancer cells lack or fail to respond to normal mechanisms that control cell division or cell growth.
Cellular Changes
• generally lost some or all of their differentiation characteristics
• may have changes to chromosomes, proteins, or enzymes.
• often cannot perform the intended functions of their tissue of origin (and may no longer resemble normal healthy cells)
Invasion
• locally invading tissues nearby
Metastasis
• Process by which malignant cells travel/spread to other parts of the body through blood or lymph systems
Types of Cancer – Solid Tumours
• Solid tumours are classified by their tissue of origin
Epithelial
- Surface Epithelium Carcinoma
- Glandular Tissue Adenocarcinoma
Lots of cancers are carcinoma or adenocarciniomas
Connective Tissue
- Bone Osteosarcoma
- Striated Muscle Rhabdomyosarcoma
- Smooth Muscle Leiomyosarcoma
Neural Tissue
- Glial tissue Glioblastoma
- Astrocytes Astrocytoma
Dermal Tissue
- Melanocytes Melanoma
Gonadal Tissue
- Germ Cells Germinomas
Types of Cancer –Hematologic or “Liquid”
Malignancies
• Hematologic Malignancies are classified based on cell of
origin and further divided based on pathology/cell lineage
and presentation:
Hematopoetic cells - Leukemia
• Acute Myelogenous Leukemia
• Chronic myelogenous leukemia
• Acute Lymphocytic leukemia
Lymphoid tissue cells - Lymphoma
• Hodgkin Lymphoma
• Diffuse Large B-Cell Lymphoma
• T-cell Lymphoma
Plasma cells - Multiple Myeloma
• Multiple Myeloma
Carcinogenesis can be simplified into which 4 steps:
INITIATION: • Genetic alteration (eg. Exposure to carcinogen)
• If genetic alterations are not repaired, result is irreversible cellular changes.
• Changed cells may have a growth advantage that permits the development of a clonal population of the changed (cancer) cells.
- Genetic change has happened, Immune response did not sto it
PROMOTION: • Carcinogens or other factors alter the environment to favour growth of the changed cell population (compared to normal cells)
CONVERSION or TRANSFORMATION
• The altered cells (or clonal population) becomes cancerous, Becomes malignant problem
PROGRESSION: • Further genetic alterations that lead to increased proliferation of
the cancerous cells
Germline Gene Mutation Somatic Gene Mutation
INHERITED genetic alteration occurring in
the germ cells (eg: parent sperm or egg)
ACQUIRED alteration in DNA (mutation)
within a cell /lineage/colony occurring after
conception
Present in all cells vs Present only in some cells
Can be passed on to offspring vs. Not passed on to offspring
Sample: Cheek swab or blood vs. Sample: Biopsy of malignant tissue
Relevance to Cancer:
• Impact drug metabolizing enzymes
(CYP450 polymorphisms)
• Impact cancer risk (eg. BRCA1/BRCA2
mutation)
Relevance to Cancer:
• Can drive the development of a malignancy
• Can be a therapeutic target
define Oncogenes
• An oncogene is a gene that has the potential to cause cancer.
• Most began as proto-oncogenes and through mutation were up-regulated
to oncogenes
• An activated oncogene leads to excessive production of genetic
product (cell signal/protein). The genetic product may be abnormal.
• The result of an activated oncogene is dysregulation of normal cell
growth, a growth advantage to the cell, and/or increased probability
of transformation to cancer
Proto-oncogenes define
Normal gene, present in all cells and essential regulators of normal
cellular functions.
• When a proto-oncogene is changed (becomes mutated) it can
become an oncogene. The mutation is usually acquired (somatic).
• Tumor suppressor genes define
what is TP53
• Role in normal cells is to regulate and inhibit inappropriate cellular growth and proliferation
• Genetic alterations can lead to loss of control over normal cell growth
- Stop things from happeningt ht can cause cancer
Example TP53
• TP53 gene provides instructions to make p53 protein. This protein is abnegative regulator of cell division
• Stops cells from growing or dividing too quickly
• Will halt the cell cycle when cell DNA is damaged to allow for repairs or corrections or cell death/self destruction (apoptosis).
• A mutation is TP53 gene is a frequent alteration in malignancies
• The mutation is usually somatic but can be inherited
• Inherited TP53 mutation is known as “Li-Fraumeni syndrome”
Dont have any brakes
Somatic mutation of TP53 bad marker for cancer
• DNA Repair genes
• Role in normal cells is to repair DNA that is damaged by environmental factors or DNA replication errors.
• If errors are not corrected, these flaws can lead to activation of
oncogenes or deactivation of tumor suppressor genes.
6 Hallmarks of Cancer
- Enabling replicative immortality: Continue to replicate over and over
- Angiogenesis: make their own blood vessels
- Resisting cell death: no apoptosis
- Sustaining proliferative signaling: keeps telling it to grow
- Evading growth suppressors: not stopping
- Activing invastion and metastasis: moving to other organs
Emerging Hallmarks and Enabling
Characteristics of Cancer
2 more hallmarks
- Avoid immune destruction
- Deregulate cellular energetics: other methods of metabolism to continue to have function
2 enabling characterstics:
- tumor promoting inflamm: Inflammation is helping tumor
- genome instability and mutation: Keep making more genetic issues once there are a few
• In summary cancer cells have the following characteristics:
read
• Capacity for unlimited, uncontrolled, and unrestrained proliferation (not always faster)
• NOTE – Although malignant cells are often replicating rapidly, that is not
always the case. A few cancers replicate more slowly
• Lack differentiation and hence cannot perform the intended
physiologic function of their tissue of origin
• Genetic instability that lends a growth advantage enabling them to
eventually take over a local tissue environment
• Capacity to initiate angiogenesis as required
• Capacity to invade adjacent tissues
• Capacity to migrate to a distant site and establish new secondary tumours (metastasize)
describe metastasis
• Local metastases generally invade the lymphatic system
• Distant metastases commonly involve the brain, lung, bone, and liver but each cancer has a characteristic pattern of metastasis
• Example – prostate cancer commonly metastasizes to bone but rarely to the brain
• Metastases retain the characteristics of the primary cancer.
• A bone metastasis from prostate cancer is NOT bone cancer. It is “prostate cancer with mets to bone”
• Because of metastases, cancer recurrence can occur even after the removal or destruction of the primary tumour
prevention of cancer
• Reduce exposure to carcinogens
• Some vaccinations
• Example HPV vaccination which is a known link to
carcinogenesis in cervical cancer as well as some penile and anal cancers
Cancer’s Seven Warning Signs (Referral)
• Change in bowel or bladder habits
• A sore that does not heal
• Unusual bleeding or discharge
• Thickening or lump in the breast or elsewhere
• Indigestion or difficulty in swallowing
• Obvious change in wart or mole
• Chronic, unexplained, nagging cough or hoarseness
surgery or radiation tx
Surgery
• Removal of primary tumour
• Possibly removal of the lymph nodes
• Reduce Metastases
Radiation
• At high doses, radiation therapy kills cancer cells or
slows their growth by damaging their DNA. Once the
DNA is damaged beyond repair, those cancer cells
stop dividing or die
• Pharmacotherapy (Antineoplastic Agents)
6 types
Lot of side effects
All othe rapidly dividing cells
Hair, canker sores, bone marrow stem cells - reduced immune response
Atuoimmune problems if giving spoemthing to amp up immune system
Cytotoxic Chemotherapy
• damage or kill dividing cells (rapidly dividing cells are more susceptible)
Give toxic drug that kills cells and problematic for quick dividing cells, damage the DNA
Targeted Therapies
• impact cell signaling or signal transduction within the cell by targeting specific gene mutations or cell surface receptors
Immunotherapies
• influence the bodies immune response to malignant cells
Endocrine Therapies
• manipulate hormone production or action for cancers that are hormone dependent
Angiogenesis Inhibitors
• Impact cell signalling or processes that influences angiogenesis
stop making blood vessels
Impetus for workup
• The initiation of investigations to identify (or rule out)
malignancy can be triggered by various events or stimuli.
• Palpation of a mass or nodule (by patient/self or care provider)
• Routine laboratory tests (largely abnormal CBC)
• New or non-resolving symptoms
• Examples - drastic change in bowel habits or stool, unusual bleeding,
unexplained neurologic symptoms, change in skin lesion/mole
• Screening test results
• Examples – pap smear, mammogram, FIT test
Workup
history, physical exam
lab test
imaging
History and physical exam
• Consider exposure to carcinogens
• Explore co-morbidities and general health that may impact treatment tolerance
• Assess lumps & bumps
Laboratory Tests
• “Regular tests” to assess blood counts, electrolytes and organ function
• Tumour markers (if applicable) – example is LDH which can be elevated in malignancies (not definitive - it can be elevated for other reasons as well)
LDL Crude marker for rapid cell turnover
Imaging
• Ultrasound or CT or lump/mass to confirm presence of a tumour and its size. (NOTE – U/S and CT cannot determine between malignant and benign tumours)
• Xray, CT, or PET as appropriate to explore for metastases
Diagnosis – PATHOLOGIST
• A diagnosis of malignancy is made by a pathologist based on tissue from
the mass or lesion.
• The pathology is essential because many benign tumours can mimic the
appearance of cancer.
• Tissue is most commonly obtained through a biopsy
• The biopsy can be excisional or core or fine needle aspirate.
• Tissue can also be obtained from surgical resection.
• If a biopsy cannot be performed or is contraindicated, the pathologist
will use tissue from the surgical resection.
• Pathologist will also perform tests on the tissues to characterize the malignancy
• Tumour classification
• Identify any biomarkers
• Determine the tumour grade.
Grading – General Concepts
• A tumour grade is assigned based on different
pathological factors:
• Histology of cancer cells considering
• Histopathologic Type
• Morphologic Features
• Degree of differentiation
• A higher grade generally correlates with a more
aggressive tumour and poorer prognosis
Biomarkers
• Pathologist will also test for biomarkers (as appropriate)
Prognostic biomarker
• Indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumour aggressiveness
- Tumor has P53 mutation tells it is likely aggressive
Predictive biomarker
• Indicative of therapeutic efficacy because there is an interaction between the biomarker and therapy on patient outcome
Molecular profiling
• Definition: identification and documentation of the structure of a specific DNA, RNA, or protein molecule for the purpose of diagnosis or characterization of a
genetic disorder.
• “Blueprint” of possible cancer cell biomarkers
• Can summarize the somatic mutations present
Molecular Profiling Tests
Cytogenetics
• Testing samples of tissue (cancer) to look for changes in the chromosomes of the cells
Gene Mutation Screening Assays:
• Fluorescence in situ hybridization (FISH)
• Detects gene rearrangements
• Polymerase chain reaction (PCR)
• Detects point mutations
• Next-generation sequencing
• Not uniform in all commercial or institutional laboratories
• Some can detect both mutations and gene rearrangements as well as copy number variation
types of mutations review
• “Wild Type”
• Refers to genes as they are naturally occurring
• “Non Mutated”
• Types of Mutations
• Point Mutation - Alteration is a single base pair
• Deletion (removal of DNA in a chromosome)
• Translocation (trade of DNA pieces between chromosomes)
• Insertion (addition of DNA in a chromosome)
Mitotic Activity
• growth rate or doubling time
• Ki-67 (protein present in dividing cells) is a marker for the growth fraction (fraction of Ki-67 positive cells)
• Measured by Immunohistochemistry (IHC)
• Can be a prognostic biomarker (depending on the cancer)
• Could provide insight into aggressiveness of the cancer
• rapidly dividing cells could be causing higher tumour growth rate
• Could provide insight into response to chemotherapy
• rapidly dividing cells are typically more chemo-sensitive
Staging
• For solid tumours, the TNM system is commonly used
• T – size of the primary tumour
• Determined by diagnostic imaging and pathology post surgery (pT)
• N – lymph node involvement
• Determined by diagnostic imaging, use of dye during surgery (how many nodes have cancer)
• M – presence of metastases
• Determined by CT scan or PET scan
• S – Serum Markers (for testicular cancer only)
• LDH, hCG or AFP
• Cancer Stage
• Signifies the extent of disease for solid tumours
• Usually stage 0, I, II, III, IV with stage 0 being carcinoma in situ and stage
IV being metastatic disease
Stage 0 precancer
Stage I: small, contained
Stage II: larger
Stage III: spread in surrounding tissues
Stave IV: spread through blood or lymphatic system
Will NOTbe asked to stage a solid tumor
