PATH 120 ALL COMBINED

Gain of function mutations

Mutations which grant new abilities to the proteins they encode.

What types of cancers do oncogenes most often cause?

Sporadic (occur in patients with no family history of cancer).

What types of cancers do tumour suppressor gene mutations most often cause?

Familial.

Apoptosis

Programmed cell death

Tissue

Groups of specialised cells that function together as a unit.

Organ

A contained collection of tissues that perform a shared function.

System

A group of organs working collaboratively towards a common purpose.

Transporter

Integral plasma membrane protein that creates a ‘pore’

What passes through: Ions, small molecules, and proteins

Which cell types are often found in the G0 phase?

Nerve and muscle cells

The majority of a cell’s lifetime is spent in what phase?

G1

What is self renewal?

Stem cell division

What does it mean that cell division can be asymmetric?

The daughter cells arising from mitosis are genetically identical, but their gene expression differs.

Progenitor cells

Biochemical changes

To do with chemical processes in the body.

• “lab test’ values

Morphological changes

To do with the structure of cells or tissues.

• Swelling

• Alteration in differentiation

• Histology slides

• Blood smears

• Biopsy results

Functional changes

To do with physiology

• Range of motion

• Muscle strength

• Blood pressure

• Body temperature

Ontology

A way of organizing information into different categories and concepts.

Spiritual Health on the Modified Medicine Wheel

• Cultural safety

• Strengths

• Resilience

Physical Health on the Modified Medicine Wheel

• Capacities

• Mobility

• Comorbidity

• Awareness & prevention

Mental Health on the Modified Medicine Wheel

• Housing

• Family

• Community

• Ceremony

Emotional Health on the Modified Medicine Wheel

• Causality

• Access to equipment & services

Endoplasmic reticulum

Where proteins are translated and processed.

Where many lipids are made.

May also play a role in transportation.

Golgi aparatus

Where proteins are processed and packaged.

Lysosome

Where waste products are digested by enzymes into their basic building blocks.

Endosome

A transport vesicle responsible for sorting, storing, and organizing cell contents, including entering and exiting material.

Peroxisome

Where reactive oxygen species, including hydrogen peroxide and the molecules that produce them, are broken down.

*Contains catalase in abundance.

Gap 0 Phase

• Not part of the cell cycle

• Many cells enter this phase when they are not actively dividing (quiescent)

Gap 1 Phase

Cells in this phase are active and growing but have not yet committed to undergoing cell division.

S Phase

The cell replicates its entire genome in preparation for division.

Gap 2 Phase

Cells grow (cytoplasm, size of organelles) and their DNA is checked before committing to dividing.

Stem cells produce…

…stem & progenitor cells

Progenitor cells produce…

… many cell types (multipotent) but only one at a time

Necrosis

Caused by a severe lack of resources to sustain life or severe trauma, and results in the release of reactive oxygen species (ROS) and enzymes.

What cells undergo if they are damaged

Necrosis or apoptosis

A foetus losing the webbing between their fingers in the womb is an example of

apoptosis

Cancer

Abnormal cell populations that divide uncontrollably AND invade and potentially spread to other tissues.

Neoplasm

Any abnormal tissue that forms when cells grow and divide more than they should or do not die when they should.

Tumour

Any swelling or abnormal enlargement in or on the human body.

Traits of benign tumours

• Inability to invade or spread

• Can attain sizes of 50+ kg without killing the patient

• Smooth and round

• Look like a sea sponge

Traits of malignant tumours

• Ability to invade other tissues (metastasis)

• May kill before they reach 50 g in weight

• Spiky

• Look like a crab

How to determine the origin of a cancer?

full body scans & gene expression tests

Carcinoma

Effects epithelial cells:

• Prostate

• Breast

• Lung

• Colorectal

Sarcoma

Effects supporting & connecting tissues:

• Fat & muscles

• Nerves

• Tendons & joints

• Blood or lymph vessels

• Cartilage & bone

Lymphoma

Begins in the lymphocytes (found in glands, nodes, and other tissues)

Giloma

Arise in the connective tissues of the brain.

Leukemia

Cancer of blood and bone marrow.

Prevalence

A measure of total active cases of a disease in a population.

Incidence

A measure of the number of new occurrences of a disease in a population

Silent mutation

Change in the DNA sequence that does not result in a change to the amino acid sequence, or does not affect the protein product.

Oncogenic mutation

DNA sequence change that directly contributes to the development of cancer.

Transformation stage

A normal cell undergoes a change in its genetic code, leading to a tumour cell.

Progression stage

Tumour daughter cells accumulate mutations. Either exact clones or subclones (variants) may form.

Proliferation stage

Many subclones have formed within the same tumour. Additional mutations may provide daughter cells with further growth advantages.

Challenges with treating cancer

Different responses to treatment: cancer may arise from various tissue types, cancer cells are continuously mutating and are very diverse.

Drug-resistance develops in malignant cells.

Many agents are unable to cross the blood-brain barrier.

Which gene is mutated in most common cancers?

TP53

Proto-oncogenes

Unmutated oncogenes

Role of MUTATED oncogenes

Produce proteins with new or altered functions which provide selective growth advantages to cancer cells.

Growth-factor receptor pathways affected by oncogenes

Embryonic growth, homeostasis, and injury repair

How many mutations does it take to elicit pro-cancer effects from oncogenes? Why?

One (single allele) ; gain-of-function mutations are effective immediately.

How many mutations does it take to elicit pro-cancer effects from tumour suppressor genes?

Two (both alleles) ; one allele can take over for the function of the other.

NORMAL function of tumour suppressor genes

Prevention of uncontrolled cell growth by managing cell cycle checkpoints and triggering apoptosis when necessary.

Mutation type experienced by oncogenes

gain-of-function

Mutation type experienced by tumour suppressor genes

loss-of-function

TP53 gene type

Tumour-suppressor

ERBB-1 gene type

Proto-oncogene

ROLE of Epidermal Growth Factor Receptor (EGFR)

Detection of extracellular ligands and intracellular dimer formation, inducing gene expression

Role of p53 protein

Responds to genomic damage by activating transcriptional upregulation of repair genes or inducing apoptosis or senescence

G1/S checkpoint!

Epidermal Growth Factor Receptor (EGFR) PROTEIN TYPE

Tyrosine Kinase

Tyrosine Kinase

Enzyme that can transfer a phosphate group to specific proteins inside a cell.

“On” or “off” switch

Angiogenesis

The development of new blood cells

Genetic response to EGFR activation cascade

Cell migration/adhesion/invasion across tissues, angiogenesis, cell proliferation, inhibition of apoptosis,

Hyperactivation of EGFR

Same amount of ligand-binding causes activation of more secondary messengers

Constitutive activation of EGFR

Genetic response occurs without stimulus, and thus cannot be terminated.

EGFR therapies

Antibodies, kinase inhibitors

Mechanism of kinase inhibitor therapy

Small molecule inhibitors traverse the plasma membrane and disrupt signalling cascades.

What might iron-deficiency anemia indicate?

Gastrointestinal (GI) cancer in older men or post-menopausal women.

Term for epithelial neoplasm in colorectal cancer

Adenoma

Hyper-proliferation stage (colorectal cancer)

(1) a cell has incurred one or more oncogenic mutations and begins to divide

Adenomatous polyp stage (colorectal cancer)

(2) the rapidly dividing mass of cells projects into the intestinal lumen

Precancerous polyp stage (colorectal cancer)

(3) this stage may last for 7-10 years; the growth can be removed before it becomes malignant.

Adenocarcinoma stage (colorectal cancer)

(4) the growth has become invasive of adjacent tissue layers; the most common type of colorectal cancer.

Advanced (colorectal) cancer

(5) the cancer may enter the bloodstream and metastasize.

What form of (colorectal) cancer screening should individuals 50-70 years of age undergo every two years?

Fecal Immunochemical Test

What form of (colorectal) cancer screening should individuals undergo if their FIT scores are abnormal or if they are at increased risk?

Colonoscopy

What are the top reasons people give for not getting screened for colorectal cancer?

Fear of difficulty or painfulness of testing, no family history of cancer, misconceptions of who needs to be screened, cost concerns.

Hemicolectomy

Removal of part of the large intestine.

What classification describes the depth of tumour invasion?

T

What classification describes the extent of spread to the lymph nodes?

N

What classification describes whether the cancer has metastasized?

M

What classification describes the abnormality of cancer cells?

G

Irregularities in the expression of which gene is indicative of Lynch syndrome?

MSH2

Somatic mutations to what gene are found in sporadic colorectal cancer?

APC

Inherited mutations to what gene are found in familial colorectal cancer?

Mismatch repair genes

What are the prognostic factors for cancer?

• Age and general health

• Response to treatment

• Stage and grade

• Genetics

• Access and compliance

What bloodwork is indicative of leukaemia?

• Low hemoglobin count

• High white blood cell count

• Light percent blasts

• Low platelet count

Hematopoiesis

Differentiation of hematopoietic stem cells into specialized myeloid and lymphoid cells.

Hematopoietic stem cells

The parental cells of mature red and white blood cells. They have long lifespans.

Myeloid

Bone marrow tissue.

Lymphoid

Connective tissue with immune function.

Immature cells / “blasts”

Hematopoietic stem cell progenitors that aren’t fully differentiated and do not have the capability to perform their specialized cell functions.