cancer genetics

how many Canadians develop cancer in their lifetimes, and how many die of cancer

1 in 2 Canadians develop it (1 in 2.2 males and 1 in 2.3 females)

1 in 4 die (1 in 3.8 males and 1 in 4.4 females)

why do males develop cancer slightly more than females

they smoke more and go to the doctor less

top 3 cancer types in canada in males and females

males: prostate, lung, colorectal

female: breast, lung, colorectal

top 3 cancer type deaths in canada in male and females

male: lung, colorectal, prostate

female: lung, breast, colorectal

T/F solid tumors have more genetic alterations than liquid

true

what is a carcinoma

solid tumor made from cells that cover external/inner body surfaces (epithelial)

lung, breast, colon, etc

what is a sarcoma

arise from cells in supporting tissues (bone, cartilage, fat, muscle, etc)

describe lymphomas

arise in lymph nodes and tissues of body’s immune system, hematological (liquid) tumor

describe leukemias

cancer of immature blood cells that grow in the bone, hematological (liquid) tumor

T/F there need to be more alive cells than dead cells

false, they need to be balanced

if normal cell devision goes from 1 cell to 2 cells, how do we maintain a certain number of cells?

one of the daughter cells dies

describe hyperplasia

non-cancerous enhanced tissue growth, more cell numbers but cell structure is normal and tissue structure is normal

eg. callous on hand

describe dysplasia

non-cancerous abnormal cell growth where the cells are abnormally shaped and can become malignant (harmful)

describe carcinoma

dysplasia but invasive and harmful

what is a benign tumor

not cancerous and cant invade or metastasize (enter blood vessels and travel)

difference between early stage cancer and late stage

early stage still hasn’t invaded other tissues but late stage has

3 enabling features of cancer

genome instability and mutation, sustaining proliferation signal, evading growth suppressors

why do cancer cells have more mutations

because they keep replicating so it increases chance of mutation, there isn’t 1 mutation that means cancer, it is a series of mutations

difference between truncal vs branch mutations

truncal - occurred early on before any branching so all descendants from different branches have the same mutation

branch - later on and not everyone has it

how do you know a cancer mutation was inherited by germline

all the cells in the body have the same mutation

describe FAP colon cancer

familial adenomatous polyposis is a heritable cancer predisposition, autosomal dominant where its a 100% risk to develop colorectal cancer, many many intestinal polyps and APC gene mutations (adenomatous polyposis coli) which is a tumor suppressor gene

describe Lynch syndrome

hereditary non-polyposis colon cancer (HNPCC) with an 80% risk to get colorectal cancer

MMR defect (mismatch repair) causes DNA not to be fixed; base mismatches when unrepaired causes a point mutation, insertion/deletion loops cause microsatellite instability which lead to accumulation of stepwise mutations

what is a microsatellite

variable amount of tandem repeats typically found in non-coding regions with a higher mutation rate and replication slippage

which cancers does Lynch syndrome mainly cause

mostly (80%) colorectal, but also a lot of endometrial (50-60%)

what is the 3-2-1 rule when looking at Lynch syndrome (Amsterdam criteria)

3+ relatives with colorectal cancer

2+ successive generations

1 diagnosis before the age of 50

what are the causes of sporadic CRC

15% are microsatellite instability, 60% is MLH1 promotor being methylated and silenced

how many DNA damaging events per hour (all cells combined)

3e16-17

describe sporadic cancers

randomly arising de novo with no heritable content (not all cells in the body have the mutation), ≥80% of all cancer types are sporadic often taking years to fully develop

explain chemical carcinogens

cause chemical adducts on DNA, eg. arsenic (cause lung cancer) and benzene (cause leukaemia), up two 50% of all cancers are linked to smoking (1 mutation / 15 cigarettes)

different types of carcinogenic radiation

ionizing - liberate electrons from an atom causing ds breaks, depends on proximity, dose, and time of exposure, example is chemotherapy or radon found in basements

non-ionizing - electromagnetic radiation from power lines and X-rays, radiofrequency energy from phones (possible carcinogen), UV radiation

list 3 types of UV radiation

UV-A - longest wavelength and deep penetrating inducing gene damage, associated with skin aging and wrinkles

UV-B - shorter wavelength introduces thymine dimers associated with sunburns and melanoma

UV-C - shortest wavelength and most damaging but filtered out by ozone layer

how is diet and food related to cancer

obesity leads to a predisposition for breast cancer and CRC

preservatives have carcinogen, acrylamide in fried food is a mutagen, caffeine is a repair inhibitor, and alcohol impacts gene regulation

how are viruses and bacteria associated with cancer

insertional mutagenesis from chromosome integration disrupts genes (like tumor suppressors) and induce damage, promotors of viral genomes drive expression of proton-oncogenes

list 6 types of genetic alterations that implicate tumorigenesis

subtle alterations (synonymous vs non-synonymous, indels)

DNA amplification and deletion of tumor suppressor/oncogenes

translocations (philadelphia chromosome causing chronic myeloid leukemia)

chromosomal changes (like number of chromosomes or structure)

exogenous DNA sequences from viruses and bacteria

epigenetic reprogramming (DNA methylations or acetylation)

what are proto-oncogenes

not cancer causing normal genes that become oncogenes by developing GOF mutations, encode for proteins that deal with cell proliferation

what are oncogenes

genes with the potential to cause cancer by upregulating gene expression

list 3 specific gene alterations that are associated with cancer

hyperactive protein, gene amplification/overexpression (hypomorphic), rearrangement

describe the human epidermal growth factor receptor 2 (HER2/Neu, ERBB2)

breast and ovarian cancer oncogene, has a surface bound tyrosine kinase receptor where the growth factor binding induces dimerization and signalling by phosphorylation

describe the breast cancer therapy Herceptin

antibody binds to the tyrosine kinase and inhibits it/its binding, or recruits cytotoxic cell

describe the inheritance of tumor suppressor genes

dominant inheritance in familial cancers but recessive effect cellularly (generally require loss of both functional alleles)

describe the TP53 gene

tumor suppressor known as “guardian of the genome” maintaining genome integrity and overlooking cell cycle progression, repair, apoptosis, etc and is mutated is more than 50% of cancers

why is the probability of sporadic retinoblastoma happening in both eyes 0

what are the odds both eyes get the exact same mutation

what are the causes of ds breaks and what are the repair methods

natural causes can be recombination, collapsed replication forks, or ROS, can be exogenous source like ionizing radiation

can fix by NHEJ or HR

when does NHEJ vs HR happen

NHEJ happens at any point through the cell cycle, HR happens in G2 and S

what does chromosome instability affect

increases the rate at which chromosomes (or large parts of) are gained or lost

what helps tumors be resistant to drugs

tumor heterogeneity - not all cells are identical, more associated with highly aggressive tumors and poor patient prognosis

how do we assess chromosome instability

flow cytometry (analyze content not chromosome numbers by seeing how much fluorescence comes from labelled DNA (higher = higher content)

karyotype analysis to see numerical and structural anomalies

chromosome ideogram

what does a chromosome ideogram show

size, centromere position, and banding pattern

why is karyotype staining not done in solid but done in liquid?

easy for liquid cancers but hard in solid tumors because most cells are in interphase and you cant do it if its in interphase

what does chronic myeloid leukaemia cause

weird tyrosine kinase activity driving WBC growth from a fusion of the BCR gene on ch 22, and the ABL gene on ch 9 resulting in a Philadelphia chromosome

what was the first treatment for CML by Novartis

BCR:ABL-specific tyrosine kinase inhibitor where 53/54 patients responded and FDA passed the drug (imatinib mesylate)

what does the BRAF oncogene lead to

Metastatic melanoma where a mitogen (extracellular stimulus for cell growth) initiates signalling can case to induce a change in gene expression

what is the treatment for BRAF and can the cancer come back (and why)

inhibitor for BRAF so it cant continue the pathway after BRAF but it can come back if the pathway changes and is activated after where BRAF is inhibited

describe synthetic lethality, example, and how to treat

rare lethal combination of 2 mutations that on their own are not lethal

eg. breast and ovarian cancer together

treat by down regulating/inhibiting a second gene with interacts with the mutations