Cancer genetics 1

Can you inherit cancer?

• No, except for one type of rlly rare umbilical cancer

How many Canadians develop cancer in lifetime?

1 in 2 Canadians

• Males: 1 in 2.2

• Females 1 in 2.3

How many Canadian will die of cancer?

1 in 4 Canadians will die of cancer

• Males: 1 in 3.8

• Females: 1 in 4.4

Why are males more susceptible to cancer?

• Cuz of sex chromosomes, the prostate, and hormones

What’re the most common cancers men get?

1. Prostate = 20.3%

2. Lung = 13.2%

3. Colorectal = 12.9%

What’re the most common cancers women get?

1. Breast = 25%

2. Lung = 13.5%

3. Colorectal = 10.9%

What’re the cancers that cause the most deaths in men?

1. Lung = 25.2%

2. Colorectal = 12%

3. Prostate = 9.5%

What’re the cancers that cause the most female deaths?

1. Lung = 26.1%

2. Breast = 12.9%

3. Colorectal = 11.4%

What’re the 2 types of tumors/ malignancies?

1. Solid tumors/ malignancies

2. Liquid tumors/ malignancies

What’re the 2 types of cancerous solid tumors And where do they occur?

• Carcinoma

  • Most common types of cancer

  • Arise from cells that cover external/ internal body surfaces (epithelial): lung, breast, colon

• Sarcoma

  • Arise from cells found in supporting tissues: bone, cartilage fat, connective tissues and muscle

What’re the 2 types of cancers from solid tumors and where do they occur?

• Lymphomas

  • Arise in the lymph nodes and tissues of the body’s immune system

• Leukaemias

  • Cancers of the immature blood cells that grow in the bone marrow

Whats the difference between solid and liquid tumors?

• Solid: Genetically complex (many genetic alteration, more than liquid)

• Liquid: Genetically simple ( Fewer genetic alterations, some have specific rearrangements)

Whats cancer?

Disease of the cell cycle

• Cells that proliferate/ divides uncontrollably

What’re the 2 different genes involved in cancer and what do they do?

• Tumor suppressor genes (brakes)

• Oncogenes (accelerators)

Whats the cancer development benign to malignant pathway?

• Hyperlasia → Dysplasia → Carcinoma

Whats hyperlasia?

• 1st step towards cancer

• Enhanced tissue growth (NON CANCEROUS)

• Larger than normal cell numbers

• Cell structure is normal

• Tissue structure is normal

Whats an example of hyperlasia?

• Callous on hand: Not cancerous but repeated stress causes excess cell growth

Whats dysplasia?

• Abnormal/ excessive cell growth (NON CANEROUS)

• Loss of normal tissue arrangement

• Loss of normal cell structure

• Can become malignant (not cancerous but may need to be treated)

Whats an example of dysplasia?

• Intestinal polyp: not cancerous/ pre cancerous but needs to be surgically removed cuz it can become cancerous

Whats happens from dysplasia to carcinoma?

• Invasive malignancy (metastatic)

  • Invade through basal layer and become cancerous and can metastasize

Are all tumors cancerous?

• NO

Whats the difference between benign vs malignant tumors?

• Benign

  • Not cancerous

  • Abnormal cell growth (locally restricted)

  • Incapable of invasion or metastasis

• Malignant

  • Cancerous

  • Can invade neighbouring tissues

  • Can enter blood vessels (metastasis)

  • Can metastasize to distant sites (other organs)

What’re the steps of growth and invasion?

1. Development of tumor/ neoplasm

2. Invasion of surrounding tissue

3. Metastasis = spreading to other organs

Why is staging a tumor important?

• Cuz with it we can see how severe it is/ what parts of the body are affected by it

What’re the different stages of colorectal cancer?

Stage 0: high grade dysplasia

Stage 1: Invading through basal membrane

Stage 2: Invading deeper

Stage 3: In colon cancer involves lymph nodes

Stage 4: Metastasis to other organs (usually liver for colorectal cancer)

Why is cancer potentially dangerous?

• Can impair normal tissue/ organ function such as the brain and liver depending on location and size

• Malignant tumors can metastasize which disrupts normal function

  • >80% of deaths attributed to metastases

How long does it take to go from benign to malignant?

• 10-20 years on average

Whatre the 10 hallmarks/ enabling features of cancer

The ones in green are what we discuss in class

What drives cancer initiation and progression?

• Loss of cell growth control

• Accumulation of mutations

What can attribute to loss of cell growth control in cancer?

• Defects in apoptosis

• Accumulation of mutations → cellular transformation

Explain how the accumulation of mutations is a stepwise process

Explain how cancer is a “survival of the fittest” process and explain genetic heterogeneity

Why are cancer therapies hard to do?

• Because cancers are so genetically diverse

Explain Truncal vs branch mutations (cancer tree)

Is cancer a heritable disease?

• No, but you can inherit genes that may give you a higher predisposition for it

Explain some heritable cancer syndromes

• Familial cancer syndromes (~5-15% of cancers)

• Inherited germline mutations

  • All cells within the body have the same mutation

  • Inherit a PREDISPOSITION to cause cancer, NOT cancer itself

Do all defective genes cause cancer?

• No, they js come with an associated risk to develop cancer

What’re some examples of inherited cancer genes?

Are colon polyps cancerous

• No, dysplasia

What is/ explain Familila Adenomatous polyposis (FAP)?

• Heritable cancer predisposition

• Autosomal dominant disorder

  • Individuals have ~100% risk to develop colorectal cancer (CRC)

• People with FAP have 100s to 1000s of intestinal polyps in their colon

• The deleted gene is in the APC gene (APC mutations)

  • Adenomatous polyposis coli (tumor suppressor gene)

What is/ why does Lynch syndrome arise?

• It’s a familial cancer syndrome

  • Hereditary Non-Polyposis Colon Cancer or HNPCC

  • 80% lifetime risk to develop CRC

• Arises dues to DNA Mismatch Repair (MMR) defect

  • Genes affected are MSH2, MLH1, MSH6 and PMS2

  • Causes microsatellite instability

What is MMR?

• Evolutionarily conserved DNA repair pathway

• Functions to correct errors associated with DNA replication and repair

  • Often in regions of highly repetitive DNA sequence

Why is MMR important?

1. Repairs base mismatches

2. Repairs insertion/ deletion loops which would cause microsatellite instability is unrepaired

What’re the steps of how MMR corrects base mismatches Repairs errors?

1. Mis-incorporation of nucleotide is recognized by methylation (parental strand methylated, newly synthesized strand isn’t methylated)

2. Excision of mis-matched nucleotide or unmethylated strand through DNA resynthesis/ repair or DNA methylation

Whats microsatellite DNA?

• Class of variable number of tandem repeats

• Repeat size is 2-6 nucleotides in length, repeated 3 to 100s of times

• Typically in non coding regions

What’re heritable markers/ features of microsatellite DNA?

• Stable within an individual

• Heterogenous between individuals

• Higher mutation rate

  • Replication slippage (slipped-strand mispairing)

How do test for microsatellite instability?

• PCR genes, and we can look at STR regions

• Multiple bands in reaction = microsatellite instability

Explain how MMR defects cause lynch syndrome

What’re the genetics of lynch syndrome?

• Autosomal dominant

  • Occurrence of 1:1000 births

  • 80% lifetime risk with a mean age of diagnosis 44yrs vs 64 yrs for sporadic

  • Surveillance can start at 10-12 yrs

  • Cancers can develop by 19 yrs of age

• Germline defect in DNA MMR gene

  • Aside: ~15% of sporadic CRC have MSI

• Increased risk for extra colonic cancers

CAUSES INCREASED RISK FOR OTHER CANCERS

What’re some typical lynch syndrome case studies?

• 3-2-1 rule

Whats the consequence of dimished repair capacity?

• DNA damage > DNA repair

  • Can lead to early senescence, apoptosis, increased sensitivity to carcinogens or cancer

  • Accelerated aging diseases (Werners’ or XP) (cancer predispositions)

How many DNA damaging events happen in body?

• Total DNA damaging events/ cell/day = ~67000

• Total DNA damaging events/cell/hour = ~2750

What’re sporadic cancers?

• Randomly arising (de novo)

  • No known heritable component

  • Not all cells in body have mutation

• Vast majority of cells are sporadic

  • ~85% of CRCs are sporadic

• Often takes years to develop cancer

  • Colorectal cancer 15-20 years

What cancers promote sporadic cancer?

1. Chemical

2. Radiation

3. Diet/ food

4. Viruses/ Bacteria

5. Environment

How do chemicals cause cancer and give some examples

• Chemical carcinogens can lead to DNA damage which includes double stranded breaks

• Ex:

  • Arsenic (pesticides and apple seeds) - lung cancer

  • Benzene (oil industry) - myelogenous leukemia

Explain why cigarettes/ tobacco smoke cause cancer

• Cigarettes have >24 known carcinogens

• Up to 50% of cancers are linked to smoking

• 1 mutation/ 15 cigarettes - for comparison 1 mutation / cell division

What’re 2 types of radiation?

1. Ionizing radiation

2. Non ionizing radiation

What’re some important things about ionizing radiation and whats an example?

• Proximity, dose and time is most important

• Used in cancer radiation therapy

• Liberates electron from an atom causing DNA DSBs

Ex: Radon (RN): naturally occurring gas in basements

What’re the different Non-ionizing radiation types?

• Electromagnetic radiation

• Radio frequency energy (cell phones)

What do the different wavelengths of non-ionizing (UV radiation) do?

Explain how diet/ food cause cancer

Explain how viruses and bacteria cause cancer

Explain how environment causes cancer

What’re the different types of genetic alterations?

What’re the 3 main genes that causes mutations/ cancer?