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Flashcards in Genes: Cancer Deck (30):
1

First thing to consider with cancer

- family history

2

Non-heritable vs heritable

Non-heritable: most cancers, somatic mutation, occurs in non-germline tissues
Heritable: Germline mutation, present in egg or sperm, causes family cancer syndromes, affects every cell in offspring

3

Genetic processes associated with cancer:

- Oncogenes
- Tumour suppressor genes
- DNA damage-response for DNA

4

Oncogenes

can accelerate cell division

5

Proto-oncogenes

- Normal gene that codes for proteins to regulate cell growth and differentiation
- A mutation can change proto-oncogene into an oncogene
- > Cells get stuck in growth mode
- An oncogene virus can active an oncogene e.g. HPV

6

Tumour suppressor genes

- Cell's brakes for cell growth
- Genes inhibit cell cycle or promote apoptosis or both
- Cancer arises when the genes cease to do this along with DNA damage response

7

Two-Hit Hypothesis

- Inherit an autosomal dominant mutation, 1st hit isn't enough but you are susceptible to cancer
- 2nd hit by coincidence results in tumours -> leads to cancer

8

DNA damage-response genes

- Repair mechanics for DNA. Spell checker
- Cancer arises comes from tumour suppressor genes and DNA damage response fail
- The result is an accumulation of mutations in other critical genes

9

Failure of mismatch repair genes

- If there is a defective DNA repair then this can lead to microsatellite instability (MSI)
- MSI is evidence of MMR nor working
- These types of cells accumulate errors
- Shows a predisposition for bowel cancer

10

Examples of oncogenes and syndrome

-Genes: RET
- Syndrome: MEND2 (Multiple endocrine neoplasia)

11

Examples of tumour suppressor gene and syndrm

- Genes: BRCA1, BRCA2, APC, RB
- Breast/ovarian cancer, FAP, retinoblastoma

12

Examples of DNA repair genes and syndromes

- Genes: MLH1, MSH2, PMS1, PMS2
- Syndrome: HNPCC (Hereditary non-polyposis colon cancer)/Lynch syndrome

13

Other causes

- Autosome recessive syndromes: MYH polyposis
- Multiple modifier genes of lower genetic risk

14

De Novo mutations

- New mutation occurs in germ cell of parent, no family history
- e.g. familial adenomatous polyposis (30% of cases), multiple endocrine neoplasia 2B
- Hereditary retinoblastoma

15

Retinoblastoma

- Most common eye tumour in children
- Heritable and nonheritable forms
- Identifying at-risk infants substantially reduces morbidity and mortality

16

Heritable retinoblastoma

- Bilateral
- 20% of cases
- Increased risk of secondary primaries: osteosarcoma, other sarcomas, melanoma

17

Nonheritable retinoblastoma

- Unilateral
- No secondary primaries

18

Risk factors for breast cancer

- Ageing
- FH (20-40% of hereditary cases)
- Dietary factors
- Lack of exercise
- Early menarche/late menopause i.e. long exposure of breast tissues to hormones
- Oestrogen use: pill and HRT
- No kids/no breast feeding

19

BRCA1 functions

- Checkpoint mediator
- DNA damage signalling and repair
- Chromatin remodelling (inactive X chromosome)
- Transcription

20

BRCA1 associated cancers

- Breast cancer: 50-85% (often early age at onset)
- Second primary breast cancer: 40-60%
- Ovarian cancer: 15-45%

21

BRCA2 associated cancers

- Breast: 50-85%
- Ovarian: 10-20%
- Male breast cancer: 6%

22

Risk factors for colorectal cancer

- Age
- Personal history of CRC or adenomas (dysplastic polyps)
- High fat, low-fibre diet
- Inflammatory bowel disease
- FH, failure of MMR

23

Non-polyposis

- Hereditary non-polyposis colon cancer: CRC or endometrial cancer
- Early diagnosis: around 45
- Tumour site is throughout rather than descending colon (site of sporadic cancer)
- Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel etc

24

Types of polyposis

- Multiple adenomas
- Familial adenomatous polyposis
- Attenuated familial adenomatous polyposis
- MYH associated polyposis

25

FAP

- severe colonic polyposis (with or without CRC)
- 90% penetrance
- risk of extracolonic tumours - upper GI, brain, thyroid
- Untreated leads to 100% risk of cancer
- Develop cancer by mid to late 30s
- Congenital hypertropy of the retinal pigment eithelium (CHRPE), spot at back of ete
- >4 CHRPEs is a greater risk of FAP

26

AFAP

- less severe colonic polyposis (with or without CRC)
- Later onset, around 50
- No associated CHRPE
- Few polyps but you do get upper GI polps
- Associated with mutations at 5' and 3' ends of APC gene

27

MAP

- varying degree of severity (with or without CRC)
- similar GI features to attenuated FAP
- Recessive inheritance

28

Management

- Surveillance
- Surgery
- Chemoprevention: certain nonsteroidal anti-inflammatory drugs can slow polyp formation
- HMPCC: adult carriers take aspirin and can significantly reduce risks

29

Predictive gene tests:

- Not always available
- Problem with gene variants of unknown signficance
- For adult onset cancers, predictive test not offered until adulthood

30

Advances in predictive test

- Exome sequencing
- Genome sequencing, still don't know what to do with reults