Genetic Predisposition to Cancer

Question 1

Cancer is a genetic disease of

Answer 1

somatic cells

Question 2

Most cancers happen by

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‘chance’ or due to envinronmental factors

Question 3

Somatic mutations

Answer 3

• Occur in nongermline tissues

- Are nonheritable

Question 4

Germline mutations

Answer 4

• Present in egg or sperm
• Are heritable
• Cause cancer family syndromes
• All cells affected in offspring

Question 5

Different genetic processes associated with Cancer

Answer 5

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

Question 6

Proto-oncogenes =

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normal gene that codes for proteins to regulate cell growth and differentiation.

Question 7

Mutations can change a proto-oncogene into

Answer 7

an oncogene

• Oncogenes can accelerate cell division
• Cancer arises when stuck in “on” mode

Question 8

Tumour suppressor genes

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• The cell’s brakes for cell growth
• Genes inhibit cell cycle or promote apoptosis or both
• Cancer arises when both brakes fail
  ‘Two – hit’ hypothesis (Knudson 1971)

Question 9

The Two-Hit Hypothesis example

Answer 9

First hit in germline of child
- Second hit (tumor)

not everyonewho has the gene will develop the cancer but they have a higher risk of having it than someone who doesnt have the first hit.

Question 10

oncogenes are

Answer 10

dominant genes in effect

Question 11

tumour suppressor genes are

Answer 11

recessive genes in effect

- second mutation or loss results in cancer

Question 12

DNA damage-response genes

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The repair mechanics for DNA

- Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes

Question 13

HNPCC Results From

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Failure of Mismatch Repair (MMR) Genes

Question 14

Mismatch Repair Failure Leads to

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Microsatellite Instability (MSI)
- addition of nucleotide repeats

Question 15

MMR corrects errors that

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spontaneously occur during DNA replication like single base mismatches or short insertions and deletions

Question 16

Cells with abnormally functioning MMR tend to

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accumulate errors.

Question 17

Microsatellites (aka Simple Sequence Repeats SSR) are

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repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs

Question 18

MSI (changes in microsatellite sequences) is the

Answer 18

phenotypic evidence that MMR is not functioning normally – genetic hypermutability

Question 19

BENIGN =

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lacks ability to metastasize. Rarely or never become cancerous.
Can still cause negative health effects due to pressure on other organs.

Question 20

DYSPLASTIC =

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‘benign’ but could progress to malignancy.
Cells show abnormalities of appearance & cell maturation. Sometimes referred to as ‘pre-malignant’.

(NB distinguish from ‘hip dysplasia’ which is macroscopically abnormal but not pre-malignant!)

Question 21

MALIGNANT =

Answer 21

not ‘benign’. Able to metastasize.

NB distinguish from ‘malignant hypertension’, ‘malignant hyperthermia’

Question 22

Tumour suppressor genes that are common dominantly inherited cancer syndromes

Answer 22

BRAC1, BRAC2
APC
P53
RB

Question 23

Mutation of P53 leads to

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Li-Fraumeni syndrome

Question 24

Oncogenes that are common dominantly inherited cancer syndromes

Answer 24

RET

Question 25

Mutation of RET causes

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MEN2 (multiple endocrine neoplasia) | familial medullary thyroid cancer

Question 26

DNA repair (mis-match repair) that are common dominantly inherited cancer syndromes

Answer 26

MLH1, MSH2, MSH6, | PMS1, PMS2

Question 27

mutations of MLH1, MSH2, MSH6, PMS1 or PMS2 can lead to

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HNPCC/Lynch syndrome

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Autosomal recessive syndromes =

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both copies of the gene have inherited mutations | - MYH polyposis

Question 29

New (de novo) mutation occurs in

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germ cell of parent | - no family history of hereditary cancer syndrome

Question 30

de novo mutations are common in:

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- Familial adenomatous polyposis - Multiple endocrine neoplasia 2B - Hereditary retinoblastoma

Question 31

How do we look for an inherited cancer predisposition syndrome?

Answer 31

TAKE A FAMILY HISTORY!

Question 32

Most Cancer Susceptibility Genes Are

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Dominant With Incomplete Penetrance. - May appear to “skip” generations - Individuals inherit altered cancer susceptibility gene, not cancer

Question 33

Features of Retinoblastoma

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- Most common eye tumor in children - Occurs in heritable and nonheritable forms - Identifying at-risk infants substantially reduces morbidity and mortality

Question 34

Heritable Retinoblastoma is

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Usually bilateral - some in family history - inccreased risk of osteosarcoma, other sarcoma, melanoma - less than one years old

Question 35

Inheritable retinablastoma is

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unilateral - no family history - no risk of secondary primaries - around 2 years old

Question 36

Risk Factors for Breast Cancer

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- Ageing - Dietary factors (eg: alcohol) - Lack of exercise - Family history - Late menopause - Estrogen use

Question 37

Genes contributing to familial ovarian cancer

Answer 37

``` BRCA1 BRCA2 TP53 RAD51C RAD51D Mis-match repair gene ```

Question 38

Genes contributing to familial breast cancer

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``` BRCA1 BRCA2 TP53 PALB2 PTEN ```

Question 39

BRCA1-Associated Cancers: | Lifetime Risk

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likelihood of having secondary breast cancer and ovarian cancer. - Possible increased risk of other cancers (eg, prostate, colon)

Question 40

BRCA2-Associated Cancers: | Lifetime Risk

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occurs in men too. | Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)

Question 41

Risk Factors for Colorectal Cancer (CRC)

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- Ageing - Personal history of CRC or adenomas - High-fat, low-fibre diet - Inflammatory bowel disease - Family history of CRC

Question 42

Clinical Features of HNPCC

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- Early but variable age at CRC diagnosis (~45 years) - Tumor site throughout colon rather than descending colon - Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

Question 43

Untreated polyposis leads to

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100% risk of cancer

Question 44

Attenuated FAP is

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Later onset (CRC ~age 50) - Few colonic adenomas - Not associated with CHRPE - Upper GI lesions - Associated with mutations at 5' and 3' ends of APC gene

Question 45

Attenuated FAP is associated with mutations at

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5' and 3' ends of APC gene

Question 46

Recessive MYH polyposis have

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Similar clinical GI features to attenuated FAP

Question 47

Managing cancer risk in Adenomatous Polyposis syndromes can be done through

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- Surveillance - Surgery - Chemoprevention

Question 48

Mutation testing is now being carried out routinely on certain cancers, to

Answer 48

identify familial mutations and to target therapies