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EMS - GiM > (5) Familial cancer syndromes > Flashcards

(5) Familial cancer syndromes Flashcards

1
Q

Which genetic factors contribute to the carcinogenic process?

A

Caretaker genes

  • DNA repair
  • carcinogen metabolism

Gatekeeper genes

  • cell cycle control
  • programmed cell death
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2
Q

Which macro environmental factors contribute to the carcinogenic process?

A
  • chemicals
  • viruses
  • radiation
  • physical agents
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3
Q

Which micro environmental factors contribute to the carcinogenic process?

A
  • oxyradicals
  • hormones
  • growth factors
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4
Q

What does multi-stage carcinogenesis mean?

A

A series of genetic changes occur within cells leading to increasingly abnormal behaviour and histology

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5
Q

What is the two hit hypothesis?

A

The hypothesis that cancer is the result of accumulated mutations to a cell’s DNA

If first hit is a germ line mutation (inherited), second somatic mutation more likely to enable cancer

If sporadic, two hits are required in a single cell

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6
Q

What is penetrance?

A

Percentage with a gene change who develop the condition

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7
Q

What may penetrance be modified by?

A

Other genetic variations and also environmental factors

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8
Q

Name 3 types of genes involved in cancer and preventing cancer

A
  • gatekeepers
  • caretakers
  • landscapers
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9
Q

What is the function of gatekeepers?

A

Directly regulate tumour growth. Monitor and control cell division and death, preventing accumulation of mutations

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10
Q

What is the function of caretakers?

A

Improve genomic stability ie. repair of mutations

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11
Q

What is the function of landscapers?

A

Control the surrounding stromal environment

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12
Q

What is the function of tumour suppressor genes?

A

Protects cells from becoming cancerous

Loss of function increases the risk of cancer

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13
Q

Give some examples of tumour suppressor genes

A
  • APC
  • BRCA1/2
  • TP53
  • Rb
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14
Q

What is the function of oncogenes?

A

Regulate cell growth and differentiation

Gain of function/activating mutations increase the risk of cancer

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15
Q

Give some examples of oncogenes

A
  • growth and signal transduction factors

- RET gene

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16
Q

Most cancer genes obey which hypothesis?

A

Knudson’s two hit hypothesis

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17
Q

What does being recessive at the cellular level mean?

A

Both copies of the gene have to be inactivated to have effect

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18
Q

Most cancer syndromes show which pattern of inheritance?

A

Autosomal dominant

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19
Q

A few cancer syndromes show autosomal recessive inheritance. Give examples

A
  • MYH associated polyposis
  • Fanconi anaemia
  • ataxia telangiectasia
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20
Q

What is required of the parents for the child to have a recessive cancer syndrome?

A

Each parent is a carrier of one fault copy, usually without the disease

Appears to skip generations and may account for some sporadic cases

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21
Q

If both parents are a carrier of the cancer syndrome gene, what percentage of children will have the cancer risk?

A

25%

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22
Q

Name 3 different mutation types?

A
  • splice site mutations
  • large deletions and duplications
  • translocations
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23
Q

What techniques are used to find familial cancer genes?

A
  • family studies - linkage analysis
  • candidate gene analysis
  • new technologies eg. whole exome sequencing
  • disease-causing translocations may give locations
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24
Q

What should you include when taking a family history

A
  • include maternal and paternal sides
  • at least 3 generations
  • types of cancer, age of diagnosis
  • confirm: medical records, cancer registries, death certificate
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25
Q

What are the clues indicating sporadic cancers?

A
  • onset at older age
  • one cancer in individual
  • unaffected family members
  • cancers that are rarely genetic eg. cervix, lung
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26
Q

What are the clues indicating familial cancers?

A
  • onset at a younger age
  • multiple primaries in individual
  • other family members affected
  • same type/genetically-related cancers
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27
Q

What is the purpose of genetic assessment?

A
  • diagnosis/explanation of family history
  • counselling of advantages and disadvantages of testing
  • risk of further cancers for affected cases
  • risk of cancer for unaffected relatives
  • screening
  • prevention
  • treatment
  • research
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28
Q

What are the disadvantages of genetic assessment?

A
  • anxiety/unhappiness (self, children etc)
  • genetic discrimination
  • results may not lead to any change in management
  • financial costs to NHS
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29
Q

Who is initial diagnostic testing (mutational analysis) performed on?

A

Usually performed on DNA from a relative affected with cancer to try to identify the familial mutation

30
Q

When and why is predictive testing offered?

A

If a mutation is identified in the family by diagnostic testing, predictive testing for the specific mutation may then be offered to other relatives to determine whether or not they are at risk

31
Q

Give a classic example following Knudson’s 2-hit hypothesis

A

Retinoblastoma

32
Q

What is retinoblastoma?

A

A childhood ocular cancer

33
Q

How common is retinoblastoma?

A

Very rare (1 in 15,000-30,000 live births)

30-50 children per year in the UK

34
Q

Which gene is involved in retinoblastoma?

A

Rb1 gene

35
Q

Explain how retinoblastoma follows the 2-hit hypothesis

A
  • both genes mutated/lost in the tumour

- genetic cases = one mutation is present in the germline (inherited cases occur at younger average age)

36
Q

How many cases of retinoblastoma are germline?

A
  • bilateral cases almost always germline

- 15% of apparently sporadic unilateral cases are germline (high new mutation rate)

37
Q

What are the other cancer risks associated with retinoblastoma?

A

Osteosarcoma

Early screening for children at risk

38
Q

What is familial adenomatous polyposis (FAP)?

A

Inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine

Hundreds of bowel polyps (adenomas) from teens onwards

39
Q

Is there a risk of bowel cancer in FAP?

A

High risk (up to 100%) of bowel cancer if left untreated

FAP accounts for 1% of bowel cancers

40
Q

Give some other features of FAP

A
  • CHRPE
  • desmoid tumours
  • osteomas
41
Q

Which gene causes FAP?

A

APC tumour suppressor gene defects on chromosome 5

42
Q

What type of inheritance pattern does FAP show?

A

Autosomal dominant inheritance

43
Q

What surgical procedure might be needed in FAP?

A

Total colectomy in late teens/early 20s

44
Q

What is hereditary non-polyposis colorectal cancer (HNPCC)?

A

Genetic condition that has a high risk of colon cancer. The increased risk is due to inherited mutations that impair DNA mismatch repair. It is a type of cancer syndrome.

45
Q

What proportion of bowel cancers does HNPCC account for?

A

2-3%

46
Q

Are polyps common in HNPCC?

A

Polyps are common, but not polyposis

47
Q

What is the risk of bowel adenomas in HNPCC?

A

60-80% risk of bowel adenomas or cancer from mid 20s onwards

48
Q

HNPCC also gives increased risk of which other cancers?

A
  • endometrial
  • ovarian
  • stomach
  • GU
49
Q

What types of genes are involved in HNPCC?

A

Mismatch repair genes

MLH1 (50%)
MSH2 (40%)
MSH6 (10%)
PMS1/2 (rare)

50
Q

What type of inheritance pattern does HNPCC show?

A

Autosomal dominant inheritance

51
Q

What is the Amsterdam criteria for HNPCC?

A
  • 1 member diagnosed with colorectal cancer before age 50
  • 2 affected generations
  • 3 affected relatives, 1 of them a first degree relative of the other 2
  • FAP should be excluded
  • tumours should be verified by pathologic examination
52
Q

How often should patients with HNPCC have colonoscopy?

A

Every 18-24 months from age 25

53
Q

What are the benefits of colonoscopy screening in HNPCC?

A
  • removal of polyps

- early detection of cancer improves survival

54
Q

What are the types of HNPCC preventative surgery?

A
  • prophylactic colectomy is not usually recommended

- however, women may cosier hysterectomy (+BSO)

55
Q

What is a bilateral salpingo-oophorectomy (BSO)?

A

When both ovaries and both Fallopian tubes are removed

56
Q

BRCA1 and BRCA2 genes are involved in what?

A

DNA repair

57
Q

BRCA genes are involved in how many cases of breast cancer?

A
  • 10% of cases of breast cancer under 40

- 25% of cases of breast cancer with strong FH

58
Q

What type of inheritance pattern do BRCA genes show?

A

Autosomal dominant inheritance

59
Q

BRCA mutations are common in which populations?

A

Common mutations in Jewish and some other found populations

60
Q

What are the cancer risks with BRCA genes?

A

Risk of breast cancer = 80%

Risk of ovarian cancer: BRCA1 = 40%, BRCA2 = 10-20%

61
Q

Along with breast cancer and ovarian cancer, there is some increased risk of which other cancers with BRCA genes?

A
  • prostate
  • melanoma
  • male breast cancer
62
Q

What are the options for BRCA1 and BRCA2 gene carriers?

A
  • breast screening (annual MRI 30-50, annual mammography from 35-40)
  • mastectomies +/- reconstruction
  • BSO
  • lifestyle changes
  • pharmacological prevention studies
63
Q

What is Li Fraumeni syndrome?

A

A rare inherited genetic cancer disorder that greatly increases one’s risk of developing cancer during their lifetime. Sometimes people with LFS develop multiple cancers and multiple tumors often in childhood or as young adults.

64
Q

What is the mutation in Li Fraumeni syndrome?

A

P53 mutations

65
Q

What type of inheritance pattern does LFS show?

A

Autosomal dominant

66
Q

What is the overall risk of cancer in LFS?

A

50% risk of cancer by age 40, close to 100% lifetime

67
Q

What type of cancers does LFS give increased risk of?

A
  • breast
  • sarcoma
  • brain
  • adrenocorticol
  • leukaemia
68
Q

Why should radiotherapy by avoided in LFS?

A

Risk of inducing cancers

69
Q

What is the prognosis in LFS?

A

Poor prognosis

  • limited screening
  • value of genetic testing less clear
70
Q

What is involved in the future for familial cancer syndromes?

A
  • greater availability of genetic testing
  • testing of moderate penetrance genes as well as high
  • testing in lower risk groups/general populations (cost, ethical issues)
  • more targeted preventative treatments

EMS - GiM (14 decks)

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