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3. Week 1 - Medical Genetics > Familial Cancer > Flashcards

Familial Cancer Flashcards

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1
Q

How do genetic alterations arise for most cancers?

A

exposure to environmental carcinogens (not inherited)

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2
Q

What proteins are generally involved in genetic alterations in cancers?

A
  • tumour suppressor genes

- oncogenes

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3
Q

What are tumour suppressor genes and proto-oncogenes involved with normally?

A

The control of cellular growth and proliferation

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4
Q

What are stability genes?

A

Group of cancer genes involved in DNA repair mechanisms (e.g. MLH1)

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5
Q

Do mutations in stability genes cause a gain or loss of function?

A

Loss in function

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6
Q

What protective cellular mechanisms can cancers overcome?

A
  • Apoptosis

- Replicative senescence

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7
Q

What is replicative senescence?

A

The irreversible cell cycle arrest that is responsible for the limited number of cell divisions achievable by non-stem cells

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8
Q

What is the most common inheritance pattern for familial cancers?

A

autosomal dominant with incomplete penetrance

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9
Q

List functions of tumour suppressor genes

A
  • negatively regulate cell-cycle progression
  • promote apoptosis
  • play a role in cell adhesion
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10
Q

Do mutations in tumour suppressor genes cause a gain or loss of function?

A

loss in function

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11
Q

TSG alterations may be due to:

A
  • missence mutation affecting a functionally important amino acid
  • a nucleotide sequence change affecting splicing
  • a protein truncating mutation
  • methylation of cytosines in CpG dinucleotides around the promoter (causing transcriptional repression or silencing
  • gene deletions
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12
Q

What is the TP53 gene responsible for?

A

Encoding p53

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13
Q

What is the role of p53?

A

important role in pathways triggering cell-cycle arrest and apoptosis

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14
Q

Envionmental mutagens that cause defects in DNA repair systems can lead to which cancers?

A
  • MUTYH associated polyposis

- BRCA1/BRCA2 related familial breast/ovarian cancer

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15
Q

What is the role of BRCA1/2

A

The accurate repair of double stranded breaks, such as those resulting from ionisation radiation or radiomimetric chemicals

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16
Q

What is the result of defective BRCA1/2?

A

mutations or large scale genomic instability

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17
Q

Which genes are associated with defects in accidental base incorporations at time of DNA replication and what would their products normally do?

A
  • MSH2
  • MLH1
  • PMS1
  • PMS2

interact to effect mismatch repair

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18
Q

Do mutations in oncogenes cause a gain or loss of function?

A

gain function, or overactivity

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19
Q

What is the result of an alteration of one oncogene?

A

Confers tumorigenic effect on the cell

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20
Q

Are TSGs or oncogenes more commonly responsible for tumour susceptibility syndromes?

A

TSGs

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21
Q

Give examples of oncogene associated familial cancers

A
  • RET associated with multiple endocrine neoplasia

- MET associated with hereditary papillary renal cell carcinoma

22
Q

What gene mutations are commonly associated with familial breast and ovarian cancer?

A
  • BRCA1

- BRCA2

23
Q

What are the rarer causes of familial breast and ovarian cancer?

A
  • Li Fraumeni syndrome
  • Cowden disease (PTEN)
  • Peutz-Jeghers syndrome (STKII)
24
Q

What features would make you suspect inherited breast cancer?

A
  • early age of onset
  • bilateral disease
  • coexistant ovarian cancer
  • family history of breast or ovarian cancer
25
Q

What is the female lifetime risk of developing breast cancer in the UK?

A

1 in 9

26
Q

What percentage of breat cancer cases was the disease inherited?

A

2-5%

27
Q

What is the female lifetime risk of ovarian cancer?

A

1 in 60-70

28
Q

What percentage of ovarian cancer cases are caused by BRCA1/2?

A
  • BRCA1 = 60%

- BRCA2 = 25%

29
Q

When would HNPCC be suspected in cases of a family history of ovarian cancer?

A

family history of colorectal cancer or endometrial cancers also present

30
Q

What is the result of a mutation in BRCA1 or BRCA2?

A

highly penetrant autosomal dominant predisposition to breast cancer and ovarian cancer

31
Q

What other cancers are carriers of BRCA1 susceptible to?

A
  • malignant melenoma
  • prostate
  • pancreatic
  • gall-bladder and bile duct
  • stomach
32
Q

What are the roles of BRCA1 and 2?

A
  • DNA repair
  • transcriptional regulation of other genes
  • cell-cycle regulation
  • maintenance of genomic integrity via homologous recombination
33
Q

What are PARP1 inhibitors?

A

Molecularly target drugs

  • promotes apoptosis
34
Q

What are the treatment options for BRCA1/2 carriers?

A

Prophylactic surgery:

  • bilateral mastectomies
  • removal of ovaries and fallopian tubes
35
Q

What is the benefit of a bilateral mastectomy for a BRCA1/2 carrier?

A

reduces cancer risk by 90%

36
Q

What is the benefit of removing the ovaries and fallopian tubes?

A

reduces ovarian cancer risk by 80-96% and reduces breast cancer risk by 50-55%

37
Q

What is the population risk for colorectal cancer?

A

1 in 50

38
Q

What factors contribute to colorectal cancer?

A
  • environmental factors play the predominant role

- genetic susceptibility accounts for 5-10%

39
Q

What is the most common form of inherited colorectal cancer?

A

HNPCC = hereditary non polyposis colon cancer (aka lynch syndrome)

40
Q

What are rarer causes of inherited colorectal cancer?

A
  • FAP = familial adenomatous polyposis

- MUTYH-associated polyposis

41
Q

What features would make you suspect familial colon cancer?

A
  • many polyps present
  • an early age of onset or multifocal cancer
  • family history of colorectal or other related cancers, such as endometrial cancer
42
Q

What are the features of HNPCC

A
  • colorectal tumours common

- polyps may be present but ~10-50

43
Q

What is the sex distribution of colorectal cancer in those with HNPCC?

A
  • 80-90% males

- 40% females

44
Q

What are the less common primary tumour sites associated with HNPCC?

A
  • stomach
  • pancreas
  • ovary
  • kidney
  • brain
45
Q

What other cancer are females likely to develop if they have HNPCC?

A

40-60% - endometrial sarcoma

46
Q

What are the features of FAP?

A
  • > 100 polyps in the intestines, especially the colon from early childhood
  • congenital hyperplasia of the retinal pigment epithelium (CHRPE)
  • an increased risk of gastrointestinal tract cancer
47
Q

What mutation is linked with FAP?

A

Mutation in APC

48
Q

What is the significance of polyps in FAP?

A

Adenomas and if left untreated - cancer develops by 40 years

49
Q

What are the features of MUTYH-associated polyps?

A
  • 15-200 polyps
50
Q

What mutation is linked with MUTYH-associated polyps?

A

mutation in MUTYH gene

51
Q

What is the inheritance pattern in MUTYH-associated polyps?

A

Autosomal recesive inheritance

52
Q

What genes are implicated in HNPCC?

A
  • MSH2
  • MLH1
  • MSH6
  • PMS2

3. Week 1 - Medical Genetics (7 decks)

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