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MBOD Week 16 > BRCA1 and BRCA2 > Flashcards

BRCA1 and BRCA2 Flashcards

1
Q

T or F: most breast/ovarian cancer is caused by heritable mutations

A

False, most of these cancers arise sporadically

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2
Q

What kind of proteins do the BRCA1 and BRCA2 genes code for?

A

TUMOR SUPPRESSOR GENES - codes for proteins that are important for responding to DNA damage and maintenance of gene integrity

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3
Q

What is HBOC?

A

Hereditary Breast and Ovarian Cancer

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4
Q

T or F: patients with HBOC are heterozygous for a mutation in BRCA1 or BRCA2 but NOT BOTH.

A

True

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5
Q

What chromosomes are BRCA1 and BRCA2 located on?

A

BRCA1:
Chromosome 17

BRCA2:
Chromosome 13

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6
Q

T or F: women must be homozygous to be affected by BRCA gene mutations

A

False, heterozygous individuals are affected

**AUTOSOMAL DOMINANT

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7
Q

What is the population risk of breast cancer?

  • BRCA1 risk
  • BRCA2 risk
A

Population:
1 in 10

BRCA1:
6 in 10

BRCA2:
4 in 10

**Women heterozygous for BRCA1/2 are at a much elevated risk even over population risk

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8
Q

What is reduced penetrance?

- how does is apply to BRCA1/2

A

Carrying the BRCA1/2 Allele does not necessarily mean that cancer will develop in that individual.

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9
Q

What is variable expressivity?

- how does it apply to BRCA1/2

A
  • A parent may have a BRCA1/2 mutation, die of BREAST CANCER and pass that mutation to offspring.
  • Offspring may die of OVARIAN cancer or some other type related to the BRCA1/2 gene

**Disease will manifest itself in different ways

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10
Q

What are 2 reasons for reduced penetrance in individuals with a BRCA1/2 mutation?

A
  1. Disease may just never manifest

2. Typical late onset of breast cancer may mean the individual dies of something else before breast cancer developes

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11
Q

What is the average penetrance of BRCA1/2?

A 
BRCA1 = 6/10 develop cancer
BRCA2 = 4/10 develop cancer

Overall penetrance = 50%

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12
Q

What approach is used used to detect mutations in the BRCA1/2 genes?
- why is this necessary?

A
  • Scanning SEQUENCING approach usually paired with an ARRAY
  • used because of the large number of mutations on the BRCA1/2 genes

***These mutations are mostly point mutations they why a SEQUENCING approach is most useful

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13
Q

With the large amount of information obtained from the scanning approach, how do you determine if mutations are meaningful or just typical benign polymorphisms?

A
  • Pathogenic Variants have been documented

**Those not known to be benign or pathogenic are given the label of UNCERTAIN SIGNIFICANCE

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14
Q

T or F: mutations to the BRCA1/2 genes often results in loss of function

A

True

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15
Q

T or F: BRCA1/2 are always sequenced together

A

True

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16
Q

Where are samples drawn to look for BRCA1/2 mutations?

  • DNA type
  • what is sequenced
A
  • Blood or Saliva can be used
  • GENOMIC DNA (both alleles) is obtained from these samples and sequences
  • BRCA1/2 genes from BOTH alleles are sequenced
17
Q

What are the 3 categories of pathogenicity for mutations in BRCA genes (or any other genes)?

A
  • Pathogenic
  • Benign
  • Uncertain Significance
18
Q

What areas of the BRCA genes are targeted when sequencing data?

A

Regions:

  • Promoter
  • Coding
  • All areas needed for accurate splicing

**Introns are rarely used in analysis

19
Q

T or F: while point mutations and other small mutations are the predominant mutation forms in the BRCA gene, a significant portion of mutations are large deletions

A

True, ~15% of all mutations are mutations that span several exons

20
Q

What is unique about founder populations with regard to:

  • Allele Frequency
  • Allelic Heterogeneity
A

Allele Frequency:
- Much HIGHER because small populations inbreed

Allelic Heterogeneity:
- Is REDUCED because the same mutated allele stays in the population rather than having several pathogenic variants

21
Q

Compare the frequency of BRCA genes in the general population to the Ashkenazi Jew population.

  • Prevalence
  • Mutation location
A

General Population:

  • Prevalence = 1/500
  • Mutations Found in many different spots across different people

Ashkenazi Jews:

  • Prevalence = 1/40
  • Several common founder mutations
22
Q

How would your approach to testing an individual in the Ashkenazi Jew population differ from testing the general population?

A

General Population:
- Scanning Approach due to high amount of Allelic Heterogeneity

Ashkenazi Jew:
- Targeted approach can be used because of Reduced Allelic Heterogeneity

23
Q

T or F: 90% of mutations occur at one of 3 points on the BRCA1 and BRCA2 genes in the general population

A

False, this is ONLY true for the Ashkenazi Jew population that has reduced allelic heterogeneity

24
Q

If a targeted test (for an Ashkenazi Jew) for a mutation in the BRCA gene comes back negative, what is the next step?

A
  • Use a scanning approach
25
Q

What are 2 strengths of the scanning approach to Genetic Testing for BRCA1/2?

A
  1. Its Comprehensive and Powerful method for detecting mutations (in BRCA1/2)
  2. Gene Panels Provide Options for Expanded Genetic Testing (outside of BRCA1/2)
26
Q

What are 3 limitations to the scanning approach to Genetic Testing for BRCA1/2?

A
  1. Not all mutations will be found
  2. Some variants are difficult to interpret
  3. More genes sequenced the greater the possibility of encountering VUS (variants of uncertain significance)
27
Q

Does having a negative test for a BRCA1/2 test rule out hereditary risk of getting breast cancer?

A

NO, there are other heritable mutations that are not included in this test

28
Q

If a patient has a strong family history of breast and ovarian cancer but has a negative result for BRCA1/2 mutations, how would additional genetic testing be done?

A
  • You would run a gene panel of several other genes that could potentially be the cause

***Remember the more tests like this you run, the more likely you are to run into variants of unspecified Significance

29
Q

How does finding a variant of unspecified significance (VUS) affect your care plan for the patient?

A

It does NOT have any impact on the care plan, you just go back to treating how you were before the test

30
Q

A person has a history of breast and ovarian cancer in the family and wants to know her risk of getting the disease, what are the steps in figuring out if its hereditary?

A
  1. Test (an) AFFECTED RELATIVE(S) of the consultand

2. Look fore same mutation in the consultand

31
Q

What can you tell the consultand if her mother tested positive for mutation in a BRCA1/2 gene, but the consultand tested negative for that mutation?

A

The consultand is then at population risk of getting breast cancer

32
Q

Suppose the consultand can’t get any of her Affected family members to give a sample for DNA testing but she herself undergoes testing and gets a negative result for mutations, what can you tell the consultand?

A

Without a sample from relative, you don’t know where to look for the mutation so the result is INCONCLUSIVE

33
Q

T or F: failure to find pathogenic variants in a patient rules out the hereditary risk of breast cancer?

A

False

MBOD Week 16 (4 decks)

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