HRD1 Flashcards
What is the lifetime risk of developing ovarian cancer in women with gBRCAm?
1.5–2% lifetime risk in the overall female population
10–20% lifetime risk in gBRCA2m women
30–60% lifetime risk in gBRCA1m women
What % of ovarian cancer are HRD?
Up to 66% of ovarian cancer tumours are HRD-positive
What do PARP inhibitors do?
PARP inhibitors prevent repair of SSBs by trapping PARP, increasing the frequency of DSBs
• In the absence of intact HRR, these DSBs cannot be
repaired accurately, increasing genomic instability and cell death
• Some tumours defective in HRR rely on PARP-mediated DNA repair for survival, and are therefore sensitive to its inhibition
How are DSB repaired?
DSBs are repaired through two different pathways:
• NHEJ ligates DSB ends without a template and is
error-prone
• HRR uses a homologous DNA template to repair
the DSB and is error-free
How does BRCA mutation affect prognosis?
Patients with a BRCAm tend to have a longer remission and respond differently to platinum-based chemotherapy
• Presence of a BRCAm is associated with a superior PFS and OS compared to BRCAwt ovarian cancers
What % of epithelial ovarian cancer patients carry a BRCA mutation?
22%
What % of EOC carry a somatic BRCA mutation?
7% (15% carry a germline BRCA mutation)
What is the largest gauge of biopsy needle that can be used without concerns over haemorrhage or bowel perforations?
14
How should samples be fixed?
8–48 hours in 10% buffered
formalin, depending on the size of
sample
What are the pre-requisites for testing FFPE tissue?
5–10µM section thickness containing
a percentage of tumour cells ≥3x the
limit of the detection method used, sufficient
neoplastic material (≥15%), Sufficient numbers
of cells (~15,000)
What are the main methods for enrichment of BRCA1 and BRCA2 regions?
The main methods for enrichment of BRCA1 and/or BRCA2 are “amplicon-based” or “capture-based”
Reports should…:
- Be brief and unambiguous
- Clearly state the test being reported (i.e. BRCA1 and/or BRCA2)
- Clearly state the clinical significance of the result (e.g.
positive for BRCA1 pathogenic variant) - State any limitations of the sample or test and if any
follow-up procedures are required
What does the Myriad myChoice HRD test look for?
- Loss of heterozygosity (LOH) – a cross-chromosomal event in which one of the parental copies of a heterozygous region of DNA is lost and the other retained
- Telomeric allelic imbalance (TAI) – The number of sub-chromosomal regions with allelic imbalance extending to the telomere
- Large-scale state transition (LST) – large chromosomal breaks
What Myriad score is deemed HRD positive?
> or = to 42
What genomic instability test was used for trials with Olaparib and Niraparib?
Myriad myChoice HRD
