BRCA1/2 Flashcards
How does PARP function?
Polymerises ADP-ribose on surrounding histones, TFs and itself –> chromatin relaxation. Highly negatively charged polymer allows recruitment of SSB repair factors to SSB.
What is Lynparza?
2014 FDA approved Olaparib to treat advanced ovarian BRCA-associated cancer.
In 2017 met primary endpoint of phase II trial - statistically significant improvement in PFS compared to chemo for BRCA mutated breast cancers.
Why is OLYMPIA?
Olaparib in adjutant BRCAm breast cancer. Asks if we can cure women with gBC if give Olaparib.
4 hospitals around world - random allocation of women at high risk of metastasis to olaparib and placebo gps.
What is the role of RAD51?
binds ssDNA –> enables unwinding of homologous DS helices –> essential for HR initiation.
How does NHEJ drive a mutator phenotype?
What is NHEJ normally required for?
alignment between DNA segments being fused, not informed by WT DNA sequences on sister chromatid --> end to end fusions generate mutant sequences at sites of joining. VDJ recombination and class switching.
What other function may contribute to the destabilisation seen on mutation of Brca1?
Carries in a domain a function –> monoubiquitylation of histone H2A (an adaptor for E3 subunit of Uq ligase complex) –> formation of constitutive HETEROCHROMATIN. In absence of this –> repeat sequences normally shut down –> expressed.
How is BRCA2 mutated?
One missing coding base = BRCA2 c.6174delT
Frameshift mutation and truncated protein.
What mechanisms allow tumours to regain HR repair fitness and thus survive some of chemo effects?
Brca mutation reversions - 1 frameshifts back into frame. 2 has mutated sequence spliced out.
53BPI loss - (promotes NHEJ over HR)
Briefly outline HR detect.
A single gene defect such as BRCA1 or 2 –> at least 5 mutational signatures as a direct consequence of abrogation of DNA repair pathway. Integrate these signatures to identify individuals with BRCA 1/2 mutations
