Loading
The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
Single-strand breaks recruit PARP1 for base-excision repair. Unrepaired breaks collapse replication forks into double-strand breaks, repaired by homologous recombination (BRCA1, BRCA2, PALB2, RAD51) in S/G2 or by error-prone NHEJ/POLQ-mediated end joining. ATR senses replication stress and signals via CHK1; ATM senses double-strand breaks. HR-deficient tumours (BRCA mutation, HRD) depend on PARP, POLQ, and ATR: the basis of synthetic lethality. Resistance: BRCA reversion, 53BP1/Shieldin loss restoring HR, drug efflux.
Two repair crews for a road: PARP fixes potholes, BRCA rebuilds collapsed bridges. A town that has lost its bridge crew (BRCA mutation) survives as long as potholes are fixed before they become bridge collapses. Block the pothole crew (PARP inhibitor) and the bridges fall.
Germline testing for every pancreatic cancer patient, platinum first line for BRCA carriers, and olaparib maintenance for those who respond are all downstream of POLO.
It is the second half of the argument for unselected germline testing, and it widens the target beyond BRCA: two thirds of the actionable inherited findings in prostate cancer are in other genes, including the mismatch repair genes that open a checkpoint inhibitor route.
Family history misses most carriers, so the NCCN and ASCO guidelines moved to testing every patient; each carrier found is a family that can be offered surveillance and a patient who may be eligible for platinum and PARP inhibition.
It links a line on a UK pathology report to a question about a family. Intraductal carcinoma is a reportable item in the current dataset, and its presence is a practical prompt to check that germline testing has actually been offered rather than assumed.
With Moffitt's classical and basal-like split (the squamous and basal-like groups overlap) this fixed the molecular vocabulary of the disease and gave Precision-Panc and the UK's Glasgow group their trial framework.
The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well.
The genomic case for platinum in BRCA-type pancreatic cancer, four years before POLO built a maintenance strategy on top of it.
It matters for how the test is done. A mismatch repair assay designed around the colorectal mechanism, looking for MLH1 promoter methylation and simple mutations, can miss the prostate mechanism entirely, which is one reason microsatellite instability was under-recognised in this disease for so long.
Shares Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer, Intraductal and ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer, Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines, POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
Shares Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer, Intraductal and ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer, Enabling characteristic: genome instability and mutation, Whole genomes redefine the mutational landscape of pancreatic cancer.
Shares Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer, Intraductal and ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer, Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines, POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
Shares Basal-like 1 triple-negative breast cancer (BL1), BRCA-associated triple-negative breast cancer, HRD & BRCA testing, PARP.
Shares POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, HRD & BRCA testing, Talazoparib, PARP.
Shares HRD & BRCA testing, Talazoparib, Niraparib, PARP.
Shares POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, Base excision repair, PARP & alkylation damage, DNA replication stress, Homologous recombination repair gene mutation in prostate cancer.
Shares Intraductal and ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer, Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines, Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Homologous recombination repair gene mutation in prostate cancer.