Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
The PROfound trial showed that olaparib prolonged imaging-based progression-free survival among patients whose tumors contained defects in the homologous recombination repair genes
BRCA1
,
BRCA2
, or
...ATM
. With longer follow-up, the trial now shows that olaparib prolonged overall survival in these patients. Toxic effects included anemia, nausea, and asthenia.
Fanconi anemia (FA) is a complex cancer susceptibility disorder associated with DNA repair defects and infertility, yet the precise function of the FA proteins in genome maintenance remains unclear. ...Here we report that C. elegans FANCD2 (fcd-2) is dispensable for normal meiotic recombination but is required in crossover defective mutants to prevent illegitimate repair of meiotic breaks by nonhomologous end joining (NHEJ). In mitotic cells, we show that DNA repair defects of C. elegans fcd-2 mutants and FA-deficient human cells are significantly suppressed by eliminating NHEJ. Moreover, NHEJ factors are inappropriately recruited to sites of replication stress in the absence of FANCD2. Our findings are consistent with the interpretation that FA results from the promiscuous action of NHEJ during DNA repair. We propose that a critical function of the FA pathway is to channel lesions into accurate, as opposed to error-prone, repair pathways.
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► C. elegans FCD-2 prevents illegitimate repair of DSBs in meiotic and mitotic cells ► Eliminating NHEJ by lig-4 deletion rescues the ICL repair defects of fcd-2 mutants ► Loss of NHEJ suppresses the ICL sensitivity of mammalian cells lacking FANCA, FANCC, or FANCD2 ► FANCD2 prevents improper engagement of DNA-PKcs with sites of replication stress
We have recently shown that hypomorphic Mre11 complex mouse mutants exhibit defects in the repair of meiotic double strand breaks (DSBs). This is associated with perturbation of synaptonemal complex ...morphogenesis, repair and regulation of crossover formation. To further assess the Mre11 complex's role in meiotic progression, we identified testis-specific NBS1-interacting proteins via two-hybrid screening in yeast. In this screen, Zip4h (Tex11), a male germ cell specific X-linked gene was isolated. Based on sequence and predicted structural similarity to the S. cerevisiae and A. thaliana Zip4 orthologs, ZIP4H appears to be the mammalian ortholog. In S. cerevisiae and A. thaliana, Zip4 is a meiosis-specific protein that regulates the level of meiotic crossovers, thus influencing homologous chromosome segregation in these organisms. As is true for hypomorphic Nbs1 (Nbs1(DeltaB/DeltaB)) mice, Zip4h(-/Y) mutant mice were fertile. Analysis of spermatocytes revealed a delay in meiotic double strand break repair and decreased crossover formation as inferred from DMC1 and MLH1 staining patterns, respectively. Achiasmate chromosomes at the first meiotic division were also observed in Zip4h(-/Y) mutants, consistent with the observed reduction in MLH1 focus formation. These results indicate that meiotic functions of Zip4 family members are conserved and support the view that the Mre11 complex and ZIP4H interact functionally during the execution of the meiotic program in mammals.
Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke ...template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway.
Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future ...molecularly targeted therapies.
An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation.
A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages >10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact.
The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.
Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of ...difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.
Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.
81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.
We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
Prostate cancer is among the most common diseases worldwide. Despite recent progress with treatments, patients with advanced prostate cancer have poor outcomes and there is a high unmet need in this ...population. Understanding molecular determinants underlying prostate cancer and the aggressive phenotype of disease can help with design of better clinical trials and improve treatments for these patients. One of the pathways often altered in advanced prostate cancer is DNA damage response (DDR), including alterations in
and other homologous recombination repair (HRR) genes. Alterations in the DDR pathway are particularly prevalent in metastatic prostate cancer. In this review, we summarise the prevalence of DDR alterations in primary and advanced prostate cancer and discuss the impact of alterations in the DDR pathway on aggressive disease phenotype, prognosis and the association of germline pathogenic alterations in DDR genes with risk of developing prostate cancer.
The Arctic Ocean is known to be contaminated by various persistent organic pollutants (POPs). The Fram Strait, the only deepwater passage to the Arctic Ocean (from the Atlantic Ocean), represents an ...unquantified gateway for POPs fluxes into and out of the Arctic. Polyethylene passive samplers were deployed in vertical profiles in the Fram Strait and in air and surface water in the Canadian Archipelago to determine the concentrations, profiles, and mass fluxes of dissolved polychlorinated biphenyls (PCBs) and organochlorine pesticides. In the Fram Strait, higher concentrations of ΣPCBs (1.3–3.6 pg/L) and dichlorodiphenyltrichloroethanes (ΣDDTs, 5.2–9.1 pg/L) were observed in the deepwater masses (below 1,000 m), similar to nutrient‐like vertical profiles. There was net southward transport of hexachlorobenzene and hexachlorocyclohexanes (ΣHCHs) of 0.70 and 14 Mg/year but a net northward transport of ΣPCBs at 0.16 Mg/year through the Fram Strait.
Plain Language Summary
Persistent organic pollutants can reach the Arctic Ocean by long‐range atmospheric transport, ocean currents, and inputs from the large Arctic rivers. Polychlorinated biphenyls (PCBs) and organochlorine pesticides, which have been extensively used since the 1930s, were banned and listed in the United Nations Environment Programme Stockholm Convention on persistent organic pollutants in 2001. We performed the first pan‐Arctic deployments of passive samplers to gain knowledge of the occurrence, transport, and fate of these legacy contaminants in the remote Arctic. Our results demonstrated the ubiquitous presence of persistent industrial and agricultural contaminants across the Canadian Arctic and throughout the water column of the Fram Strait. While atmospheric transport seems mostly responsible for the presence of these pollutants in the surface Arctic Ocean, in the Fram Strait, concentrations of PCBs and dichlorodiphenyltrichloroethanes (DDTs) increased in deep waters, indicating their penetration to the deep ocean environment. Our results also showed the legacy hexachlorocyclohexanes (HCHs) and hexachlorobenzene (HCB) are released from the Arctic Ocean to the Atlantic Ocean via the deepwater Fram Strait, while PCBs are still loaded from the Atlantic Ocean to the Arctic Ocean.
Key Points
Deep waters of the Fram Strait carried highest concentrations of polychlorinated biphenyls and dichlorodiphenyltrichloroethane
A fractionation of organic pollutants with depth was observed; contributions of the more hydrophobic compounds increased with depth
There is a net export of hexachlorocyclohexanes and hexachlorobenzene from the Arctic Ocean through the deepwater passage Fram Strait
Organophosphate esters (OPEs) have been found in remote environments at unexpectedly high concentrations, but very few measurements of OPE concentrations in seawater are available, and none are ...available in subsurface seawater. In this study, passive polyethylene samplers (PEs) deployed on deep-water moorings in the Fram Strait and in surface waters of Canadian Arctic lakes and coastal sites were analyzed for a suite of common OPEs. Total OPEs ( ∑11OPE) at deep-water sites were dominated by chlorinated OPEs, and ranged from 6.3 to 440 pg/L. Concentrations were similar in eastern and western Fram Strait. Chlorinated OPEs were also dominant in Canadian Arctic surface waters (mean concentration ranged from < DL to 4400 pg/L), while nonhalogenated alkyl/aryl-substituted OPEs remained low (1.3–55 pg/L), possibly due to the greater long-range transport potential of chlorinated OPEs. Polybrominated diphenyl ethers (PBDEs) were found at much lower concentrations than OPEs (<DL-14 pg/L). Surface-water concentrations of tris(2-chloroethyl) phosphate (TCEP) and tris(1,3-dichloroisopropyl) phosphate (TDCIPP) were similar for both active and passive sampling approaches. Several OPEs were estimated to be undergoing net transport out of the Arctic, ranging from 17 kg/yr for ethylhexyldiphenylphosphate (EHDPP) to 3400 kg/yr for tris (2-chloroisopropyl) phosphate (TCIPP). This study highlights the importance of OPEs as poorly understood contaminants present at unexpectedly high concentrations in remote marine environments.
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