Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in over... more Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpress...
Accurate assessment of ALK rearrangement in NSCLCs is critical to identify patients likely to res... more Accurate assessment of ALK rearrangement in NSCLCs is critical to identify patients likely to respond to crizotinib. We evaluated the ALK/EML4 TriCheck FISH Probe in a series of NSCLCs enriched for tumours with equivocal ALK status. ALK FISH was prospectively performed on 45 NSCLCs using the ALK/EML4 TriCheck Probe (ZytoVision) and the Vysis ALK Break-Apart Probe (Abbott Molecular). ALK immunohistochemistry was performed using 5A4 and D5F3 antibodies. Fourteen cases had equivocal ALK status based on borderline or focal FISH positivity, atypical FISH pattern or discrepancy between ALK FISH and immunohistochemistry. Four of the 14 equivocal cases showed discordance between the two FISH probes. All other cases were concordant. The Tricheck probe showed that of 31 unequivocal cases, 15 were ALK rearranged, of which 60% had EML4 as the translocation partner. Within the group of 14 equivocal cases, 12 showed rearrangement by the Tricheck probe of which only one showed EML4 rearrangement. ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most co... more Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion...
Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We prev... more Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We previously showed that mice expressing an Eµ-v-abl oncogene solely develop plasmacytomas. Here we show that loss of the proapoptotic BH3-only protein Bim or, to a lesser extent, overexpression of antiapoptotic Bcl-2 or Mcl-1, significantly accelerated the development of plasmacytomas and increased their incidence. Disease was preceded by an increased abundance of plasma cells, presumably reflecting their enhanced survival capacity in vivo. Plasmacytomas of each genotype expressed high levels of v-abl and frequently harbored a rearranged c-myc gene, probably as a result of chromosome translocation. As in human multiple myelomas, elevated expression of cyclin D genes was common, and p53 deregulation was rare. Our results for plasmacytomas highlight the significance of antiapoptotic changes in multiple myeloma, which include elevated expression of Mcl-1 and, less frequently, Bcl-2, and suggest ...
Leukaemia inhibitory factor (LIF) is able to promote megakaryocytopoiesis in vitro and elevate pl... more Leukaemia inhibitory factor (LIF) is able to promote megakaryocytopoiesis in vitro and elevate platelet counts in vivo, and is a potential new therapeutic agent for the treatment of thrombocytopenia. To determine whether platelets released under conditions of LIF-stimulated megakaryocytopoiesis have intact function, we compared aggregation responses of platelets from mice with constitutively elevated LIF levels (FD/LIF mice) and mice injected with recombinant murine LIF (rmLIF mice) with their respective control mice. We report that ex vivo platelet aggregability and thromboxane B2 release were intact in the LIF-treated mice, and were significantly enhanced in some situations. LIF-treated mice also had significantly increased platelet counts (FD/LIF mice: 1302 +/- 173 x 10(9)/l compared to 1012 +/- 99 x 10(9)/l for FD mice; rmLIF mice: 1460 +/- 193 x 10(9)/l compared to 985 +/- 67 x 10(9)/l for FCS/NS mice), increased platelet volumes and elevated plasma fibrinogen and calcium levels. The platelet hyperreactivity seen in the LIF-treated mice is likely to reflect the larger platelet volumes and/or the effect of plasma components such as fibrinogen, elevated levels of which were due to the concomitant action of LIF as a stimulant of acute phase protein synthesis.
Current epidemiological evidence supports a pathogenetic model of gastric cancer involving interm... more Current epidemiological evidence supports a pathogenetic model of gastric cancer involving intermediate stages that include chronic gastritis and intestinal metaplasia. This study explores the molecular features of gastric cancer and premalignant stages using DNA microarray-based gene expression profiling and relates these findings to clinical, pathological, and ethnic parameters. A total of 124 tumor and adjacent mucosa samples were analyzed using spotted cDNA microarrays containing 9381 nonredundant gene elements. Tumor specimens were diffuse, intestinal, or mixed gastric cancer and adjacent mucosa, which generally displayed signs of chronic gastritis or intestinal metaplasia. Expression patterns could be discerned that readily defined premalignant and tumor subtypes. Chronic gastritis exhibits a pronounced mitochondrial gene expression signature, which may be linked to Helicobacter pylori pathogenesis. Intestinal metaplasia was associated with increased expression of many intesti...
... e Institute of Oncology, Prince of Wales Hospital, Randwick, Australia. Corresponding Author ... more ... e Institute of Oncology, Prince of Wales Hospital, Randwick, Australia. Corresponding Author Information Correspondence to: Dr Desmond Yip, Medical Oncology Unit, Canberra Hospital, PO Box 11, Woden Australian Capital Territory 2606, Australia. ...
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in over... more Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpress...
Accurate assessment of ALK rearrangement in NSCLCs is critical to identify patients likely to res... more Accurate assessment of ALK rearrangement in NSCLCs is critical to identify patients likely to respond to crizotinib. We evaluated the ALK/EML4 TriCheck FISH Probe in a series of NSCLCs enriched for tumours with equivocal ALK status. ALK FISH was prospectively performed on 45 NSCLCs using the ALK/EML4 TriCheck Probe (ZytoVision) and the Vysis ALK Break-Apart Probe (Abbott Molecular). ALK immunohistochemistry was performed using 5A4 and D5F3 antibodies. Fourteen cases had equivocal ALK status based on borderline or focal FISH positivity, atypical FISH pattern or discrepancy between ALK FISH and immunohistochemistry. Four of the 14 equivocal cases showed discordance between the two FISH probes. All other cases were concordant. The Tricheck probe showed that of 31 unequivocal cases, 15 were ALK rearranged, of which 60% had EML4 as the translocation partner. Within the group of 14 equivocal cases, 12 showed rearrangement by the Tricheck probe of which only one showed EML4 rearrangement. ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most co... more Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion...
Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We prev... more Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We previously showed that mice expressing an Eµ-v-abl oncogene solely develop plasmacytomas. Here we show that loss of the proapoptotic BH3-only protein Bim or, to a lesser extent, overexpression of antiapoptotic Bcl-2 or Mcl-1, significantly accelerated the development of plasmacytomas and increased their incidence. Disease was preceded by an increased abundance of plasma cells, presumably reflecting their enhanced survival capacity in vivo. Plasmacytomas of each genotype expressed high levels of v-abl and frequently harbored a rearranged c-myc gene, probably as a result of chromosome translocation. As in human multiple myelomas, elevated expression of cyclin D genes was common, and p53 deregulation was rare. Our results for plasmacytomas highlight the significance of antiapoptotic changes in multiple myeloma, which include elevated expression of Mcl-1 and, less frequently, Bcl-2, and suggest ...
Leukaemia inhibitory factor (LIF) is able to promote megakaryocytopoiesis in vitro and elevate pl... more Leukaemia inhibitory factor (LIF) is able to promote megakaryocytopoiesis in vitro and elevate platelet counts in vivo, and is a potential new therapeutic agent for the treatment of thrombocytopenia. To determine whether platelets released under conditions of LIF-stimulated megakaryocytopoiesis have intact function, we compared aggregation responses of platelets from mice with constitutively elevated LIF levels (FD/LIF mice) and mice injected with recombinant murine LIF (rmLIF mice) with their respective control mice. We report that ex vivo platelet aggregability and thromboxane B2 release were intact in the LIF-treated mice, and were significantly enhanced in some situations. LIF-treated mice also had significantly increased platelet counts (FD/LIF mice: 1302 +/- 173 x 10(9)/l compared to 1012 +/- 99 x 10(9)/l for FD mice; rmLIF mice: 1460 +/- 193 x 10(9)/l compared to 985 +/- 67 x 10(9)/l for FCS/NS mice), increased platelet volumes and elevated plasma fibrinogen and calcium levels. The platelet hyperreactivity seen in the LIF-treated mice is likely to reflect the larger platelet volumes and/or the effect of plasma components such as fibrinogen, elevated levels of which were due to the concomitant action of LIF as a stimulant of acute phase protein synthesis.
Current epidemiological evidence supports a pathogenetic model of gastric cancer involving interm... more Current epidemiological evidence supports a pathogenetic model of gastric cancer involving intermediate stages that include chronic gastritis and intestinal metaplasia. This study explores the molecular features of gastric cancer and premalignant stages using DNA microarray-based gene expression profiling and relates these findings to clinical, pathological, and ethnic parameters. A total of 124 tumor and adjacent mucosa samples were analyzed using spotted cDNA microarrays containing 9381 nonredundant gene elements. Tumor specimens were diffuse, intestinal, or mixed gastric cancer and adjacent mucosa, which generally displayed signs of chronic gastritis or intestinal metaplasia. Expression patterns could be discerned that readily defined premalignant and tumor subtypes. Chronic gastritis exhibits a pronounced mitochondrial gene expression signature, which may be linked to Helicobacter pylori pathogenesis. Intestinal metaplasia was associated with increased expression of many intesti...
... e Institute of Oncology, Prince of Wales Hospital, Randwick, Australia. Corresponding Author ... more ... e Institute of Oncology, Prince of Wales Hospital, Randwick, Australia. Corresponding Author Information Correspondence to: Dr Desmond Yip, Medical Oncology Unit, Canberra Hospital, PO Box 11, Woden Australian Capital Territory 2606, Australia. ...
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Papers by Paul Waring