ORCID Profile
0000-0002-0217-3808
Current Organisation
The University of Auckland
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Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.TRANON.2022.101478
Abstract: Endometrial cancer (EC) is the most common gynaecological malignancy in the developed world, and concerningly incidence is rising, particularly in younger people. Therefore, there is increased interest in novel diagnostic and prognostic biomarkers. Extracellular vesicles (EVs) are membrane-bound particles present in bodily fluids that have the potential to facilitate non-invasive, early diagnosis of EC and could aid with monitoring of recurrence and treatment response. EV cargo provides molecular insight into the tumor, with the lipid bilayer providing stability for RNA species usually prone to degradation. miRNAs have recently become a focus for EV biomarker research due to their ability to regulate cancer related pathways and influence cancer development and progression. This review evaluates the current literature on EV miRNA biomarkers with a focus on EC, and discusses the challenges facing this research. This review finally highlights areas of focus for EV miRNA biomarker research going forward, such as standardization of normalization approaches, s le storage and processing, extensive reporting of methodologies and moving away from single miRNA biomarkers.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551082
Abstract: Tumor evolution underlies many challenges facing precision oncology, and improving our understanding has the potential to improve clinical care. This study represents a rare opportunity to study tumor heterogeneity and evolution in a patient with an understudied cancer type. A patient with pulmonary atypical carcinoid, a neuroendocrine tumor, metastatic to 90 sites, requested and consented to donate tissues for research. 42 tumor s les collected at rapid autopsy from 14 anatomically distinct sites were analyzed through DNA whole-exome sequencing and RNA sequencing, and five analyzed through linked-read sequencing. Targeted DNA sequencing was completed on two clinical tissue biopsies and one blood plasma s le. Chromosomal alterations and gene variants accumulated over time, and specific chromosomal alterations preceded the single predicted gene driver variant ( i ARID1A) /i . At the time of autopsy, all sites shared the gain of one copy of Chr 5, loss of one copy of Chr 6 and 21, chromothripsis of one copy of Chr 11, and 39 small variants. Two tumor clones (carrying additional variants) were detected at metastatic sites, and occasionally in different regions of the same organ (e.g., within the pancreas). Circulating tumor DNA (ctDNA) sequencing detected shared tumor variants in the blood plasma and captured marked genomic heterogeneity, including all metastatic clones but few private tumor variants. This study describes genomic tumor evolution and dissemination of a pulmonary atypical carcinoid donated by a single generous patient. It highlights the critical role of chromosomal alterations in tumor initiation and explores the potential of ctDNA analysis to represent genomically heterogeneous disease. Significance: DNA sequencing data from tumor s les and blood plasma from a single patient highlighted the critical early role of chromosomal alterations in atypical carcinoid tumor development. Common tumor variants were readily detected in the blood plasma, unlike emerging tumor variants, which has implications for using ctDNA to capture cancer evolution. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546068
Abstract: Supplementary Figure S5: Inference of putative sequences of genomic changes consistent with the data using the LICHeE and REVOLVER methods LICHeE and Revolver were used to further speculate the order of genomic changes in this patient's dataset. ClonEvol was also trialed, using PyClone putative clonal clusters as input, however the results did not converge. A, LICHeE was run according to the tool creator's instructions, using VAFs as input, to generate clonal relationships of tumor s les. Numbers inside colored circles represent the number of mutations defining a clone, and the squares represent the clonal structures of in idual s les. Shaded regions indicate the proportion of cells belonging to that clone, where the white regions represent normal cells. Four dominant tumor groups were apparent. Where two or more colors are present, LICHeE has predicted the s le to contain a mixture of clones (most apparent in Pa1 and Lu1 but also present in In2, Pa6 and others). This feature is also visible in the VAF plot (Figure 5a) but not represented on the DNA phylogram (Figure 5b). Technical reasons prevented the inclusion of some s les, e.g. Lu8 and Pa5. B, Clonal relationships between tumor s les as predicted by REVOLVER, using PyClone putative clonal clusters as input (from VAF and chromosomal copy number), and default tool parameters. Clones are labeled according to one variant defining that clone (e.g., MASTL), and the circle size is proportional to the number of variants defining the clone. Number refers to clone number. REVOLVER highlighted the same pattern of progression seen in other analyses: from normal cells, common variants accumulate (labeled as MASTL in Figure 5b), and a further set of variants shared by most tumors was identified (labeled GPAM) before a split into two dominant tumor groups, each characterized by their own set of variants (labeled SLIT1 and PAQR6 respectively). REVOLVER highlights the progression of variant accumulation across all s les, rather than indicating in idual s les. All coloring consistent with Figure 5. Overall, LICHeE and REVOLVER explore the clonal and subclonal structure of in idual tumor s les and suggest the same sequence of genomic progression evident in the DNA phylogram (Figure 5b). None of these cancer-specific methods attempts to time the evolutionary ergence events.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546065
Abstract: Supplementary Figure S6: ctDNA detection of private variants While only four private variants were reported by the sequencing platform’s IonReporter software (indicated in orange, key top right), there were sequencing reads to support other private variants. Private variants unique to s les La1 (3 variants) and Pa6 (1 variant) were supported by 2 to 3 variant molecules, and there was a single variant molecule detected to support private variant detection in the following s les: Br2, Cr1, In2, Ki2, La1, Lh1, Lh2, Lu6, Lu7, Lu9, Pa2, Pa3, Pa6, Sc7, Th1, Th2, Ut1, Ve2, Ve3.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546062.V1
Abstract: Supplementary Table S1 includes a description of the tumour s les analysed. Supplementary Table S2 includes DNA WES summary statistics. Supplementary Table S3 includes RNA-Seq summary statistics. Supplementary Table S4 includes WGS linked-read summary statistics. Supplementary Table S5 includes regions covered in the custom ThermoFisher Scientific Ampliseq HD panel. Supplementary Table S6 includes targeted DNA sequencing custom panel summary statistics. Supplementary Table S7 includes low-coverage DNA WES summary statistics. Supplementary Table S8 includes gene set enrichment of genes lost from Chr 11. Supplementary Table S9 includes variants identified in two or more tumour sites. Supplementary Table S10 includes the consequence of somatic variants in Biopsy 1.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546068.V1
Abstract: Supplementary Figure S5: Inference of putative sequences of genomic changes consistent with the data using the LICHeE and REVOLVER methods LICHeE and Revolver were used to further speculate the order of genomic changes in this patient's dataset. ClonEvol was also trialed, using PyClone putative clonal clusters as input, however the results did not converge. A, LICHeE was run according to the tool creator's instructions, using VAFs as input, to generate clonal relationships of tumor s les. Numbers inside colored circles represent the number of mutations defining a clone, and the squares represent the clonal structures of in idual s les. Shaded regions indicate the proportion of cells belonging to that clone, where the white regions represent normal cells. Four dominant tumor groups were apparent. Where two or more colors are present, LICHeE has predicted the s le to contain a mixture of clones (most apparent in Pa1 and Lu1 but also present in In2, Pa6 and others). This feature is also visible in the VAF plot (Figure 5a) but not represented on the DNA phylogram (Figure 5b). Technical reasons prevented the inclusion of some s les, e.g. Lu8 and Pa5. B, Clonal relationships between tumor s les as predicted by REVOLVER, using PyClone putative clonal clusters as input (from VAF and chromosomal copy number), and default tool parameters. Clones are labeled according to one variant defining that clone (e.g., MASTL), and the circle size is proportional to the number of variants defining the clone. Number refers to clone number. REVOLVER highlighted the same pattern of progression seen in other analyses: from normal cells, common variants accumulate (labeled as MASTL in Figure 5b), and a further set of variants shared by most tumors was identified (labeled GPAM) before a split into two dominant tumor groups, each characterized by their own set of variants (labeled SLIT1 and PAQR6 respectively). REVOLVER highlights the progression of variant accumulation across all s les, rather than indicating in idual s les. All coloring consistent with Figure 5. Overall, LICHeE and REVOLVER explore the clonal and subclonal structure of in idual tumor s les and suggest the same sequence of genomic progression evident in the DNA phylogram (Figure 5b). None of these cancer-specific methods attempts to time the evolutionary ergence events.
Publisher: Cold Spring Harbor Laboratory
Date: 08-11-2017
DOI: 10.1101/214585
Abstract: Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern – these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of ≥1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM ) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN ) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.
Publisher: Wiley
Date: 23-11-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546074.V1
Abstract: Supplementary Figure S3: Mutational signatures across all s les collected at autopsy A, Overall mutational burden does not reveal significant mutational signatures (MuSiCa). The signature contribution is indicated by the degree of shading (key to right). The signature with the highest contribution was Signature 3, however it was not statistically significant in most s les according to tool Signal. B, The scarHRD method for quantifying homologous recombination deficiency did not identify any tumors to be HR-deficient with all having an HRD-sum score 20 (known HR-deficient tumors usually have HRD-sums of 40)28.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546074
Abstract: Supplementary Figure S3: Mutational signatures across all s les collected at autopsy A, Overall mutational burden does not reveal significant mutational signatures (MuSiCa). The signature contribution is indicated by the degree of shading (key to right). The signature with the highest contribution was Signature 3, however it was not statistically significant in most s les according to tool Signal. B, The scarHRD method for quantifying homologous recombination deficiency did not identify any tumors to be HR-deficient with all having an HRD-sum score 20 (known HR-deficient tumors usually have HRD-sums of 40)28.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2018
DOI: 10.1038/S41525-018-0058-3
Abstract: Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM ) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN ) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.
Publisher: American Chemical Society (ACS)
Date: 06-08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546071
Abstract: Supplementary Figure S4: Absence of ARID1A variant in targeted panel sequencing of Biopsy 1 despite adequate depth Top panel shows Biopsy 1 targeted panel sequencing. Bottom panel shows representative tumor s led at autopsy (Sc6) with heterozygous deletion in ARID1A, clearly absent from Biopsy 1 sequencing despite adequate depth (7240 unique molecules). The probability of not s ling the ARID1A variant in Biopsy 1 due to chance alone was calculated assuming tumor cellularity of 80% and the heterozygous ARID1A variant being present in 50% of tumor reads. 7240 unique molecules covered this genomic position. The binomial distribution in R was used to calculate the probability of not s ling this variant: dbinom(7240, size=7240, prob=0.6).
Publisher: American Association for Cancer Research (AACR)
Date: 10-01-2023
DOI: 10.1158/2767-9764.CRC-22-0101
Abstract: Tumor evolution underlies many challenges facing precision oncology, and improving our understanding has the potential to improve clinical care. This study represents a rare opportunity to study tumor heterogeneity and evolution in a patient with an understudied cancer type. A patient with pulmonary atypical carcinoid, a neuroendocrine tumor, metastatic to 90 sites, requested and consented to donate tissues for research. 42 tumor s les collected at rapid autopsy from 14 anatomically distinct sites were analyzed through DNA whole-exome sequencing and RNA sequencing, and five analyzed through linked-read sequencing. Targeted DNA sequencing was completed on two clinical tissue biopsies and one blood plasma s le. Chromosomal alterations and gene variants accumulated over time, and specific chromosomal alterations preceded the single predicted gene driver variant (ARID1A). At the time of autopsy, all sites shared the gain of one copy of Chr 5, loss of one copy of Chr 6 and 21, chromothripsis of one copy of Chr 11, and 39 small variants. Two tumor clones (carrying additional variants) were detected at metastatic sites, and occasionally in different regions of the same organ (e.g., within the pancreas). Circulating tumor DNA (ctDNA) sequencing detected shared tumor variants in the blood plasma and captured marked genomic heterogeneity, including all metastatic clones but few private tumor variants. This study describes genomic tumor evolution and dissemination of a pulmonary atypical carcinoid donated by a single generous patient. It highlights the critical role of chromosomal alterations in tumor initiation and explores the potential of ctDNA analysis to represent genomically heterogeneous disease. DNA sequencing data from tumor s les and blood plasma from a single patient highlighted the critical early role of chromosomal alterations in atypical carcinoid tumor development. Common tumor variants were readily detected in the blood plasma, unlike emerging tumor variants, which has implications for using ctDNA to capture cancer evolution.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551082.V1
Abstract: Tumor evolution underlies many challenges facing precision oncology, and improving our understanding has the potential to improve clinical care. This study represents a rare opportunity to study tumor heterogeneity and evolution in a patient with an understudied cancer type. A patient with pulmonary atypical carcinoid, a neuroendocrine tumor, metastatic to 90 sites, requested and consented to donate tissues for research. 42 tumor s les collected at rapid autopsy from 14 anatomically distinct sites were analyzed through DNA whole-exome sequencing and RNA sequencing, and five analyzed through linked-read sequencing. Targeted DNA sequencing was completed on two clinical tissue biopsies and one blood plasma s le. Chromosomal alterations and gene variants accumulated over time, and specific chromosomal alterations preceded the single predicted gene driver variant ( i ARID1A) /i . At the time of autopsy, all sites shared the gain of one copy of Chr 5, loss of one copy of Chr 6 and 21, chromothripsis of one copy of Chr 11, and 39 small variants. Two tumor clones (carrying additional variants) were detected at metastatic sites, and occasionally in different regions of the same organ (e.g., within the pancreas). Circulating tumor DNA (ctDNA) sequencing detected shared tumor variants in the blood plasma and captured marked genomic heterogeneity, including all metastatic clones but few private tumor variants. This study describes genomic tumor evolution and dissemination of a pulmonary atypical carcinoid donated by a single generous patient. It highlights the critical role of chromosomal alterations in tumor initiation and explores the potential of ctDNA analysis to represent genomically heterogeneous disease. Significance: DNA sequencing data from tumor s les and blood plasma from a single patient highlighted the critical early role of chromosomal alterations in atypical carcinoid tumor development. Common tumor variants were readily detected in the blood plasma, unlike emerging tumor variants, which has implications for using ctDNA to capture cancer evolution. /
Publisher: Wiley
Date: 17-06-2020
DOI: 10.1113/EP088744
Abstract: What is the central question of this study? Does short‐term high‐intensity interval training alter the composition of the microbiome and is this associated with exercise‐induced improvements in cardiorespiratory fitness and insulin sensitivity? What is the main finding and its importance? Although high‐intensity interval training increased insulin sensitivity and cardiovascular fitness, it did not alter the composition of the microbiome. This suggests that changes in the composition of the microbiome that occur with prolonged exercise training might be in response to changes in metabolic health rather than driving exercise training‐induced adaptations. Regular exercise reduces the risk of metabolic diseases, and the composition of the gut microbiome has been associated with metabolic function. We investigated whether short‐term high‐intensity interval training (HIIT) altered the ersity and composition of the bacterial community and whether there were associations with markers of insulin sensitivity or aerobic fitness. Cardiorespiratory fitness ( ) and body composition (dual energy X‐ray absorptiometry scan) were assessed and faecal and fasted blood s les collected from 14 lean (fat mass 21 ± 2%, aged 29 ± 2 years) and 15 overweight (fat mass 33 ± 2%, aged 31 ± 2 years) men before and after 3 weeks of HIIT training (8–12 × 60 s cycle ergometer bouts at power output interspersed by 75 s rest, three times per week). Gut microbiome composition was analysed by 16S rRNA gene licon sequencing. The HIIT significantly increased the aerobic fitness of both groups ( P 0.001) and improved markers of insulin sensitivity (lowered fasted insulin and HOMA‐IR P 0.001) in the overweight group. Despite differences in the abundance of several bacterial taxa being evident between the lean and overweight group, HIIT did not affect the overall bacterial ersity or community structure (α‐ ersity or β‐ ersity). No associations were found between the top 50 most abundant bacterial genera and cardiorespiratory fitness markers however, significant associations ( P 0.05) were observed between the abundance of the bacterial species Coprococcus _3, Blautia , Lachnospiraceae_ge and Dorea and insulin sensitivity markers in the overweight group. Our results suggest that short‐term HIIT does not greatly impact the overall composition of the gut microbiome, but that certain microbiome genera are associated with insulin sensitivity markers that were improved by HIIT in overweight participants.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546065.V1
Abstract: Supplementary Figure S6: ctDNA detection of private variants While only four private variants were reported by the sequencing platform’s IonReporter software (indicated in orange, key top right), there were sequencing reads to support other private variants. Private variants unique to s les La1 (3 variants) and Pa6 (1 variant) were supported by 2 to 3 variant molecules, and there was a single variant molecule detected to support private variant detection in the following s les: Br2, Cr1, In2, Ki2, La1, Lh1, Lh2, Lu6, Lu7, Lu9, Pa2, Pa3, Pa6, Sc7, Th1, Th2, Ut1, Ve2, Ve3.
Publisher: Oxford University Press (OUP)
Date: 08-09-2018
DOI: 10.1111/BJD.16903
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546077
Abstract: Supplementary Figure S2: Breakpoints in 10x Loupe software linked-reads view. Each bar represents a sequencing read, and those joined with a horizontal line share the same barcode. Reads are grouped by haplotype (green and purple), with unphased reads in grey. Vertical orange lines indicate putative breakpoints defined by the software. Given that the maximum region of the chromosome phased was significantly shorter than the length of Chr 11 (as indicated in the ‘phase block view’ plot), some breakpoints are assigned to different haplotypes, therefore haplotypes should not be compared between regions (the breakpoint appears in purple in some regions and in green in others). The copy number patterns are consistent with all breakpoints occurring on the same copy of the chromosome.
Publisher: Bentham Science Publishers Ltd.
Date: 08-05-2017
Publisher: Elsevier BV
Date: 07-2021
Publisher: American Physiological Society
Date: 10-2018
DOI: 10.1152/AJPENDO.00138.2018
Abstract: MicroRNAs (miRNAs) regulate gene expression via transcript degradation and translational inhibition, and they may also function as long distance signaling molecules. Circulatory miRNAs are either protein-bound or packaged within vesicles (exosomes). Ten young men (24.6 ± 4.0 yr) underwent a single bout of high-intensity interval cycling exercise. Vastus lateralis biopsies and plasma were collected immediately before and after exercise, as well as 4 h following the exercise bout. Twenty-nine miRNAs previously reported to be regulated by acute exercise were assessed within muscle, venous plasma, and enriched circulatory exosomes via qRT-PCR. Of the 29 targeted miRNAs, 11 were altered in muscle, 8 in plasma, and 9 in the exosome fraction. Although changes in muscle and plasma expression were bidirectional, all regulated exosomal miRNAs increased following exercise. Three miRNAs were altered in all three s le pools (miR-1-3p, -16-5p, and -222-3p), three in both muscle and plasma (miR-21-5p, -134-3p, and -107), three in both muscle and exosomes (miR-23a-3p, -208a-3p, and -150-5p), and three in both plasma and exosomes (miR-486-5p, -126-3p, and -378a-5p). There was a marked discrepancy between the observed alterations between s le pools. A subset of exosomal miRNAs increased in abundance following exercise, suggesting an exercise-induced release of exosomes enriched in specific miRNAs. The uniqueness of the exosomal miRNA response suggests its relevance as a s le pool that needs to be further explored in better understanding biological functions.
Publisher: Georg Thieme Verlag KG
Date: 04-2020
Abstract: The release of calcium ions (Ca2+) from the endoplasmic reticulum (ER) and related store-operated calcium entry (SOCE) regulate maturation of normal megakaryocytes. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) provides an additional mechanism for Ca2+ influx in megakaryocytic cells, but its role remains unclear. We created a model of NMDAR hypofunction in Meg-01 cells using CRISPR-Cas9 mediated knockout of the GRIN1 gene, which encodes an obligate, GluN1 subunit of the NMDAR. We found that compared with unmodified Meg-01 cells, Meg-01-GRIN1 −/− cells underwent atypical differentiation biased toward erythropoiesis, associated with increased basal ER stress and cell death. Resting cytoplasmic Ca2+ levels were higher in Meg-01-GRIN1 −/− cells, but ER Ca2+ release and SOCE were lower after activation. Lysosome-related organelles accumulated including immature dense granules that may have contributed an alternative source of intracellular Ca2+. Microarray analysis revealed that Meg-01-GRIN1 −/− cells had deregulated expression of transcripts involved in Ca2+ metabolism, together with a shift in the pattern of hematopoietic transcription factors toward erythropoiesis. In keeping with the observed pro-cell death phenotype induced by GRIN1 deletion, memantine (NMDAR inhibitor) increased cytotoxic effects of cytarabine in unmodified Meg-01 cells. In conclusion, NMDARs comprise an integral component of the Ca2+ regulatory network in Meg-01 cells that help balance ER stress and megakaryocytic-erythroid differentiation. We also provide the first evidence that megakaryocytic NMDARs regulate biogenesis of lysosome-related organelles, including dense granules. Our results argue that intracellular Ca2+ homeostasis may be more important for normal megakaryocytic and erythroid differentiation than currently recognized thus, modulation may offer therapeutic opportunities.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546077.V1
Abstract: Supplementary Figure S2: Breakpoints in 10x Loupe software linked-reads view. Each bar represents a sequencing read, and those joined with a horizontal line share the same barcode. Reads are grouped by haplotype (green and purple), with unphased reads in grey. Vertical orange lines indicate putative breakpoints defined by the software. Given that the maximum region of the chromosome phased was significantly shorter than the length of Chr 11 (as indicated in the ‘phase block view’ plot), some breakpoints are assigned to different haplotypes, therefore haplotypes should not be compared between regions (the breakpoint appears in purple in some regions and in green in others). The copy number patterns are consistent with all breakpoints occurring on the same copy of the chromosome.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546080.V1
Abstract: Supplementary Figure S1: ADTEx copy number analysis of Biopsy 1 from low coverage WES Copy number profile of low-coverage WES of Biopsy 1 revealing A, likely lification of Chr 5 and B, loss of Chr 21. Top panels display DOC ratio, colored by predicted copy number state. Bottom panels display BAF, colored by predicted copy number alteration. The separation of BAF towards 0.3 and 0.6 in Chr 5 indicates chromosomal gain, whereas the separation of BAF towards 0 and 1 in Chr 21 indicates LoH. There was insufficient evidence conclusively identify the presence or absence of the loss of C, Chr 6 and D, chromothripsis of one copy of Chr 11 based on ADTEx analysis of the low-coverage WES of Biopsy 1, however it is likely that they were absent. Copy number analysis was plagued with high levels of noise from low coverage and large differences in coverage between the Biopsy 1 and normal s le. The sole Chr 11 breakpoint covered by the exome sequencing did not provide read support for chromothripsis. The apparent lifications of regions of each chromosome do not match up to any known alterations in high-quality DNA s les from tumours collected at autopsy and are likely attributable to noise in the low coverage WES.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546071.V1
Abstract: Supplementary Figure S4: Absence of ARID1A variant in targeted panel sequencing of Biopsy 1 despite adequate depth Top panel shows Biopsy 1 targeted panel sequencing. Bottom panel shows representative tumor s led at autopsy (Sc6) with heterozygous deletion in ARID1A, clearly absent from Biopsy 1 sequencing despite adequate depth (7240 unique molecules). The probability of not s ling the ARID1A variant in Biopsy 1 due to chance alone was calculated assuming tumor cellularity of 80% and the heterozygous ARID1A variant being present in 50% of tumor reads. 7240 unique molecules covered this genomic position. The binomial distribution in R was used to calculate the probability of not s ling this variant: dbinom(7240, size=7240, prob=0.6).
Publisher: Springer Science and Business Media LLC
Date: 30-01-2017
DOI: 10.1007/S11523-017-0476-7
Abstract: miRNAs are a well-studied class of non-coding RNAs, predominantly functioning to down-regulate gene expression from messenger RNA (mRNA) in a targeted manner by binding to complementary sequence on the target mRNA. Many miRNAs have been linked to the development of hallmarks of cancer. miRNAs represent valuable therapeutic targets to exploit in the search for novel cancer treatments, due to their ubiquitous expression and their ability to tightly regulate the gene expression of a whole host of genes and pathways in a single hit. The miRNA system may be harnessed for therapeutic use either through replacement of tumour suppressive miRNAs lost in cancer, or through inhibition of oncogenic miRNAs overexpressed in cancer. There is a large body of work investigating optimal systemic and localised delivery strategies, and while miRNA therapeutics show promise, it is clear that further developments to delivery strategies may be required to allow safe translation of miRNAs to the clinic. The information gleaned from miRNA signatures as biomarkers is already proving invaluable in the fight to better understand and treat in idual tumours, and there is great promise to the applications of these small, but mighty molecules in the future of cancer therapeutics.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546062
Abstract: Supplementary Table S1 includes a description of the tumour s les analysed. Supplementary Table S2 includes DNA WES summary statistics. Supplementary Table S3 includes RNA-Seq summary statistics. Supplementary Table S4 includes WGS linked-read summary statistics. Supplementary Table S5 includes regions covered in the custom ThermoFisher Scientific Ampliseq HD panel. Supplementary Table S6 includes targeted DNA sequencing custom panel summary statistics. Supplementary Table S7 includes low-coverage DNA WES summary statistics. Supplementary Table S8 includes gene set enrichment of genes lost from Chr 11. Supplementary Table S9 includes variants identified in two or more tumour sites. Supplementary Table S10 includes the consequence of somatic variants in Biopsy 1.
Publisher: MDPI AG
Date: 22-01-2021
Abstract: Outstanding questions plaguing oncologists, centred around tumour evolution and heterogeneity, include the development of treatment resistance, immune evasion, and optimal drug targeting strategies. Such questions are difficult to study in limited cancer tissues collected during a patient’s routine clinical care, and may be better investigated in the breadth of cancer tissues that may be permissible to collect during autopsies. We are starting to better understand key tumour evolution challenges based on advances facilitated by autopsy studies completed to date. This review article explores the great progress in understanding that cancer tissues collected at autopsy have already enabled, including the shared origin of metastatic cells, the importance of early whole-genome doubling events for lifying genes needed for tumour survival, and the creation of a wealth of tissue resources powered to answer future questions, including patient-derived xenografts, cell lines, and a wide range of banked tissues. We also highlight the future role of these programmes in advancing our understanding of cancer evolution. The research autopsy provides a special opportunity for cancer patients to give the ultimate gift—to selflessly donate their tissues towards better cancer care.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2018
DOI: 10.1158/2767-9764.22546080
Abstract: Supplementary Figure S1: ADTEx copy number analysis of Biopsy 1 from low coverage WES Copy number profile of low-coverage WES of Biopsy 1 revealing A, likely lification of Chr 5 and B, loss of Chr 21. Top panels display DOC ratio, colored by predicted copy number state. Bottom panels display BAF, colored by predicted copy number alteration. The separation of BAF towards 0.3 and 0.6 in Chr 5 indicates chromosomal gain, whereas the separation of BAF towards 0 and 1 in Chr 21 indicates LoH. There was insufficient evidence conclusively identify the presence or absence of the loss of C, Chr 6 and D, chromothripsis of one copy of Chr 11 based on ADTEx analysis of the low-coverage WES of Biopsy 1, however it is likely that they were absent. Copy number analysis was plagued with high levels of noise from low coverage and large differences in coverage between the Biopsy 1 and normal s le. The sole Chr 11 breakpoint covered by the exome sequencing did not provide read support for chromothripsis. The apparent lifications of regions of each chromosome do not match up to any known alterations in high-quality DNA s les from tumours collected at autopsy and are likely attributable to noise in the low coverage WES.
No related grants have been discovered for Cherie Blenkiron.