Publications by authors named "Qinying Xu"

35 Publications

System analysis of in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets.

Int J Biol Markers 2022 Mar 7:3936155221084056. Epub 2022 Mar 7.

Department of Parasitology, 12453Guangdong Medical University, Zhanjiang 524023,Guangdong, China.

Background: Fragile histidine triad () is a strong tumor suppressor gene, and cells deficient in are prone to acquiring cancer-promoting mutations. Due to its location, deletions within are common in cancer. Over 50% of cancers show loss of expression. However, to date, expression levels, gene regulatory networks, prognostic value, and target prediction of in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have not been fully reported. Therefore, systematic analysis of expression, gene regulatory network, prognostic value, and targeted prediction in patients with LUAD and LUSC has important guiding significance, providing new therapeutic targets and strategies for clinical treatment of lung cancer to further improve the therapeutic effect of lung cancer.

Methods: Multiple free online databases were used for the abovementioned analysis in this study, including cBioPortal, TRRUST, Human Protein Atlas, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER.

Results: was upregulated in patients with LUAD, and downregulated in patients with LUSC. Genetic alterations of were found in patients with LUAD (7%), and LUSC (10%). The promoter methylation of was lower in patients with LUAD and LUSC. expression significantly correlated with LUSC pathological stages. Furthermore, patients with LUAD and LUSC having low expression levels had a longer survival than those having high expression levels. and its neighboring genes (the 50 most frequently altered neighboring genes of ) functioned in the regulation of protein kinase and DNA binding in patients with LUAD, as well as cell channels and membrane potential in patients with LUSC. Gene ontology enrichment analysis revealed that the functions of and its neighboring genes are mainly related to disordered domain-specific binding, protein kinase binding, and ion gated channel activity in patients with LUAD, as well as calcium ion binding and intracellular ligand-gated ion channel activity in patients with LUSC. Transcription factor targets of and its neighboring genes in patients with lung cancer were found: USF1, SOX6, USF2, SIRT1, VHL, LEF1, EZH2, TP53, HDAC1, ESR1, EGR1, YY1, MYC, RELA, NFKB1, and E2F1 in LUAD; and HDAC1, DNMT1, and E2F1 in LUSC. We further explored the -associated kinase (PRKCQ, AURKB and ATM in LUAD as well as PLK3 in LUSC) and -associated miRNA targets (MIR-188, MIR-323, and MIR-518A-2 in LUAD). Furthermore, the following genes had the strongest correlation with expression in patients with lung cancer: and in LUAD and and in LUSC. expression was positively associated with immune cell infiltration (B cell) in patients with LUAD, as well as B cell, CD8 + T, CD4 + T cells, macrophages, and dendritic cells in patients with LUSC. Nevertheless, expression was negatively associated with CD8 + T cells and neutrophils in patients with LUAD.

Conclusions: The expression, gene regulatory network, prognostic value and targeted prediction of in patients with LUAD and LUSC were systematically analyzed and revealed in this study, thereby laying a foundation for further research on the role of in LUAD and LUSC occurrence. This study provides new LUAD and LUSC therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.
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http://dx.doi.org/10.1177/03936155221084056DOI Listing
March 2022

System analysis of in renal cell carcinoma: The expression, prognosis, gene regulation network and regulation targets.

Int J Biol Markers 2022 Mar 6;37(1):90-101. Epub 2021 Dec 6.

Department of Parasitology, 12453Guangdong Medical University, Zhanjiang, China.

Background: VEGFA is one of the most important regulators of angiogenesis and plays a crucial role in cancer angiogenesis and progression. Recent studies have highlighted a relationship between expression and renal cell carcinoma occurrence. However, the expression level, gene regulation network, prognostic value, and target prediction of in renal cell carcinoma remain unclear. Therefore, system analysis of the expression, gene regulation network, prognostic value, and target prediction of in patients with renal cell carcinoma is of great theoretical significance as there is a clinical demand for the discovery of new renal cell carcinoma treatment targets and strategies to further improve renal cell carcinoma treatment efficacy.

Methods: This study used multiple free online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, Metascape, and TIMER for the abovementioned analysis.

Results: was upregulated in patients with kidney renal clear cell carcinoma (KIRC) and kidney chromophobe (KICH), and downregulated in patients with kidney renal papillary cell carcinoma (KIRP). Moreover, genetic alterations of were found in patients with renal cell carcinoma as follows: 4% (KIRC), 8% (KICH), and 4% (KIRP). The promoter methylation of was lower and higher in patients with clinical stages of KIRC and stage 1 KIRP, respectively. expression significantly correlated with KIRC and KIRP pathological stages. Furthermore, patients with KICH and KIRP having low expression levels had a longer survival than those having high expression levels. and its neighboring genes functioned in the regulation of protein methylation and glycosylation, as well as muscle fiber growth and differentiation in patients with renal cell carcinoma. Gene Ontology enrichment analysis revealed that the functions of and its neighboring genes in patients with renal cell carcinoma are mainly related to cell adhesion molecule binding, catalytic activity, acting on RNA, ATPase activity, actin filament binding, protease binding, transcription coactivator activity, cysteine-type peptidase activity, and calmodulin binding. Transcription factor targets of and its neighboring genes in patients with renal cell carcinoma were found: HIF1A, TFAP2A, and ESR1 in KIRC; STAT3, NFKB1, and HIPK2 in KICH; and FOXO3, TFAP2A, and ETS1 in KIRP. We further explored the -associated kinase (ATM in KICH as well as CDK1 and AURKB in KIRP) and -associated microRNA (miRNA) targets (MIR-21 in KICH as well as MIR-213, MIR-383, and MIR-492 in KIRP). Furthermore, the following genes had the strongest correlation with expression in patients with renal cell carcinoma: , , and in KIRC; , , and in KICH; and , , and in KIRP. expression in patients with renal cell carcinoma was positively associated with immune cell infiltration, including CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells.

Conclusions: This study revealed expression and potential gene regulatory network in patients with renal cell carcinoma, thereby laying a foundation for further research on the role of in renal cell carcinoma occurrence. Moreover, the study provides new renal cell carcinoma therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.
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http://dx.doi.org/10.1177/17246008211063501DOI Listing
March 2022

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

Nat Commun 2020 10 16;11(1):5259. Epub 2020 Oct 16.

Center for Rare Melanomas, University of Colorado Cancer Center, Aurora, Colorado, USA.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
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http://dx.doi.org/10.1038/s41467-020-18988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567804PMC
October 2020

Using whole-genome sequencing data to derive the homologous recombination deficiency scores.

NPJ Breast Cancer 2020 7;6:33. Epub 2020 Aug 7.

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD Australia.

The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particular or deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicative of response to certain therapeutic strategies. Studies have used whole-exome sequencing to derive the HRD score, however, with increasing use of whole-genome sequencing (WGS) to characterise tumour genomes, there has yet to be a comprehensive comparison between HRD scores derived by array versus WGS. Here we demonstrate that there is both a high correlation and a good agreement between array- and WGS-derived HRD scores and between the scores derived from WGS and downsampled WGS to represent shallow WGS. For samples with an HRD score close to threshold for stratifying HR proficiency or deficiency there was however some disagreement in the HR status between array and WGS data, highlighting the importance of not relying on a single method of ascertaining the homologous recombination status of a tumour.
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http://dx.doi.org/10.1038/s41523-020-0172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414867PMC
August 2020

Hypercalcemia, hyperuricemia, and kidney dysfunction in a 35-month-old boy: Questions.

Pediatr Nephrol 2021 01 2;36(1):71-72. Epub 2020 Jun 2.

Department of Nephrology and Immunology, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou, Jiangsu Province, The People's Republic of China.

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http://dx.doi.org/10.1007/s00467-020-04601-8DOI Listing
January 2021

Hypercalcemia, hyperuricemia, and kidney dysfunction in a 35-month-old boy: Answers.

Pediatr Nephrol 2021 01;36(1):73-76

Department of Nephrology and Immunology, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou, Jiangsu Province, The People's Republic of China.

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http://dx.doi.org/10.1007/s00467-020-04603-6DOI Listing
January 2021

Acute pancreatitis and macrophage activation syndrome in pediatric systemic lupus erythematosus: case-based review.

Rheumatol Int 2020 May 3;40(5):811-819. Epub 2019 Aug 3.

Department of Nephrology and Immunology, Children's Hospital of Soochow University, 303, Jingde Road, Suzhou, Jiangsu, The People's Republic of China.

Pancreatitis is uncommon in systemic lupus erythematosus (SLE) and is rarely reported in children, possibly being related to macrophage activation syndrome (MAS). The incidence of MAS in children with lupus pancreatitis is unknown, as is their prognosis. In this case-based review, we report a pediatric patient with SLE complicated with pancreatitis and MAS, and performed a literature review. We report an 11-year-old girl with SLE and MAS who developed pancreatitis on the second day of methylprednisolone pulse therapy (500 mg/day). We continued methylprednisolone pulse therapy, and performed three rounds of DNA-immunoadsorption and three rounds of hemoperfusion. A second course of methylprednisolone pulse therapy was initiated 9 days later. The patient received a monthly cyclophosphamide pulse therapy (10 mg/kg/day, 2 consecutive days every month) for 6 months, after which she was treated with mycophenolate mofetil 20 mg/kg/day. The condition of the patient gradually improved, her blood amylase and lipase decreased. She was in a stable condition during 13-month follow-up period. Review of the literature of pediatric patients with SLE and pancreatitis showed that there are 127 cases that have been reported in the past 30 years, 40 cases were excluded in our study because of inadequate information. Of the 87 patients included in our literature review, the mortality rate was 33.33%, and 52.86% of the patients with pancreatitis had MAS at the same time. Pancreatitis is uncommon in SLE, but must be suspected if a patient with SLE develops digestive symptoms. Patients with SLE with pancreatitis have a high incidence of MAS and high mortality rate; however, early recognition and effective treatment can relieve the disease symptoms.
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http://dx.doi.org/10.1007/s00296-019-04388-4DOI Listing
May 2020

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Nat Commun 2019 07 18;10(1):3163. Epub 2019 Jul 18.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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http://dx.doi.org/10.1038/s41467-019-11107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639323PMC
July 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications.

J Pathol 2019 02 20;247(2):214-227. Epub 2018 Dec 20.

Department of Histopathology, Sullivan Nicolaides Pathology, Bowen Hills, Australia.

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5184DOI Listing
February 2019

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility.

Int J Cancer 2019 03 21;144(5):1049-1060. Epub 2018 Nov 21.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.
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http://dx.doi.org/10.1002/ijc.31791DOI Listing
March 2019

Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing.

PLoS One 2018 10;13(1):e0190264. Epub 2018 Jan 10.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studies have primarily utilised the Illumina HiSeq platforms. In this study we performed whole genome sequencing of three malignant pleural mesothelioma and matched normal samples using a new platform, the BGISEQ-500, and compared the results obtained with Illumina HiSeq X Ten. Germline and somatic, single nucleotide variants and small insertions or deletions were independently identified from data aligned human genome reference. The BGISEQ-500 and HiSeq X Ten platforms showed high concordance for germline calls with genotypes from SNP arrays (>99%). The germline and somatic single nucleotide variants identified in both sequencing platforms were highly concordant (86% and 72% respectively). These results indicate the potential applicability of the BGISEQ-500 platform for the identification of somatic and germline single nucleotide variants by whole genome sequencing. The BGISEQ-500 datasets described here represent the first publicly-available cancer genome sequencing performed using this platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190264PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761881PMC
February 2018

Whole-genome landscapes of major melanoma subtypes.

Nature 2017 05 3;545(7653):175-180. Epub 2017 May 3.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
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http://dx.doi.org/10.1038/nature22071DOI Listing
May 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

J Pathol 2015 Nov 19;237(3):363-78. Epub 2015 Aug 19.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
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http://dx.doi.org/10.1002/path.4583DOI Listing
November 2015

Whole-genome characterization of chemoresistant ovarian cancer.

Nature 2015 May;521(7553):489-94

Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.

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 overexpression of the drug efflux pump MDR1.
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http://dx.doi.org/10.1038/nature14410DOI Listing
May 2015

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nat Commun 2014 Oct 29;5:5224. Epub 2014 Oct 29.

QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
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http://dx.doi.org/10.1038/ncomms6224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596003PMC
October 2014

A workflow to increase verification rate of chromosomal structural rearrangements using high-throughput next-generation sequencing.

Biotechniques 2014 Jul 1;57(1):31-8. Epub 2014 Jul 1.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, QLD, Australia; Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.

Somatic rearrangements, which are commonly found in human cancer genomes, contribute to the progression and maintenance of cancers. Conventionally, the verification of somatic rearrangements comprises many manual steps and Sanger sequencing. This is labor intensive when verifying a large number of rearrangements in a large cohort. To increase the verification throughput, we devised a high-throughput workflow that utilizes benchtop next-generation sequencing and in-house bioinformatics tools to link the laboratory processes. In the proposed workflow, primers are automatically designed. PCR and an optional gel electrophoresis step to confirm the somatic nature of the rearrangements are performed. PCR products of somatic events are pooled for Ion Torrent PGM and/or Illumina MiSeq sequencing, the resulting sequence reads are assembled into consensus contigs by a consensus assembler, and an automated BLAT is used to resolve the breakpoints to base level. We compared sequences and breakpoints of verified somatic rearrangements between the conventional and high-throughput workflow. The results showed that next-generation sequencing methods are comparable to conventional Sanger sequencing. The identified breakpoints obtained from next-generation sequencing methods were highly accurate and reproducible. Furthermore, the proposed workflow allows hundreds of events to be processed in a shorter time frame compared with the conventional workflow.
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http://dx.doi.org/10.2144/000114189DOI Listing
July 2014

Somatic point mutation calling in low cellularity tumors.

PLoS One 2013 8;8(11):e74380. Epub 2013 Nov 8.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826759PMC
March 2015

Separation and characterization of the active species in Ti-doped NaAlH4.

Chem Commun (Camb) 2013 Mar;49(20):2046-8

Science and Technology on Surface Physics and Chemistry Laboratory, Mianyang, 621907, China.

The catalytic mechanism of doped complex hydrides for hydrogen storage remains unconfirmed. Here, we report a simple method to separate the active species of Ti-based catalysts in NaAlH(4) by filtration using tetrahydrofuran (THF) as solvent. The results show that the average particle size of the obtained Al-Ti active species is 30-50 nm.
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http://dx.doi.org/10.1039/c2cc38553hDOI Listing
March 2013

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Nature 2012 Nov 24;491(7424):399-405. Epub 2012 Oct 24.

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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http://dx.doi.org/10.1038/nature11547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898PMC
November 2012

qpure: A tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles.

PLoS One 2012 25;7(9):e45835. Epub 2012 Sep 25.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland, Australia.

Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH) in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001) between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16) between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004) between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457972PMC
May 2013

A facile method for gold decoration of [email protected] nanorods in aqueous solution.

J Colloid Interface Sci 2012 Oct 22;383(1):43-8. Epub 2012 Jun 22.

Advanced Photonics Center, School of Electronic Science and Engineering, Southeast University, Nanjing 210096, China.

Colloidal synthesis of metal-semiconductor hybrid nanostructures is mainly achieved in organic solution. In some applications of hybrid nanoparticles relevant in aqueous media, phase transfer of hydrophobic metal-semiconductor hybrid nanostructures is essential. In this work, we present a simple method for direct synthesis of water-soluble gold (Au) decorated [email protected] hybrid nanorods (NRs) at room temperature by using aqueous [email protected] NRs as templates, which were preformed by using CdTe nanocrystals (NCs) as precursor in the presence of hydrazine hydrate (N(2)H(4)). Our results showed that NRs were decorated with Au islands both on tips and along the surface of the NRs. The size and density of Au islands can be controlled by varying the amount of Au precursor (mixture of HAuCl(4) and thioglycolic acid (TGA)) and TGA/HAuCl(4) ratio. A possible growth mechanism for the Au decoration of [email protected] NRs is concluded as three steps: (1) the formation of AuTe(1.7) via the substitution reaction of Cd(2+) by Au(3+), (2) adsorption of Au-TGA complex onto the preformed AuTe(1.7) anchors and following reduction by CdTe and N(2)H(4), leading to the formation of small Au NCs, (3) Au NCs grow to bigger ones, followed by reduction of more Au precursor by N(2)H(4).
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http://dx.doi.org/10.1016/j.jcis.2012.06.016DOI Listing
October 2012

Henoch-Schönlein purpura with hypocomplementemia.

Pediatr Nephrol 2012 May 21;27(5):801-6. Epub 2012 Jan 21.

Department of Nephrology, Children's Hospital Affiliated to Soochow University, Suzhou 215003, Jiangsu Province, The People's Republic of China.

Background: Abnormalities of the complement system in Henoch-Schönlein purpura (HSP) have been reported, but how this abnormality in the complement system impacts on the prognosis of HSP remains unknown.

Methods: We retrospectively studied patients hospitalized for HSP in the Children's Hospital Affiliated to Soochow University between October 2010 and May 2011. Patients with HSP and hypocomplementemia were the cases, and those without hypocomplementemia were the HSP controls. Another group of children (n = 50) with upper respiratory tract infections, but without HSP acted as negative controls.

Results: A total number of 338 HSP patients were included in this study (n = 53 cases, n = 285 controls). In the cases, C3 and C4 levels decreased in 29 patients, C3 was low in 6, and C4 in 18. Complement levels returned to normal within 3 months in all HSP patients except one. Case group patients had higher levels of serum IgG and arthralgia, as well as positive titers of antistreptolysin-O. Rates of abdominal pain, gastrointestinal bleeding, Henoch-Schönlein purpura nephritis (HSPN), and serum IgA and IgM levels were similar in the two HSP groups.

Conclusion: Hypocomplementemia associated with HSP is a transient phenomenon. The incidence of significant sequelae such as HSPN between patients with and without hypocomplementemia does not differ.
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http://dx.doi.org/10.1007/s00467-011-2070-zDOI Listing
May 2012

MicroRNAs and their isomiRs function cooperatively to target common biological pathways.

Genome Biol 2011 Dec 30;12(12):R126. Epub 2011 Dec 30.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.

Background: Variants of microRNAs (miRNAs), called isomiRs, are commonly reported in deep-sequencing studies; however, the functional significance of these variants remains controversial. Observational studies show that isomiR patterns are non-random, hinting that these molecules could be regulated and therefore functional, although no conclusive biological role has been demonstrated for these molecules.

Results: To assess the biological relevance of isomiRs, we have performed ultra-deep miRNA-seq on ten adult human tissues, and created an analysis pipeline called miRNA-MATE to align, annotate, and analyze miRNAs and their isomiRs. We find that isomiRs share sequence and expression characteristics with canonical miRNAs, and are generally strongly correlated with canonical miRNA expression. A large proportion of isomiRs potentially derive from AGO2 cleavage independent of Dicer. We isolated polyribosome-associated mRNA, captured the mRNA-bound miRNAs, and found that isomiRs and canonical miRNAs are equally associated with translational machinery. Finally, we transfected cells with biotinylated RNA duplexes encoding isomiRs or their canonical counterparts and directly assayed their mRNA targets. These studies allow us to experimentally determine genome-wide mRNA targets, and these experiments showed substantial overlap in functional mRNA networks suppressed by both canonical miRNAs and their isomiRs.

Conclusions: Together, these results find isomiRs to be biologically relevant and functionally cooperative partners of canonical miRNAs that act coordinately to target pathways of functionally related genes. This work exposes the complexity of the miRNA-transcriptome, and helps explain a major miRNA paradox: how specific regulation of biological processes can occur when the specificity of miRNA targeting is mediated by only 6 to 11 nucleotides.
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http://dx.doi.org/10.1186/gb-2011-12-12-r126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334621PMC
December 2011
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