ORCID Profile
0000-0002-2832-1303
Current Organisations
Royal National Orthopaedic Hospital - Stanmore
,
London Sarcoma Service
,
National Institute for Health Research
,
Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
,
University College London
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Publications
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma
Publisher: American Medical Association (AMA)
Date: 05-2020
Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 09-2005
DOI: 10.1158/0008-5472.CAN-05-1855
Abstract: Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (∼1.3 Mb of DNA per s le) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were “passenger” mutations that are not causally implicated in oncogenesis. However, an excess of ∼40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between in idual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G & A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
Genome‐wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients
Publisher: Wiley
Date: 23-12-2017
DOI: 10.1002/IJC.31195
Pan-cancer analysis of whole genomes
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma
Publisher: American Association for Cancer Research (AACR)
Date: 09-2015
DOI: 10.1158/2159-8290.CD-15-0125
Abstract: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10−9 OR, 2.43 95% confidence interval, 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene. Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma. Cancer Discov 5(9) 920–31. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 893
A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer
Publisher: Springer Science and Business Media LLC
Date: 22-05-2005
DOI: 10.1038/NG1571
Abstract: We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per s le, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.
Processed pseudogenes acquired somatically during cancer development
Publisher: Springer Science and Business Media LLC
Date: 09-04-2014
DOI: 10.1038/NCOMMS4644
Abstract: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer s les for somatically acquired pseudogenes. We find 42 events in 17 s les, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA , abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially erse functional consequences depending on genomic context.
Diagnostic classification of childhood cancer using multiscale transcriptomics
Publisher: Springer Science and Business Media LLC
Date: 03-2023
DOI: 10.1038/S41591-023-02221-X
Abstract: The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were ided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional ersity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.
Hypoxia stimulates osteoclast formation from human peripheral blood
Publisher: Wiley
Date: 15-06-2010
DOI: 10.1002/CBF.1660
Abstract: Active pathological bone destruction in humans often occurs in locations where oxygen tension (pO(2)) is likely to be low, for ex le, at the sites of tumours, inflammation, infections and fractures, or the poorly vascularized yellow fatty marrow of the elderly. We examined the effect of pO(2) on formation of osteoclasts, the cells responsible for bone resorption, in 14-day cultures of normal human peripheral blood mononuclear cells (hPBMCs) on ivory discs. Hypoxia (1-2% O(2)) caused threefold increases in the number of osteoclasts formed, compared with 20% O(2). Hypoxia also caused a twofold increase in the number of nuclei per osteoclast, leading to stimulations of resorption pit formation of up to 10-fold. Exposure to hypoxia led to stabilization of the hypoxia-inducible factors, HIF1alpha and HIF2alpha, and upregulation of vascular endothelial growth factor and interleukin-6 expression by hPBMCs. These findings help explain why extravasation of mononuclear precursors into relatively O(2)-deficient bone microenvironments could result in osteoclast formation and suggest a new mechanism for the bone loss associated with the pathophysiological conditions where hypoxia commonly occurs.
BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals
Publisher: Springer Science and Business Media LLC
Date: 11-04-2008
DOI: 10.1038/CDD.2008.42
Genome-wide association study identifies two susceptibility loci for osteosarcoma
Publisher: Springer Science and Business Media LLC
Date: 02-06-2013
DOI: 10.1038/NG.2645
Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2015
Abstract: Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.
Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer
Publisher: eLife Sciences Publications, Ltd
Date: 10-2014
DOI: 10.7554/ELIFE.02935
Abstract: Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C T and A G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
Related Organisations
St George's Hospital
Location: United Kingdom of Great Britain and Northern Ireland
University College London Hospitals NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
Royal National Orthopaedic Hospital - Stanmore
Location: United Kingdom of Great Britain and Northern Ireland
St Bartholomew's Hospital
Location: United Kingdom of Great Britain and Northern Ireland
London Sarcoma Service
Location: United Kingdom of Great Britain and Northern Ireland
National Institute For Health Research
Location: United Kingdom of Great Britain and Northern Ireland
Robert Jones And Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
Royal National Orthopaedic Hospital NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
University College London
Location: United Kingdom of Great Britain and Northern Ireland
Altnagelvin Area Hospital
Location: United Kingdom of Great Britain and Northern Ireland
Hammersmith Hospital
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College Healthcare NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College London Faculty Of Medicine
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Adrienne Flanagan.