Publications by authors named "Anna L Paterson"

11 Publications

  • Page 1 of 1

Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.

Cells 2020 02 14;9(2). Epub 2020 Feb 14.

Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Torino, Italy.

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a variant in PDXs from a high grade serous EOC. Allele frequencies of in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of and addiction of carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.
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http://dx.doi.org/10.3390/cells9020442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072782PMC
February 2020

Role of TFF3 as an adjunct in the diagnosis of Barrett's esophagus using a minimally invasive esophageal sampling device-The Cytosponge.

Diagn Cytopathol 2020 Mar 9;48(3):253-264. Epub 2019 Dec 9.

Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

The incidence of esophageal carcinoma continues to increase whilst its prognosis remains poor. The most dramatic reduction in mortality is likely to follow early diagnosis of the preinvasive precursor lesion, Barrett's esophagus (BE), coupled with treatment of dysplastic lesions. The major risk factor for BE is gastroesophageal reflux disease, however this is highly prevalent and only a small proportion of individuals have BE, therefore an endoscopy-based screening strategy to detect BE is unfeasible. Minimally invasive esophageal sampling devices offer an alternative, cost-effective strategy which can be deployed within an at-risk population in a primary care setting to identify individuals with probable BE who can then be referred for endoscopic confirmation. The device that has currently progressed furthest in clinical trials is the Cytosponge which collects cells from the gastric cardia, gastroesophageal junction and along the whole esophageal length. The cell sample is processed into a formalin-fixed paraffin-embedded block and sections assessed for the presence of intestinal metaplasia. TFF3 immunohistochemistry has consistently been shown to be a valuable adjunct that increases the accuracy of the Cytosponge test by highlighting early goblet cells which may be missed on morphological assessment and by allowing pseudogoblet cells to be differentiated from true goblet cells.
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http://dx.doi.org/10.1002/dc.24354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075710PMC
March 2020

The role and contribution of clonality studies in the diagnosis of lymphoproliferative disorders.

Eur J Haematol 2019 Jun 28;102(6):472-478. Epub 2019 Mar 28.

Haematopathology and Oncology Diagnostics Service, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Objectives: To explore the frequency, context and diagnostic impact of B- and T-lymphocyte clonality assay use in the assessment of possible lymphoproliferative disorders at a central haematopathology diagnostics hub.

Methods: All cases reported by haematopathologists over a sixteen-month period were identified, n = 4462, and those which had clonality studies undertaken analysed further.

Results: Clonality studies were requested in 9% of cases, directly contributing to a diagnosis being made in 79%. They were most frequently used to help distinguish reactive lymphoid infiltrates from low-grade B-cell lymphomas and in cases of possible T-cell lymphoma, facilitating a diagnosis being made in over 90% of these. In contrast when clonality assays were requested as a diagnostic adjunct in cases with an atypical cutaneous lymphoid infiltrate, and in occasional cases of lymphoid proliferations with Hodgkin-like cells or EBV-driven proliferations, a definitive final diagnosis was possible in less than 60% of cases.

Conclusions: Clonality studies were used in 9% of cases assessed for a possible lymphoproliferative disorder and had a differing impact depending on the differential diagnoses being considered. These findings can be used to guide access to clonality assays by highlighting the likelihood of an informative result in different diagnostic settings.
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http://dx.doi.org/10.1111/ejh.13228DOI Listing
June 2019

Contribution of immunoglobulin lambda light chain gene rearrangement analysis in the diagnosis of B-cell neoplasms.

Br J Haematol 2019 04 25;185(2):261-265. Epub 2019 Jan 25.

Haematopathology and Oncology Diagnostics Service, Addenbrooke's Hospital, Cambridge University NHS Foundation Trust, Cambridge, UK.

Identification of clonal IGH, IGK and IGL gene rearrangements offers diagnostic adjunct in suspected B-cell neoplasms. However, many centres omit IGL analysis as its value is uncertain. A review of 567 cases with IGH, IGK and IGL rearrangement assessed using BIOMED-2 assays showed clonal immunoglobulin gene rearrangement in 54% of cases, of which 24% had a clonal IGL rearrangement. In two cases, the clonal rearrangement was detected exclusively by IGL analysis. This finding demonstrates the added value of IGL analysis for clonality assessment, especially in suspected B-cell neoplasms in which a clonal IGH and/or IGK rearrangement is not detected or is equivocal.
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http://dx.doi.org/10.1111/bjh.15762DOI Listing
April 2019

Range of pathologies diagnosed using a minimally invasive capsule sponge to evaluate patients with reflux symptoms.

Histopathology 2017 Jan 12;70(2):203-210. Epub 2016 Oct 12.

MRC Cancer Unit, Hutchison-MRC Research Centre, Cambridge, UK.

Aims: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms.

Methods And Results: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411). All patients were investigated using the Cytosponge and endoscopy. Significant epithelial inflammation was present in 130 (16%) Cytosponge samples, 32 of which had ulcer slough. Candida and significant inflammation was detected in a further 22 (2.3%) cases; epithelial infiltration with >15 eosinophils/high-power field reflecting possible eosinophilic oesophagitis (EOE) in five (0.6%); and viral inclusions suggestive of herpes oesophagitis in one (0.1%). No significant pathology was detected in the majority, 662 (81%), of Cytosponge samples. Cytosponge and endoscopy findings were in agreement in 574 (70%) cases, in 165 (67%) of the discordant cases one investigation showed mild inflammation while the other was negative, with an additional 22 (8.9%) differing on the extent of inflammation. Eighteen cases with severe inflammation, six with candida and two with EOE were detected only at endoscopy, while 18 with candida and significant inflammation, 13 with ulcer slough, one probable EOE and one viral oesophagitis were identified on the Cytosponge only.

Conclusions: The Cytosponge detects a range of benign oesophageal pathologies, and therefore has potential clinical utility in the triaging of patients with troublesome reflux symptoms. This warrants further investigation.
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http://dx.doi.org/10.1111/his.13039DOI Listing
January 2017

Any value in a specialist review of liver biopsies? Conclusions of a 4-year review.

Histopathology 2016 Aug 15;69(2):315-21. Epub 2016 Mar 15.

Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Aims: Liver pathology is a challenging subspeciality, with histopathologists frequently seeking specialist opinions. This study aims to determine the impact of specialist reviews on the final diagnosis and patient management.

Methods And Results: Agreement with the initial reporting centre in the histopathological diagnosis of 1265 liver biopsies was determined. The nature of differences was explored in more depth for 103 discrepant cases. Differences in the histopathological interpretation were present in 749 of 1265 (59%) biopsies, of which 505 of 749 (67%) were predicted at the time of reporting to impact upon patient management. Agreement was good in cases with chronic viral hepatitis, fatty liver disease, malignancy and minimal pathological changes, while diagnostic differences occurred in more than 70% with biliary disease, autoimmune hepatitis or vascular/architectural changes. A clinical review of a subset of reports with histopathological differences predicted changes in patient management in 63 of 103 (61%).

Conclusions: Clinically significant differences in liver biopsy interpretation between local pathologists and subspecialists are common. Diagnoses with frequent discrepancies, such as biliary disease, may benefit from a specialist review as standard when diagnosed initially, while cases requiring specialist advice from disease subgroups where discrepancies are less common, such as chronic viral hepatitis, could be selected during the clinicopathological conference process.
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http://dx.doi.org/10.1111/his.12940DOI Listing
August 2016

Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis.

BMC Genomics 2015 Jul 10;16:473. Epub 2015 Jul 10.

Department of Pathology, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK.

Background: Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes.

Results: While analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring L1s, both L1s in the reference genome and L1s not present in the reference. Many of the resulting inserts were small fragments that include little or no recognisable mobile element sequence. We found 6 loci in the reference genome to which sequence reads from inserts were frequently mapped, probably erroneously, by alignment software: these were either L1 sequence or particularly long polyA runs. Inserts identified from such apparent rearrangement junctions averaged 16 inserts/tumour, range 0-153 insertions in 43 tumours. However, many inserts would not be detected by mapping the sequences to the reference genome, because they do not include sufficient mappable sequence. To estimate total somatic inserts we searched for polyA sequences that were not present in the matched normal or other normals from the same tumour batch, and were not associated with known polymorphisms. Samples of these candidate inserts were verified by sequencing across them or manual inspection of surrounding reads: at least 85 % were somatic and resembled L1-mediated events, most including L1Hs sequence. Approximately 100 such inserts were detected per tumour on average (range zero to approximately 700).

Conclusions: Somatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end sequencing data.
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http://dx.doi.org/10.1186/s12864-015-1685-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498532PMC
July 2015

A systematic approach to therapeutic target selection in oesophago-gastric cancer.

Gut 2013 Oct 6;62(10):1415-24. Epub 2012 Jul 6.

MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK.

Objective: The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas.

Design: Gene expression profiling from oesophago-gastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46).

Results: MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages (p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs.

Conclusions: The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy.
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http://dx.doi.org/10.1136/gutjnl-2012-302039DOI Listing
October 2013

Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis.

J Pathol 2013 May 22;230(1):118-28. Epub 2013 Mar 22.

MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

Despite being common in epithelial malignancies, the timing of receptor tyrosine kinase (RTK) up-regulation is poorly understood and therefore hampers the identification of the receptor to target for effective treatment. We aimed to determine if RTK expression changes were early events in carcinogenesis. Oesophageal adenocarcinoma and its pre-invasive lesion, Barrett's oesophagus, were used for immunohistochemical analysis of the RTK panel, EGFR, ErbB2, ErbB3, Met, and FGFR2, by utilizing a cohort of patients with invasive disease (n = 367) and two cohorts with pre-invasive disease, one cross-sectional (n = 110) and one longitudinal in time (n = 91). The results demonstrated that 51% of oesophageal adenocarcinomas overexpressed at least one of the RTK panel, with 21% of these overexpressing multiple receptors. Up-regulation of RTK expression was an early event corresponding with low-grade dysplasia development (25% in areas without dysplasia versus 63% in low-grade dysplasia, p < 0.001). There was a trend for an increase in the prevalence of concomitant overexpression of multiple receptors as intestinal metaplasia progressed to low-grade dysplasia, 7% versus 10%; and from low-grade dysplasia to high-grade dysplasia, 10% versus 19% (p = 0.06 and 0.24, respectively). The timing of receptor up-regulation varied; FGFR, ErbB2, and Met overexpression occurred as dysplasia first developed, whilst EGFR overexpression was predominately seen in invasive disease and ErbB3 overexpression was uniformly rare. We provide evidence for a frequent and early role for multiple different RTKs in oesophageal carcinogenesis. Given the early timing of receptor deregulation, inhibiting RTKs in pre-invasive disease may also represent a novel and effective chemopreventive strategy.
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http://dx.doi.org/10.1002/path.4044DOI Listing
May 2013

Biomarkers in Barrett's oesophagus and oesophageal adenocarcinoma.

Expert Opin Med Diagn 2007 Nov;1(3):363-76

MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK +44 1223 763287 ; +44 1223 763296 ;

Barrett's oesophagus is a well-recognised premalignant lesion for oesophageal adenocarcinoma. It is present in 1 - 2% of the general population, and 2 - 5% of those with gastro-oesophageal reflux disease. The majority of Barrett's cases within the population are undiagnosed, consequently most cases of oesophageal adenocarcinoma arise de novo. The incidence of oesophageal adenocarcinoma has increased by more than sixfold in the last 30 years. However, most patients with Barrett's oesophagus will not develop oesophageal adenocarcinoma. The major focus of biomarker research in Barrett's oesophagus is to find a marker that is able to identify patients at the highest risk of progressing to adenocarcinoma. Other potential roles include increasing the sensitivity of minimally invasive screening tests to identify patients with Barrett's oesophagus and predicting which patients are most likely to benefit from chemoprevention and endoscopic therapies. In established oesophageal adenocarcinoma, biomarkers would be able to individualise patient management by providing valuable information on patient prognosis and their suitability for novel targeted therapies. This review aims to explore the potential roles of biomarkers in Barrett's oesophagus and oesophageal adenocarcinoma, focusing on the most extensively studied candidates and future novel developments.
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http://dx.doi.org/10.1517/17530059.1.3.363DOI Listing
November 2007

Co-amplification of 8p12 and 11q13 in breast cancers is not the result of a single genomic event.

Genes Chromosomes Cancer 2007 May;46(5):427-39

Hutchison-MRC Research Centre, Department of Pathology, University of Cambridge, Cambridge, UK.

Epithelial cancers frequently have multiple amplifications, and particular amplicons tend to occur together. These co-amplifications have been suggested to result from amplification of pre-existing junctions between two chromosomes, that is, translocation junctions. We investigated this hypothesis for two amplifications frequent in breast cancer, at 8p12 and 11q13, which had been reported to be associated in Southern blot studies. We confirmed that both genomic amplification and expression of genes was correlated between the frequently-amplified regions of 8p and 11q, in array CGH and microarray expression data, supporting the importance of co-amplification. We examined by FISH the physical structure of co-amplifications that we had identified by array CGH, in five breast cancer cell lines (HCC1500, MDA-MB-134, MDA-MB-175, SUM44, and ZR-75-1), four breast tumors, and a pancreatic cancer cell line (SUIT2). We found a variety of arrangements: amplification of translocation junctions; entirely independent amplification of the two regions on separate chromosomes; and separate amplification of 8p and 11q sequences in distinct sites on the same rearranged chromosome. In this last arrangement, interphase nuclei often showed intermingling of FISH signals from 8p12 and 11q13, giving a false impression that the sequences were interdigitated. We conclude that co-amplification of the main 8p and 11q amplicons in breast tumors is not usually the result of a preceding translocation event but most likely reflects selection of clones that have amplified both loci. This article contains supplementary material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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http://dx.doi.org/10.1002/gcc.20424DOI Listing
May 2007