1. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Weaver JM, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M4, Murtaza M, Ong CA, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O'Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavaré S, Fitzgerald RC. OCCAMS Consortium. Nat Genet. 2014 Aug: 46(8):837-43
Summary of key findings: In order to study the order of mutations in carcinogenesis we used our ICGC data to identify a panel of 26 genes that were either mutated significantly above the background rate, or were in pathways of interest. We then asked when in the progression sequence from Barrett’s to dysplasia and adenocarcinoma these alterations occur. For the never-dysplastic cohort (median follow-up time 58 months, range 4-132), 21/40 (53%) patients were found to have mutations and importantly these occurred in several genes previously identified as drivers in OAC and other cancers, including SMARCA4, ARID1A, and CNTNAP5. Of the 43 high grade dysplasia (HGD) biopsy samples, 39 (91%) were found to have mutations in at least one of the genes. Hence, for the vast majority of genes the mutational frequency was not significantly different between never-dysplastic Barrett’s, HGD and OAC. Only TP53 (p<0.0001) and SMAD4 (p=0.0061) exhibited mutational frequencies that would distinguish between disease stages and thus identify progression towards malignancy. However, SMAD4 mutation occurs in only 13% cases. Hence, we have identified TP53 mutation detection as being critical for early diagnostic tests and we also showed proof of principle data that TP53 mutations can be detected on material obtained from our novel sampling device the Cytosponge which is also a CRUK funded project.
2. Novel insights from whole genome sequencing on clonal heterogeneity in Barrett’s carcinogenesis Caryn S. Ross-Innes, Jennifer Becq, Andrew Warren, R. Keira Cheetham, Helen Northen, Maria O’Donovan, Shalini Malhotra, Sergii Ivakhno, Miao He, Jamie M.J. Weaver, Andy G. Lynch, Zoya Kingsbury, Mark Ross, Sean Humphray, David Bentley, Rebecca C. Fitzgerald on behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group. Nat Genet. In press 2015
Summary of key findings: Using whole-genome sequencing on 23 paired Barrett’s and oesophageal adenocarcinoma samples, together with one in-depth BE case-study sampled over time and space, we have provided new insights on the following aspects: i) BE is polyclonal and highly mutated even in the absence of dysplasia; ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between cancer and adjacent Barrett’s; and iii) despite differences in specific coding mutations the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective we also found that, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett’s epithelium.
This paper was submitted as a back-to-back publication with Adam Bass’ group at the Broad Institute.
3. Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis. Anna L. Paterson, Jamie M.J. Weaver, Matthew D. Eldridge, Simon Tavaré, Rebecca C. Fitzgerald, Paul A.W. Edwards on behalf of the OCCAMS Consortium. Manuscript BMC Genomics 2015 16:473
Summary of key findings: 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. Overall we found approximately 100 such inserts were detected per tumour on average (range zero to approximately 700), 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.
Abstracts submitted to conferences
Ayesha Noorani et al on behalf of the OCCAMS Consortium. Whole Genome Sequencing of oesophageal adenocarcinoma: a progress update of the OCCAMS project. Winning poster: Association of Upper GI Surgeons in September 2014
J Weaver et al on behalf of the OCCAMS Consortium. The timing of oncogenic events in the evolution of the oesophageal adenocarcinoma genome and implications for clinical diagnostics. Winning talk: July 2014, 108th annual meeting of the Association of Physicians of Great Britain and Ireland, Cambridge, UK
RC Fitzgerald on behalf of the OCCAMS ICGC Genomic landscape of oesophageal adenocarcinoma following neo-adjuvant chemotherapy – important lessons from an undervalued resource Oral presentation at ICGC Workshop Feb 15-17, Verona 2015
J Weaver et al on behalf of the OCCAMS Consortium. The timing of oncogenic events in the evolution of the oesophageal adenocarcinoma genome and implications for clinical diagnostics. Poster of distinction: June 2014, British Society of Gastroenterology annual meeting 2014, Manchester, UK
R Fels-Elliott on behalf of the OCCAMS Consortium. The Toll-like receptor pathway is recurrently mutated in oesophageal adenocarcinoma. Best Oral Presentation in the Oesophagus/Stomach/Duodenum category, June 2014. British Society for Gastroenterology, Manchester, UK
A. Noorani on behalf of the OCCAMS Consortium. Novel insights into metastatic spread of oesophageal adenocarcinoma from whole genome sequencing data. Poster of distinction, DDF 2015, London, June 2015 and first prize poster, Barrett’s Symposium, London April 2015.
A. Noorani on behalf of the OCCAMS Consortium. Novel insights into metastatic spread of oesophageal adenocarcinoma from whole genome sequencing. Prize winning oral presentation, Cold Spring Harbor meeting, China, May 2015
R Fels-Elliott on behalf of the OCCAMS Consortium. TLR signaling is dysregulated in oesophageal adenocarcinoma through somatic mutations. Accepted Oral presentation, Award Winner, United European Gastroenterology Week, Barcelona, Spain, November 2015
A. Noorani on behalf of the OCCAMS Consortium. Reconstructing the evolutionary history of metastatic oesophageal adenocarcinoma using Whole Genome Sequencing. Oral presentation and Travel Prize United European Gastroenterology Week, Barcelona, Spain, November 2015