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Title: A compendium of genetic drivers for oesophageal adenocarcinoma defines prognostic and therapeutic biomarkers for use in the clinic
Author: Frankell, Alexander Mark
ISNI:       0000 0004 7962 0324
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Background: Oesophageal adenocarcinoma (OAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving OAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. This study aimed to use a large cohort of genomically characterised OACs to determine the landscape of genetic driver events in OAC and their possible clinic uses. Methods: We have collated a cohort of 551 genomically characterized OACs (398 whole genome sequenced and 153 whole exome sequenced) with a sub-cohort matched to RNA sequencing data (116 cases). Strelka, Manta and ASCAT were used to call SNVs and indels, structural variants and copy number aberrations respectively. A suite of published tools was used to detect regions of the genome under positive selection for mutations in OAC including dNdScv, Mutsigcv, OncodriveFM and others. Copy number drivers were identified using GISTIC and correlations with matched expression data. Univariate and Multivariate cox regressions were used to identify prognostic biomarkers. Treatment of In vitro cultures of human OAC cell lines and organoids with a range of targeted therapeutics was used to calculate AUCs and GI50s for various drugs in OAC models. These sensitivities were matched to the genomic background in these cell lines, provided by whole genome sequencing. Results: We discovered 77 putative OAC driver genes and 21 putative noncoding driver elements for OAC. We identified a mean of 4.4 driver events per tumour, which were derived more commonly from mutations than copy number alterations and compared the prevalence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated OAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of OACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of OAC cell lines and organoids. In a smaller panel of OACs we also saw evidence for specificity of BET inhibitor efficacy to MYC amplified OACs, however did not observe responses to EZH2 inhibitors, designed to target SWI/SNF mutated cancers, even upon induction of these mutations using CRISPR-Cas9. Discussion: We have complied the most comprehensive analysis to date of positively selected genomic elements in OAC, significantly improving upon previous analyses. We use this to identify prognostic and therapeutic biomarkers with considerable potential clinical value. Limitation to this study include a lack of RNA sequencing on all samples, making it difficult to assess selection for low-frequency copy number events. Future directions include functional investigation of many of the novel driver genes identified and prospective validation of clinical biomarkers in the Oelixir trial, including use of CDK4/6 inhibitors in OAC patients.
Supervisor: Fitzgerald, Rebecca C. Sponsor: Medical Research Council ; CRUK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Cancer genomics ; Oesophgeal cancer ; Cancer evolution ; Biomarkers ; CDK4/6 inhibitors