An Investigation of Mutational Signatures in the Evolution of Oesophageal adenocarcinoma
type: CreativeWork
description: An Investigation of Mutational Signatures in the Evolution of Oesophageal adenocarcinoma Sujath Abbas Oesophageal adenocarcinoma (OAC) remains a public health challenge with dismal survival rates and increasing incidence. This PhD study aimed to investigate how mutational processes act across different stages of OAC development and in metastasis for better understanding of the influence of mutational forces during tumour formation. To identify these signatures in clinical samples this study also aimed to develop a cost-effective DNA sequencing method in clinical formalin fixed OAC samples. A large study cohort was assembled comprising of 161 Barrett’s, 777 OAC primary tumours and 59 metastatic samples. Mutational signature analysis revealed 14 distinct single base substitution (SBS) mutational signatures in these genomes, SBS17b/a were most prevalent and presented early in Barrett’s. Traces of BER (SBS30), MMR(SBS44) and colibactin associated signature (SBS41) were uncovered for the first time, as well as a platinum signature (SBS35). Mostly signatures increased in their proportions from Barrett’s to invasive tumours and further in metastasis. SBS17 showed strong bias towards untranscribed and lagging strands. Nucleosome periodicity patterns were similar across the stages and SNVs were enriched in the inward facing minor groove suggesting a common mutational process throughout the disease evolution. Evaluation of evolutionary bottlenecks uncover a distinct SBS17b shift, with a decrease sub-clonally in Barrett’s, OACs and metastasis and this was by far the most dominant signal during OAC evolution. Clinical risk factors including alcohol, smoking and NSAIDs were positively correlated with signature proportions. APOBEC and colibactin processes were informative for Barrett’s and OAC classification, suggesting a role in transformation, and the BER signature (SBS30) was most prognostic in our cohort. Given that signatures have the potential to be clinically informative, …
abstract: An Investigation of Mutational Signatures in the Evolution of Oesophageal adenocarcinoma Sujath Abbas Oesophageal adenocarcinoma (OAC) remains a public health challenge with dismal survival rates and increasing incidence. This PhD study aimed to investigate how mutational processes act across different stages of OAC development and in metastasis for better understanding of the influence of mutational forces during tumour formation. To identify these signatures in clinical samples this study also aimed to develop a cost-effective DNA sequencing method in clinical formalin fixed OAC samples. A large study cohort was assembled comprising of 161 Barrett’s, 777 OAC primary tumours and 59 metastatic samples. Mutational signature analysis revealed 14 distinct single base substitution (SBS) mutational signatures in these genomes, SBS17b/a were most prevalent and presented early in Barrett’s. Traces of BER (SBS30), MMR(SBS44) and colibactin associated signature (SBS41) were uncovered for the first time, as well as a platinum signature (SBS35). Mostly signatures increased in their proportions from Barrett’s to invasive tumours and further in metastasis. SBS17 showed strong bias towards untranscribed and lagging strands. Nucleosome periodicity patterns were similar across the stages and SNVs were enriched in the inward facing minor groove suggesting a common mutational process throughout the disease evolution. Evaluation of evolutionary bottlenecks uncover a distinct SBS17b shift, with a decrease sub-clonally in Barrett’s, OACs and metastasis and this was by far the most dominant signal during OAC evolution. Clinical risk factors including alcohol, smoking and NSAIDs were positively correlated with signature proportions. APOBEC and colibactin processes were informative for Barrett’s and OAC classification, suggesting a role in transformation, and the BER signature (SBS30) was most prognostic in our cohort. Given that signatures have the potential to be clinically informative, …
author: Abbas, Sujath
language: eng
keywords: Mutational Signatures, Oesophageal adenocarcinoma
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-10-30
date modified: 2026-07-22T22:24:10Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.82082