An Investigation of Mutational Signatures in the Evolution of Oesophageal adenocarcinoma


Type
Thesis
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Authors
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, a novel cost-effective DNA sequencing method to extract mutational signatures from archival FFPE tissues was developed successfully. Computational simulations on pan-cancer WGS and an experimental confirmation of the method showed very good concordance and mirrored the WGS-derived signatures (cosine similarity >0.9%). It is hoped that this work will pave the way for further studies to understand how mutations are laid down and determine their clinical application.

Description
Date
2021-10-30
Advisors
Fitzgerald, Rebecca
Keywords
Mutational Signatures, Oesophageal adenocarcinoma
Qualification
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge