Deciphering Genomic Evolution: From Early Breast Cancer Stages to Invasive Carcinoma

This dissertation investigates the evolution of ductal carcinoma in situ (DCIS) to invasive forms such as invasive ductal carcinoma (IDC) at the individual patient level. DCIS is considered a non-obligatory precursor of IDC, being the predominant form of breast cancer detected and comprising approximately 80% of all diagnosed breast cancers. This project presents an opportunity to investigate the initial stages of breast cancer development and its progression from normal milk duct cells to invasive neoplastic forms. Through computational analyses and re-processing of a cohort of 394 broadly distributed genome samples from 77 patients, including normal milk duct, benign, atypical, DCIS, and IDC, this project aims to illuminate the genomic diversity, mutational exposures, and evolution of normal human duct milk cells and to characterize the major evolutionary forces that operate in a short space of time to develop invasive forms. This dissertation is structured in five chapters. The first chapter introduces the concepts of evolution and clonality, among the different classifications, and the early history of breast cancer treatment, ending with a discussion of the necessity to advance through early prediction. The second chapter describes the sample collection, processing, and sequencing process. Identification of issues with the sequencing data led to the development of a new computational approach to curating the data, aiming to achieve a gold standard for the processed samples. This chapter also investigates preliminary exploratory analyses of the discovered somatic variants and discusses the potential for missing data. The third chapter explores the mutational patterns assigned to mutational processes in the early stages of breast cancer development, including the exploration of potential endogenous and exogenous sources of mutation. The fourth chapter presents the methodology and results of somatic phylogenetic analyses, including reconstruction of the relationship between annotated pathological tissue types and the phylogenetic distribution of previously identified mutational signatures. The last and final chapter presents the conclusions and future directions of the research. Overall, this work traces the genomic evolution of early breast cancer stages, giving a snapshot of the complex forces, mutagenic exposures, and driver genes at the patient level and highlighting the need for larger cohorts, personalized treatment and evolution-assisted prediction.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Franco Alvarez, Jose

Advisors dc:contributor.advisor

• Rebbeck, Clare
• Markowetz, Florian

• Breast Cancer Evolution
• Cancer Genomics
• Cancer Progression
• Ductal Carcinoma In Situ
• Phylogenetic Analysis

Licence

• https://www.repository.cam.ac.uk/bitstreams/4738dee2-ba02-4ecd-8450-8e7135ba0a10/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.113437

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/376063