Genomic Pathology: from DNA mutations to cancer evolution.

TOPICS COVERED

Human cancers are heterogeneous. Dissecting how germline genetic variation and environmental factors shape tumour evolution using human datasets is limited by inherent diversity in genetic backgrounds and environmental exposures. To overcome these limitations, we re-ran early tumour evolution hundreds of times in diverged inbred mouse strains, generating matched histology and whole-genome and transcriptome sequences. Capturing genetic variation comparable with that observed across human populations, our analyses reveal that epistatic interactions between genetic background and acquired somatic mutations result in population-specific disease progression, including choice of driver mutations, occurrence of whole-genome duplication and subclonal selection dynamics that mirror both cancer susceptibility and tumour growth rate. Even modest genetic divergence, comparable with that found across human ancestry groups, can strikingly alter selection pressures during cancer development to shape both cancer risk and the trajectory of tumour evolution.
More recently, we have reanalysed these tumour cohorts using explainable machine learning to relate histological to genomic pathology. This approach enabled accurate, interpretable inference of genetic alterations from digitised H&E images. Our predictions are supported by human-interpretable biological features, addressing concerns around “black-box” technologies.

WHO SHOULD ATTEND?

This online lecture will be of interest to pathologists, pathology trainees, academic researchers and others with an interest in cancer biology, tumour evolution, genomics, digital pathology and AI.

SPEAKER

Dr Sarah Aitken is an Assistant Professor of Pathology and Yale School of Medicine and a member of the Yale Cancer Center. She is a Board-Certified Pathologist Clinician Scientist, specialising in gastrointestinal and molecular pathology. Prior to her faculty appointment at Yale in 2024, Dr Aitken trained in Medicine at the University of Edinburgh, with an intercalated BMedSci in Experimental Pathology and postgraduate MSc in Translational Medicine. She undertook a mixed experimental-computational PhD at the CRUK Cambridge Institute (University of Cambridge), followed by an EMBO Fellowship in bioinformatics at the IRB Barcelona, Spain. She then returned to Cambridge to complete her specialty training in Histopathology as an NIHR Academic Clinical Fellow and subsequently NIHR Clinical Lecturer, and worked as a Consultant Pathologist at Cambridge University Hospitals NHS Foundation Trust. Dr Aitken established her research group at the University of Cambridge in 2021 and was awarded a CRUK Clinician Scientist Fellowship.
Dr Aitken’s lab uses genomic pathology, which combines molecular biology, genomics, and image analysis, to study mechanisms of mutagenesis, the genetic and epigenetic basis of carcinogenesis, and the consequences of genetic diversity on cancer evolution.


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