Somatic evolution in normal human endometrium

For decades, the primary focus of cancer research has been the cancer tissue itself. Advances in next-generation sequencing technologies have enabled identification and characterisation of driver mutations, provided insights into the tumour burdens and underlying mutational processes, sub-clonal diversification and tumour heterogeneity. However, all cancers arise from cells that were once normal. Over time, they acquired certain mutations which increased their fitness, giving them a selective advantage over their neighbours and allowing uncontrolled growth, clonal expansion and malignant transformation. Our understanding of somatic evolution occurring in normal tissues with age and in the early stages of tumourigenesis remains relatively poorly understood. In this thesis, I aimed to investigate somatic evolution in normal ageing human tissues. Firstly, I helped to establish a robust low DNA input whole-genome sequencing workflow for laser-capture micro-dissected cellular material. I then utilised this approach to explore the genomic and evolutionary landscapes of the normal human endometrium. In the first results chapter, I investigate the clonal composition of normal endometrial glands. The majority of glands are clonal cell populations that share a common recent ancestor and the monoclonality is independent of whether they have a driver mutation. In the second results chapter, I investigate the mutational landscape of normal endometrial glands. We show that somatic mutations (base substitutions, indels and genome rearrangements) accumulate with age in a more-or-less linear manner. A small number of ubiquitous mutational processes accounts for the majority of all mutations. A remarkably high proportion of normal endometrial glands carry at least one driver mutation (of the type that one is used to finding in cancers). Accumulation of drivers is negatively affected by parity. Through phylogenetic tree reconstruction of somatic mutations in endometrial glands, we show that driver mutations often occur early in life and continue to accumulate with age. This work identifies a distinct mutational landscape in the normal endometrium that is in keeping with the presence of early positive selection in this highly regenerative tissue.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Moore, Luiza

Advisor dc:contributor.advisor

• Stratton, Michael

• genomics
• cancer
• somatic mutation
• normal endometrium

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f0bdbb20-cc4d-4f8d-a3c2-293714e651a6/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0001-5315-516X

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/318118