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Title: The role of intratumour heterogeneity and chromosomal instability in cancer
Author: Jamal-Hanjani, M.
ISNI:       0000 0004 7428 9361
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Increasing evidence supports the existence of intratumour heterogeneity in many solid and haematological tumour types, with potential clinical implications for both cancer diagnosis and treatment. Multi-region whole-exome sequencing of surgically resected non-small cell lung cancer (NSCLC) tumours demonstrated intratumour spatial and temporal heterogeneity in the mutational burden, copy number aberrations, and mutational signatures identified in these tumours. Furthermore, heterogeneity of mutations, including driver mutations, was also demonstrated in pre-invasive lung adenocarcinoma in situ lesions, suggesting that clonal evolution may be a feature of the early stages of cancer development. Whilst deciphering the clonal landscape of tumours may rely on multi-region and repeated tissue sampling, this remains challenging outside the context of clinical studies, and is not routine clinical practice. A non-invasive alternative may be the use of circulating biomarkers, such as circulating cell-free tumour DNA (cfDNA). Truncal and branch mutations were identified in cfDNA from patients with early stage NSCLC using different approaches. The detection of low frequency branch mutations, which are predicted to be subclonal in origin and may be potentially involved in the emergence of therapeutic resistance and tumour progression, were difficult to identify in cfDNA. Further studies are required to develop effective strategies for clonal and subclonal mutation detection in cfDNA, and to determine the utility of such biomarkers in representing the tumour genomic landscape, and in tracking tumour evolution in time. Chromosomal instability (CIN), describes an increased rate of numerical and structural chromosome aberrations, and is a known driver of intercellular genetic tumour heterogeneity. CIN has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer it has previously been shown that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on cellular fitness and growth. This paradoxical relationship was further validated in a large breast cancer cohort study, in which extreme CIN was associated with improved outcome in patients with ER-negative cancer (p trend = 0.03). A similar relationship was seen in ERnegative/ human epidermal growth factor receptor (HER2)-negative cancers (p trend = 0.007). Identifying such patients may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification. We are yet to uncover the true extent of intratumour heterogeneity and CIN in different cancer types, their relevance to clinical outcome, and how we may be able to overcome or exploit these features for the therapeutic gain and benefit of patients with cancer. Longitudinal studies employing serial tissue and circulating biomarker sampling have the potential to address these questions, and to truly define the breadth of genetic diversity in different tumour types and its relevance to patient outcome.
Supervisor: Swanton, C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available