The somatic mutational landscape of the normal fallopian tube epithelium
<p>There is currently no screening test available for ovarian cancer. This is largely due to the lack of understanding of mechanisms of tumour initiation. Using single cell sequencing, we have recently demonstrated the individual subtypes of the fallopian tube epithelial cells, and how these a...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2021
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| Subjects: |
| _version_ | 1797111879562166272 |
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| author | Wietek, N |
| author2 | Ahmed, A |
| author_facet | Ahmed, A Wietek, N |
| author_sort | Wietek, N |
| collection | OXFORD |
| description | <p>There is currently no screening test available for ovarian cancer. This is largely due to the lack of understanding of mechanisms of tumour initiation. Using single cell sequencing, we have recently demonstrated the individual subtypes of the fallopian tube epithelial cells, and how these are recapitulated in high grade serous ovarian cancer (HGSOC) subtypes, providing compelling evidence that the fallopian tube epithelium (FTE) harbours the elusive cell of origin of HGSOC [1]. Using these insights, it was now a priority to explore the somatic mutational landscape of the normal FTE.</p>
<p>Investigating mutational processes in normal tissue is central to our under- standing of the cancers that originate in these tissues. Recent studies have shed light on the clonal dynamics of various tissue types in the human body, informing our understanding of how somatic mutations contribute to tissue homeostasis, ageing, cancer, and other diseases.
In this study, I performed ultra-deep targeted sequencing of a collection of over 350 laser capture microdissected samples from the normal FTE of six patients (4 patients without cancer; 2 patients with concurrent HGSOC and macroscopically normal fallopian tubes). A machine learning approach was developed to enable accurate and comprehensive discovery of subclonal variants from small numbers of cells using a low-cost, high-throughput sequencing workflow.</p>
<p>This study has revealed that somatic mutations are ubiquitous in the normal fallopian tube, with considerable intra- and inter-patient heterogeneity. Muta- tional processes that underpin positive selection and clonal expansion of fallopian tube epithelial cells were explored in order to gain an understanding of the transformation of healthy cells into cancer cells. The highest burden of somatic mutations was found in FAT1, the NOTCH genes, and CSMD3, which are all known to play a role in the pathogenesis of both benign diseases and cancer. The majority of mutations were shown to be missense mutations with likely damaging impacts on protein function. TP53 mutations, which are pathognomonic for HGSOC [2], were found to be uncommon in the histologically normal FTE, suggesting that these may not confer large clonal advantages in the normal FTE, but as key drivers of HGSOC development likely occur later in the pathogenesis.</p>
<p>This is the first insight into the somatic mutational landscape of healthy human fallopian tubes and provides novel insights into fallopian tube biology and the clonal dynamics of fallopian tube epithelium. These results lay a foundation for subsequent exploration of the interface between health and disease and will be an important stepping-stone towards establishing screening tools for early detection of HGSOC.</p> |
| first_indexed | 2024-03-07T08:16:38Z |
| format | Thesis |
| id | oxford-uuid:139f337b-0fe8-4895-afc0-ee3f68ea6f07 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:16:38Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:139f337b-0fe8-4895-afc0-ee3f68ea6f072024-01-10T10:20:26ZThe somatic mutational landscape of the normal fallopian tube epitheliumThesishttp://purl.org/coar/resource_type/c_db06uuid:139f337b-0fe8-4895-afc0-ee3f68ea6f07CancerEnglishHyrax Deposit2021Wietek, NAhmed, A<p>There is currently no screening test available for ovarian cancer. This is largely due to the lack of understanding of mechanisms of tumour initiation. Using single cell sequencing, we have recently demonstrated the individual subtypes of the fallopian tube epithelial cells, and how these are recapitulated in high grade serous ovarian cancer (HGSOC) subtypes, providing compelling evidence that the fallopian tube epithelium (FTE) harbours the elusive cell of origin of HGSOC [1]. Using these insights, it was now a priority to explore the somatic mutational landscape of the normal FTE.</p> <p>Investigating mutational processes in normal tissue is central to our under- standing of the cancers that originate in these tissues. Recent studies have shed light on the clonal dynamics of various tissue types in the human body, informing our understanding of how somatic mutations contribute to tissue homeostasis, ageing, cancer, and other diseases. In this study, I performed ultra-deep targeted sequencing of a collection of over 350 laser capture microdissected samples from the normal FTE of six patients (4 patients without cancer; 2 patients with concurrent HGSOC and macroscopically normal fallopian tubes). A machine learning approach was developed to enable accurate and comprehensive discovery of subclonal variants from small numbers of cells using a low-cost, high-throughput sequencing workflow.</p> <p>This study has revealed that somatic mutations are ubiquitous in the normal fallopian tube, with considerable intra- and inter-patient heterogeneity. Muta- tional processes that underpin positive selection and clonal expansion of fallopian tube epithelial cells were explored in order to gain an understanding of the transformation of healthy cells into cancer cells. The highest burden of somatic mutations was found in FAT1, the NOTCH genes, and CSMD3, which are all known to play a role in the pathogenesis of both benign diseases and cancer. The majority of mutations were shown to be missense mutations with likely damaging impacts on protein function. TP53 mutations, which are pathognomonic for HGSOC [2], were found to be uncommon in the histologically normal FTE, suggesting that these may not confer large clonal advantages in the normal FTE, but as key drivers of HGSOC development likely occur later in the pathogenesis.</p> <p>This is the first insight into the somatic mutational landscape of healthy human fallopian tubes and provides novel insights into fallopian tube biology and the clonal dynamics of fallopian tube epithelium. These results lay a foundation for subsequent exploration of the interface between health and disease and will be an important stepping-stone towards establishing screening tools for early detection of HGSOC.</p> |
| spellingShingle | Cancer Wietek, N The somatic mutational landscape of the normal fallopian tube epithelium |
| title | The somatic mutational landscape of the normal fallopian tube epithelium |
| title_full | The somatic mutational landscape of the normal fallopian tube epithelium |
| title_fullStr | The somatic mutational landscape of the normal fallopian tube epithelium |
| title_full_unstemmed | The somatic mutational landscape of the normal fallopian tube epithelium |
| title_short | The somatic mutational landscape of the normal fallopian tube epithelium |
| title_sort | somatic mutational landscape of the normal fallopian tube epithelium |
| topic | Cancer |
| work_keys_str_mv | AT wietekn thesomaticmutationallandscapeofthenormalfallopiantubeepithelium AT wietekn somaticmutationallandscapeofthenormalfallopiantubeepithelium |