{"id":{"repo_id":"edinburgh","oai_identifier":"oai:era.ed.ac.uk:1842/41223"},"canonical_url":"https://search.dev.ndltd.org/etd/edinburgh/oai:era.ed.ac.uk:1842/41223","repository":{"repo_id":"edinburgh","name":"University of Edinburgh","base_url":"https://era.ed.ac.uk/server/oai/request"},"display":{"title":"Transcriptome-wide association analysis of survival in colorectal cancer patients","abstract":"Colorectal Cancer (CRC) is the second leading cause of cancer deaths globally. Whilst tumour stage, lymph node status and the presence/absence of distant metastases at presentation are strongly associated with survival outcome, prediction of survival for individual patients is very imprecise. This has considerable relevance to clinical care because decisions are currently made on the basis of associations made between groups of patients. Hence, there is a pressing need for new approaches for improved survival prediction that would allow tailoring of treatment interventions to individual patients who would most benefit, and also to improve prognostication to guide patient care. Recent progress in the understanding of the relationship between gene expression and genetics has made it possible to identify genes in tumours associated with survival in CRC. The association between transcriptomes in normal tissue and survival of cancer patients however is mostly unknown, although evidence does suggest a correlation. It has even been suggested that the expressed genes in normal colorectal tissue are even more informative on the individual’s survival than tumours. This study investigates whether the expressed genes in various normal tissues can be used as a biomarker to predict the survival of patients diagnosed with CRC. To investigate intrinsic factors influencing gene expression, I conducted a descriptive analysis of RNA sequencing of normal colorectal mucosa samples (238 samples of Study of Colorectal Cancer in Scotland (SOCCS) RNA-Seq study in the discovery and 380 samples of the Intermediate Phenotype Study (INTERMPHEN) study in the validation dataset). Body mass index (BMI) and sex are well known risk factors for colorectal cancer and so particular focus was paid to the relationship between these factors and differential gene expression. No systematic differences between males and females were found, nor did I find a strong relationship between gene expression and BMI. The main thrust of this thesis was to determine whether host gene expression using prediction from genotype influences survival outcome. To this end, Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH) models were used to build prediction models of gene expression. A large-scale Transcriptome-Wide-Association Study (TWAS) was conducted by applying the previously developed prediction algorithms on cohorts without gene expression (5674 individuals of the Study of Colorectal Cancer collected at the General Western Hospital (Edinburgh, Scotland) as well as 1948 cases with metastasis or locally advanced colorectal adenocarcinoma from the COntinuous versus INtermittent (COIN) as a replication dataset (Cardiff, Wales)). The TWAS aimed to study the association between gene expression and survival outcomes with the help of Cox Proportional-Hazards Regression models as well as Fine and Gray models. The analysis included well-established variables associated with survival outcome (e.g. TNM (Tumour, node, metastasis) stage). MASH models showed that variation in gene expression of ARMC10 was associated with all-cause mortality in SOCCS cohort accounting for multiple testing. A higher gene expression of ARMC10 was associated with better outcome (HR=0.31; 95%confidence interval (CI)=0.19-0.51) in liver and whole blood. Despite a convincing signal for all-cause mortality (in all stages combined and by stage separately) and appearance of the gene in the top 10 results sorted by p-value in all three analysed tissues in CRC-specific mortality in SOCCS, there was no association in the COIN dataset, perhaps due to small sample size. The stratified analysis by stage showed promising results for gene CDK7 (stage 2 and 3 combined in transverse colon) and for gene SRSF12 (for stage 4 in whole blood). The results could not be replicated in COIN, however it should be highlighted that, beside lower sample sizes, the COIN dataset contains a special group of patients with only late-stage CRC cases. Finally, gene BNC2 was identified when analysing the time to develop liver metastasis based on differences in gene expression in liver tissue in COIN. However, no significance was observed for this gene in SOCCS. In summary, a statistically significant association between gene expression and survival in CRC patients in normal tissue was found. The identified genes in this study should be replicated in a bigger dataset in order to safely exclude them from further analysis. The power of a TWAS is highly dependent on the size of the dataset and there is a chance that the COIN dataset with 1948 individuals was not able to pick up the signals. This study demonstrates the potential of the analysis of normal tissue. The identified genes in SOCCS could have further implications on the understanding of cancer formation, progression, treatment and management as well as risk and prevention and should therefore be investigated further.","abstract_html":"Colorectal Cancer (CRC) is the second leading cause of cancer deaths globally. Whilst tumour stage, lymph node status and the presence/absence of distant metastases at presentation are strongly associated with survival outcome, prediction of survival for individual patients is very imprecise. This has considerable relevance to clinical care because decisions are currently made on the basis of associations made between groups of patients. Hence, there is a pressing need for new approaches for improved survival prediction that would allow tailoring of treatment interventions to individual patients who would most benefit, and also to improve prognostication to guide patient care. Recent progress in the understanding of the relationship between gene expression and genetics has made it possible to identify genes in tumours associated with survival in CRC. The association between transcriptomes in normal tissue and survival of cancer patients however is mostly unknown, although evidence does suggest a correlation. It has even been suggested that the expressed genes in normal colorectal tissue are even more informative on the individual’s survival than tumours. This study investigates whether the expressed genes in various normal tissues can be used as a biomarker to predict the survival of patients diagnosed with CRC. To investigate intrinsic factors influencing gene expression, I conducted a descriptive analysis of RNA sequencing of normal colorectal mucosa samples (238 samples of Study of Colorectal Cancer in Scotland (SOCCS) RNA-Seq study in the discovery and 380 samples of the Intermediate Phenotype Study (INTERMPHEN) study in the validation dataset). Body mass index (BMI) and sex are well known risk factors for colorectal cancer and so particular focus was paid to the relationship between these factors and differential gene expression. No systematic differences between males and females were found, nor did I find a strong relationship between gene expression and BMI. The main thrust of this thesis was to determine whether host gene expression using prediction from genotype influences survival outcome. To this end, Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH) models were used to build prediction models of gene expression. A large-scale Transcriptome-Wide-Association Study (TWAS) was conducted by applying the previously developed prediction algorithms on cohorts without gene expression (5674 individuals of the Study of Colorectal Cancer collected at the General Western Hospital (Edinburgh, Scotland) as well as 1948 cases with metastasis or locally advanced colorectal adenocarcinoma from the COntinuous versus INtermittent (COIN) as a replication dataset (Cardiff, Wales)). The TWAS aimed to study the association between gene expression and survival outcomes with the help of Cox Proportional-Hazards Regression models as well as Fine and Gray models. The analysis included well-established variables associated with survival outcome (e.g. TNM (Tumour, node, metastasis) stage). MASH models showed that variation in gene expression of ARMC10 was associated with all-cause mortality in SOCCS cohort accounting for multiple testing. A higher gene expression of ARMC10 was associated with better outcome (HR=0.31; 95%confidence interval (CI)=0.19-0.51) in liver and whole blood. Despite a convincing signal for all-cause mortality (in all stages combined and by stage separately) and appearance of the gene in the top 10 results sorted by p-value in all three analysed tissues in CRC-specific mortality in SOCCS, there was no association in the COIN dataset, perhaps due to small sample size. The stratified analysis by stage showed promising results for gene CDK7 (stage 2 and 3 combined in transverse colon) and for gene SRSF12 (for stage 4 in whole blood). The results could not be replicated in COIN, however it should be highlighted that, beside lower sample sizes, the COIN dataset contains a special group of patients with only late-stage CRC cases. Finally, gene BNC2 was identified when analysing the time to develop liver metastasis based on differences in gene expression in liver tissue in COIN. However, no significance was observed for this gene in SOCCS. In summary, a statistically significant association between gene expression and survival in CRC patients in normal tissue was found. The identified genes in this study should be replicated in a bigger dataset in order to safely exclude them from further analysis. The power of a TWAS is highly dependent on the size of the dataset and there is a chance that the COIN dataset with 1948 individuals was not able to pick up the signals. This study demonstrates the potential of the analysis of normal tissue. The identified genes in SOCCS could have further implications on the understanding of cancer formation, progression, treatment and management as well as risk and prevention and should therefore be investigated further.","abstract_has_math":false,"creators":["Lemler, Lea"],"institution":"The University of Edinburgh","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Dunlop, Malcolm","Theodoratou, Evropi","Timofeeva, Maria"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-11-22","date_published":"2023-11-22","updated_at":"2026-07-24T02:14:03Z","subjects":["colorectal cancer","colorectal cancer patients","Colorectal Cancer in Scotland","Body mass index (BMI)","sex","Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH)","Transcriptome-Wide-Association Study (TWAS)"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://dx.doi.org/10.7488/era/3959"],"render_values":[{"text":"http://dx.doi.org/10.7488/era/3959","href":"http://dx.doi.org/10.7488/era/3959","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1842/41223","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Dunlop, Malcolm","Theodoratou, Evropi","Timofeeva, Maria"]},{"key":"dc:creator","label":"Author","values":["Lemler, Lea"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-11-22T10:42:38Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-11-22T10:42:38Z"]},{"key":"dc:date.issued","label":"Date","values":["2023-11-22"]},{"key":"dc:publisher","label":"Institution","values":["The University of Edinburgh"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or Dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["colorectal cancer","colorectal cancer patients","Colorectal Cancer in Scotland","Body mass index (BMI)","sex","Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH)","Transcriptome-Wide-Association Study (TWAS)"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1842/41223","http://dx.doi.org/10.7488/era/3959"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Colorectal Cancer (CRC) is the second leading cause of cancer deaths globally. Whilst tumour stage, lymph node status and the presence/absence of distant metastases at presentation are strongly associated with survival outcome, prediction of survival for individual patients is very imprecise. This has considerable relevance to clinical care because decisions are currently made on the basis of associations made between groups of patients. Hence, there is a pressing need for new approaches for improved survival prediction that would allow tailoring of treatment interventions to individual patients who would most benefit, and also to improve prognostication to guide patient care. Recent progress in the understanding of the relationship between gene expression and genetics has made it possible to identify genes in tumours associated with survival in CRC. The association between transcriptomes in normal tissue and survival of cancer patients however is mostly unknown, although evidence does suggest a correlation. It has even been suggested that the expressed genes in normal colorectal tissue are even more informative on the individual’s survival than tumours. This study investigates whether the expressed genes in various normal tissues can be used as a biomarker to predict the survival of patients diagnosed with CRC. To investigate intrinsic factors influencing gene expression, I conducted a descriptive analysis of RNA sequencing of normal colorectal mucosa samples (238 samples of Study of Colorectal Cancer in Scotland (SOCCS) RNA-Seq study in the discovery and 380 samples of the Intermediate Phenotype Study (INTERMPHEN) study in the validation dataset). Body mass index (BMI) and sex are well known risk factors for colorectal cancer and so particular focus was paid to the relationship between these factors and differential gene expression. No systematic differences between males and females were found, nor did I find a strong relationship between gene expression and BMI. The main thrust of this thesis was to determine whether host gene expression using prediction from genotype influences survival outcome. To this end, Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH) models were used to build prediction models of gene expression. A large-scale Transcriptome-Wide-Association Study (TWAS) was conducted by applying the previously developed prediction algorithms on cohorts without gene expression (5674 individuals of the Study of Colorectal Cancer collected at the General Western Hospital (Edinburgh, Scotland) as well as 1948 cases with metastasis or locally advanced colorectal adenocarcinoma from the COntinuous versus INtermittent (COIN) as a replication dataset (Cardiff, Wales)). The TWAS aimed to study the association between gene expression and survival outcomes with the help of Cox Proportional-Hazards Regression models as well as Fine and Gray models. The analysis included well-established variables associated with survival outcome (e.g. TNM (Tumour, node, metastasis) stage). MASH models showed that variation in gene expression of ARMC10 was associated with all-cause mortality in SOCCS cohort accounting for multiple testing. A higher gene expression of ARMC10 was associated with better outcome (HR=0.31; 95%confidence interval (CI)=0.19-0.51) in liver and whole blood. Despite a convincing signal for all-cause mortality (in all stages combined and by stage separately) and appearance of the gene in the top 10 results sorted by p-value in all three analysed tissues in CRC-specific mortality in SOCCS, there was no association in the COIN dataset, perhaps due to small sample size. The stratified analysis by stage showed promising results for gene CDK7 (stage 2 and 3 combined in transverse colon) and for gene SRSF12 (for stage 4 in whole blood). The results could not be replicated in COIN, however it should be highlighted that, beside lower sample sizes, the COIN dataset contains a special group of patients with only late-stage CRC cases. Finally, gene BNC2 was identified when analysing the time to develop liver metastasis based on differences in gene expression in liver tissue in COIN. However, no significance was observed for this gene in SOCCS. In summary, a statistically significant association between gene expression and survival in CRC patients in normal tissue was found. The identified genes in this study should be replicated in a bigger dataset in order to safely exclude them from further analysis. The power of a TWAS is highly dependent on the size of the dataset and there is a chance that the COIN dataset with 1948 individuals was not able to pick up the signals. This study demonstrates the potential of the analysis of normal tissue. The identified genes in SOCCS could have further implications on the understanding of cancer formation, progression, treatment and management as well as risk and prevention and should therefore be investigated further."]},{"key":"dc:title","label":"Title","values":["Transcriptome-wide association analysis of survival in colorectal cancer patients"]}]}],"canonical_facts":{"dc:contributor.advisor":["Dunlop, Malcolm","Theodoratou, Evropi","Timofeeva, Maria"],"dc:creator":["Lemler, Lea"],"dc:date.accessioned":["2023-11-22T10:42:38Z"],"dc:date.available":["2023-11-22T10:42:38Z"],"dc:date.issued":["2023-11-22"],"dc:description.abstract":["Colorectal Cancer (CRC) is the second leading cause of cancer deaths globally. Whilst tumour stage, lymph node status and the presence/absence of distant metastases at presentation are strongly associated with survival outcome, prediction of survival for individual patients is very imprecise. This has considerable relevance to clinical care because decisions are currently made on the basis of associations made between groups of patients. Hence, there is a pressing need for new approaches for improved survival prediction that would allow tailoring of treatment interventions to individual patients who would most benefit, and also to improve prognostication to guide patient care. Recent progress in the understanding of the relationship between gene expression and genetics has made it possible to identify genes in tumours associated with survival in CRC. The association between transcriptomes in normal tissue and survival of cancer patients however is mostly unknown, although evidence does suggest a correlation. It has even been suggested that the expressed genes in normal colorectal tissue are even more informative on the individual’s survival than tumours. This study investigates whether the expressed genes in various normal tissues can be used as a biomarker to predict the survival of patients diagnosed with CRC. To investigate intrinsic factors influencing gene expression, I conducted a descriptive analysis of RNA sequencing of normal colorectal mucosa samples (238 samples of Study of Colorectal Cancer in Scotland (SOCCS) RNA-Seq study in the discovery and 380 samples of the Intermediate Phenotype Study (INTERMPHEN) study in the validation dataset). Body mass index (BMI) and sex are well known risk factors for colorectal cancer and so particular focus was paid to the relationship between these factors and differential gene expression. No systematic differences between males and females were found, nor did I find a strong relationship between gene expression and BMI. The main thrust of this thesis was to determine whether host gene expression using prediction from genotype influences survival outcome. To this end, Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH) models were used to build prediction models of gene expression. A large-scale Transcriptome-Wide-Association Study (TWAS) was conducted by applying the previously developed prediction algorithms on cohorts without gene expression (5674 individuals of the Study of Colorectal Cancer collected at the General Western Hospital (Edinburgh, Scotland) as well as 1948 cases with metastasis or locally advanced colorectal adenocarcinoma from the COntinuous versus INtermittent (COIN) as a replication dataset (Cardiff, Wales)). The TWAS aimed to study the association between gene expression and survival outcomes with the help of Cox Proportional-Hazards Regression models as well as Fine and Gray models. The analysis included well-established variables associated with survival outcome (e.g. TNM (Tumour, node, metastasis) stage). MASH models showed that variation in gene expression of ARMC10 was associated with all-cause mortality in SOCCS cohort accounting for multiple testing. A higher gene expression of ARMC10 was associated with better outcome (HR=0.31; 95%confidence interval (CI)=0.19-0.51) in liver and whole blood. Despite a convincing signal for all-cause mortality (in all stages combined and by stage separately) and appearance of the gene in the top 10 results sorted by p-value in all three analysed tissues in CRC-specific mortality in SOCCS, there was no association in the COIN dataset, perhaps due to small sample size. The stratified analysis by stage showed promising results for gene CDK7 (stage 2 and 3 combined in transverse colon) and for gene SRSF12 (for stage 4 in whole blood). The results could not be replicated in COIN, however it should be highlighted that, beside lower sample sizes, the COIN dataset contains a special group of patients with only late-stage CRC cases. Finally, gene BNC2 was identified when analysing the time to develop liver metastasis based on differences in gene expression in liver tissue in COIN. However, no significance was observed for this gene in SOCCS. In summary, a statistically significant association between gene expression and survival in CRC patients in normal tissue was found. The identified genes in this study should be replicated in a bigger dataset in order to safely exclude them from further analysis. The power of a TWAS is highly dependent on the size of the dataset and there is a chance that the COIN dataset with 1948 individuals was not able to pick up the signals. This study demonstrates the potential of the analysis of normal tissue. The identified genes in SOCCS could have further implications on the understanding of cancer formation, progression, treatment and management as well as risk and prevention and should therefore be investigated further."],"dc:identifier.uri":["https://hdl.handle.net/1842/41223","http://dx.doi.org/10.7488/era/3959"],"dc:language.iso":["en"],"dc:publisher":["The University of Edinburgh"],"dc:subject":["colorectal cancer","colorectal cancer patients","Colorectal Cancer in Scotland","Body mass index (BMI)","sex","Genotype-Tissue Expression Multivariate Adaptive Shrinkage (MASH)","Transcriptome-Wide-Association Study (TWAS)"],"dc:title":["Transcriptome-wide association analysis of survival in colorectal cancer patients"],"dc:type":["Thesis or Dissertation"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD Doctor of Philosophy"]},"updated_at":"2026-07-24T02:14:03Z"}