Periodic Reporting for period 1 - cmiRCan (Circulating microRNAs in lynch syndrome)
Berichtszeitraum: 2022-03-01 bis 2024-02-29
Dr. Tiina Jokela has conducted a Marie Skłodowska-Curie Actions Individual Fellowship to develop a machine learning-based classification algorithm for identifying and exploiting circulating microRNA (c-miR) profiles as biomarkers in Lynch syndrome (LS) patients. LS is a hereditary cancer syndrome caused by pathogenic gene variants in DNA mismatch repair genes, leading to a significantly increased risk of developing various cancers. The project addresses the lack of research on c-miRs in LS and their potential as diagnostic and treatment tools.
This project's significance lies in its potential to improve early cancer detection and prognosis for LS patients, thus reducing the human and economic burden on both patients and society. By studying c-miR signatures in LS patients and their effects on tumor growth, the project seeks to contribute to developing innovative diagnostic and treatment protocols for LS-related cancers.
The overall objectives of the project include developing a comprehensive understanding of c-miRs in LS, investigating their functional roles in tumor growth regulation, and exploring the synergistic effects of c-miR clusters. The project utilizes blood samples and patient-derived organoids to analyze c-miR signatures and investigate their functions in the cancer microenvironment.
This project's significance lies in its potential to improve early cancer detection and prognosis for LS patients, thus reducing the human and economic burden on both patients and society. By studying c-miR signatures in LS patients and their effects on tumor growth, the project seeks to contribute to developing innovative diagnostic and treatment protocols for LS-related cancers.
The overall objectives of the project include developing a comprehensive understanding of c-miRs in LS, investigating their functional roles in tumor growth regulation, and exploring the synergistic effects of c-miR clusters. The project utilizes blood samples and patient-derived organoids to analyze c-miR signatures and investigate their functions in the cancer microenvironment.
Throughout the project period, significant strides were made in characterizing both the systemic metabolic landscape and c-miR signatures in LS carriers. Four pivotal studies were conducted, each offering valuable insights into the molecular mechanisms underlying LS predisposition to cancer.
Study 1: Systemic c-miRnome
An exploratory analysis was undertaken to characterize the systemic c-miRnomes of pathogenic mismatch-repair gene variant carriers, sporadic rectal cancer patients, and non-LS controls. This study unveiled a systemic c-miRnome consisting of 40 differentially expressed c-miRs in cancer-free path_MMR carriers, distinguishing them from non-LS controls. Pathway analysis linked these c-miRs to carcinogenesis, suggesting shared molecular mechanisms underlying cancer predisposition between LS and sporadic carcinogenesis. Work published in International Journal of Cancer, 2023.
Study 2: Circulating microRNA Signature Predicts Cancer Incidence in Lynch Syndrome – A Pilot Study
This study aimed to explore whether a c-miR)signature could predict LS cancer incidence within a 4-year prospective surveillance period and its correlation with known risk-reducing lifestyle factors. Results identified five c-miRs as predictors of LS cancer incidence, with a risk sum score correlating with a higher likelihood of cancer. The model also showed good concordance and correlation with body mass index (BMI), highlighting the potential utility of a c-miR signature in predicting LS cancer incidence and its correlation with lifestyle factors. Work accepted to publication in Cancer prevention research, 02/2024
Study 3: Circulating Metabolome
A cross-sectional analysis was conducted to compare the circulating metabolome of cancer-free LS carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. Elevated levels of circulating cholesterol, lipids, and lipoproteins were detected in LS carriers, indicating unique metabolic alterations. Similarities in circulating amino acid and ketone body profiles between LS carriers and CRC patients suggest shared metabolic patterns, providing insights into the systemic metabolic landscape of LS individuals and potential metabolic links with cancer initiation. Work published in Cancer & Metabolism 2024.
Study 4: Functional Analysis of Differentially Expressed c-miRs
This study focused on seven differentially expressed c-miRs identified in Study 1 for functional analysis. Preliminary results suggest that some transfected c-miRs may affect cell apoptosis in patient-derived LS CRC organoid cultures. Further analysis is underway to confirm and characterize these effects.
Study 1: Systemic c-miRnome
An exploratory analysis was undertaken to characterize the systemic c-miRnomes of pathogenic mismatch-repair gene variant carriers, sporadic rectal cancer patients, and non-LS controls. This study unveiled a systemic c-miRnome consisting of 40 differentially expressed c-miRs in cancer-free path_MMR carriers, distinguishing them from non-LS controls. Pathway analysis linked these c-miRs to carcinogenesis, suggesting shared molecular mechanisms underlying cancer predisposition between LS and sporadic carcinogenesis. Work published in International Journal of Cancer, 2023.
Study 2: Circulating microRNA Signature Predicts Cancer Incidence in Lynch Syndrome – A Pilot Study
This study aimed to explore whether a c-miR)signature could predict LS cancer incidence within a 4-year prospective surveillance period and its correlation with known risk-reducing lifestyle factors. Results identified five c-miRs as predictors of LS cancer incidence, with a risk sum score correlating with a higher likelihood of cancer. The model also showed good concordance and correlation with body mass index (BMI), highlighting the potential utility of a c-miR signature in predicting LS cancer incidence and its correlation with lifestyle factors. Work accepted to publication in Cancer prevention research, 02/2024
Study 3: Circulating Metabolome
A cross-sectional analysis was conducted to compare the circulating metabolome of cancer-free LS carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. Elevated levels of circulating cholesterol, lipids, and lipoproteins were detected in LS carriers, indicating unique metabolic alterations. Similarities in circulating amino acid and ketone body profiles between LS carriers and CRC patients suggest shared metabolic patterns, providing insights into the systemic metabolic landscape of LS individuals and potential metabolic links with cancer initiation. Work published in Cancer & Metabolism 2024.
Study 4: Functional Analysis of Differentially Expressed c-miRs
This study focused on seven differentially expressed c-miRs identified in Study 1 for functional analysis. Preliminary results suggest that some transfected c-miRs may affect cell apoptosis in patient-derived LS CRC organoid cultures. Further analysis is underway to confirm and characterize these effects.
The cmiRCan project has advanced beyond the current state of the art by integrating multidisciplinary approaches to understand LS predisposition to cancer comprehensively.
Key advancements:
The systemic characterization of c-miR signatures and the circulating metabolome in LS carriers provide novel insights into the molecular mechanisms underlying LS-associated cancer development. These studies go beyond existing research by uncovering unique metabolic alterations and c-miR profiles specific to LS, thus expanding our understanding of LS predisposition to cancer beyond traditional genetic factors.
The development of predictive models using c-miR signatures to forecast LS cancer incidence represents a significant advancement in personalized cancer risk assessment. By incorporating lifestyle factors such as BMI, these models offer a more holistic approach to cancer prediction, surpassing current methods that primarily rely on genetic predisposition.
The functional analysis of differentially expressed c-miRs in patient-derived LS CRC organoid cultures adds a new dimension to our understanding of LS carcinogenesis. This approach adds novel knowledge of specific molecular mechanisms underlying cancer development, moving beyond correlative studies to elucidate causal relationships.
We have disseminated our findings through peer-reviewed publications, conference presentations, and collaboration with clinical partners to ensure widespread utilization and impact on LS patient care and cancer research. We have shared our results with the scientific community and engaged with stakeholders; we have catalyzed further research and innovation in the field of LS-associated cancer.
Potential Impacts:
The development and validation of predictive models and biomarkers for LS-associated cancer risk assessment will lead to more personalized and effective clinical management strategies. Early detection and intervention can improve patient outcomes, reduce treatment costs, and alleviate the socio-economic burden associated with LS-related cancers.
By integrating lifestyle factors into cancer risk assessment models, clinicians can offer tailored recommendations for risk reduction and surveillance, empowering LS carriers to make informed decisions about their health. This personalized approach to patient care enhances quality of life and supports holistic well-being.
The project's multidisciplinary approach and focus on molecular mechanisms underlying LS predisposition to cancer contribute to the advancement of precision medicine. By targeting specific molecular pathways and biomarkers, precision medicine offers the potential for more effective and targeted cancer therapies, ultimately improving patient outcomes.
The project's findings have broader implications for public health, including the potential for population-wide screening and preventive measures for LS carriers. By identifying individuals at higher risk of LS-associated cancers, public health initiatives can implement targeted screening programs and preventive interventions, leading to early detection and improved population health outcomes.
In summary, the project's outcomes have established an excellent foundation for biomarker research, with the potential in the future to revolutionize cancer risk assessment, clinical management, and public health strategies for LS-associated cancers. Ultimately, these advancements contribute to improved patient outcomes and societal well-being.
Key advancements:
The systemic characterization of c-miR signatures and the circulating metabolome in LS carriers provide novel insights into the molecular mechanisms underlying LS-associated cancer development. These studies go beyond existing research by uncovering unique metabolic alterations and c-miR profiles specific to LS, thus expanding our understanding of LS predisposition to cancer beyond traditional genetic factors.
The development of predictive models using c-miR signatures to forecast LS cancer incidence represents a significant advancement in personalized cancer risk assessment. By incorporating lifestyle factors such as BMI, these models offer a more holistic approach to cancer prediction, surpassing current methods that primarily rely on genetic predisposition.
The functional analysis of differentially expressed c-miRs in patient-derived LS CRC organoid cultures adds a new dimension to our understanding of LS carcinogenesis. This approach adds novel knowledge of specific molecular mechanisms underlying cancer development, moving beyond correlative studies to elucidate causal relationships.
We have disseminated our findings through peer-reviewed publications, conference presentations, and collaboration with clinical partners to ensure widespread utilization and impact on LS patient care and cancer research. We have shared our results with the scientific community and engaged with stakeholders; we have catalyzed further research and innovation in the field of LS-associated cancer.
Potential Impacts:
The development and validation of predictive models and biomarkers for LS-associated cancer risk assessment will lead to more personalized and effective clinical management strategies. Early detection and intervention can improve patient outcomes, reduce treatment costs, and alleviate the socio-economic burden associated with LS-related cancers.
By integrating lifestyle factors into cancer risk assessment models, clinicians can offer tailored recommendations for risk reduction and surveillance, empowering LS carriers to make informed decisions about their health. This personalized approach to patient care enhances quality of life and supports holistic well-being.
The project's multidisciplinary approach and focus on molecular mechanisms underlying LS predisposition to cancer contribute to the advancement of precision medicine. By targeting specific molecular pathways and biomarkers, precision medicine offers the potential for more effective and targeted cancer therapies, ultimately improving patient outcomes.
The project's findings have broader implications for public health, including the potential for population-wide screening and preventive measures for LS carriers. By identifying individuals at higher risk of LS-associated cancers, public health initiatives can implement targeted screening programs and preventive interventions, leading to early detection and improved population health outcomes.
In summary, the project's outcomes have established an excellent foundation for biomarker research, with the potential in the future to revolutionize cancer risk assessment, clinical management, and public health strategies for LS-associated cancers. Ultimately, these advancements contribute to improved patient outcomes and societal well-being.