Clonal dynamics and mutational landscape of normal and cancerous tissues in cancer predisposition syndromes
Lead Research Organisation:
Wellcome Sanger Institute
Department Name: Cancer, Ageing and Somatic Mutation
Abstract
Cancer predisposition syndrome, also called inherited cancer predisposition, or familial cancers are usually caused by pathogenic mutation(s) that are inherited from one or both parents and increase the risk of developing cancer at an earlier age compared to the risk for the general population. Although all the cells in the offspring carry the same pathogenic mutation(s), yet only some cell types are sensitive to these changes and transform into malignant tumours. Moreover, some tumours emerge early in these individuals (during childhood), such as sarcoma, while others take longer to form, such as breast cancer (usually it appears around the age of 20 and above). Despite the huge effort in the field to understand tumorigenesis in individuals with cancer predisposition syndromes, yet the cellular processes that cause malignant transformation in some cells but not in every single cell in the body remain unknown.
The aim of this study is to:
1) Generate a comprehensive mutational landscape across histological normal tissues of individuals with Li-Fraumeni syndrome, which is a type of inherited cancer;
2) Identify factors that cause an early tumour transformation in some cells compared to tumours that emerge later in life;
3) Investigate DNA modifications, such as changes in methylation, which may play a role in malignant transformation across different cell types.
The results from this study will help us better understand how malignant transformation occurs in some cells in individuals with cancer predisposition syndromes. The outcome will provide important insights into cancer risk and development in general.
The aim of this study is to:
1) Generate a comprehensive mutational landscape across histological normal tissues of individuals with Li-Fraumeni syndrome, which is a type of inherited cancer;
2) Identify factors that cause an early tumour transformation in some cells compared to tumours that emerge later in life;
3) Investigate DNA modifications, such as changes in methylation, which may play a role in malignant transformation across different cell types.
The results from this study will help us better understand how malignant transformation occurs in some cells in individuals with cancer predisposition syndromes. The outcome will provide important insights into cancer risk and development in general.
Technical Summary
This study aims to investigate the consequences of TP53 inactivation in malignant transformation, as well as in the development and maintenance of healthy tissues, using tumour and histologically-normal samples from Li-Fraumeni syndrome (LFS) individuals. LFS is a rare familial cancer syndrome caused by heterozygous germline pathogenic variants in TP53, which confer an increased risk of early onset cancer in diverse tissues of origin. Specifically, we will implement a multidisciplinary approach combining spatially-resolved, multi-omic technologies with single-clone and single-molecule resolution to delineate the patterns of mutations and mutational processes, clonal evolution and phylogenetic relationships of cells in LFS individuals. In Work Package (WP) 1 we will analyse samples from diverse histological structures (at least 25) collected post-mortem from ~10 LFS individuals. We will perform laser capture microdissection (LCM) combined with low-input whole-genome sequencing (WGS) on clonal structures, and NanoSeq on non-clonal tissues. The resulting data will allow us to study the consequences of pathogenic TP53 variants on the behaviour of normal cells and clones during life across diverse tissues. In WP2, we will apply WGS on multiple regions extracted using LCM from diverse tumours arising in LFS patients. We will primarily focus on studying the early events triggering the clonal expansion of malignant clones in an LFS background, and will compare the patterns of somatic alterations observed in benign clonal expansions with those leading to malignant transformation in LFS individuals, and in sporadic tumours driven by TP53 inactivation. In WP3, we will perform RNAseq and EMseq (low-input bisulfite sequencing) on the LCM samples collected in WP1 and WP2 to study transcriptional changes and epigenetic modifications in both histologically-normal tissues and tumour samples from LFS individuals.
Publications
Sherwood K
(2023)
Author Correction: Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair.
in Nature communications
Sherwood K
(2023)
Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair.
in Nature communications
| Title | Analysis pipeline for identification of pathogenic mutations in normal and tumour samples from LFS individuals |
| Description | We have developed a novel analytical method aimed at quantifying mutation rates and identifying potential drivers within normal samples obtained from individuals diagnosed with Li-Fraumeni syndrome (LFS). This innovative tool extends its application to the analysis of tumor samples collected from participants who have already developed tumors. As a result, we have amassed a substantial sequencing dataset encompassing both normal and cancerous samples sourced from individuals affected by cancer syndromes. Upon completion of the study, we intend to publish our findings, contributing valuable insights to the scientific community. |
| Type Of Material | Biological samples |
| Year Produced | 2024 |
| Provided To Others? | No |
| Impact | The newly developed analytical method offers a novel approach that holds potential for adoption in similar studies within the field. Additionally, the unique dataset we have generated serves as a valuable resource, providing ample opportunities for further research into cancer predisposition syndromes and related areas of investigation. |
| Description | Unraveling the Influence of TP53 on Clonal Selection in Sperm and germline mutation rate |
| Organisation | Great Ormond Street Hospital (GOSH) |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Our team has been investigating the effect of TP53 on clonal selection in sperm from fathers with children diagnosed with Li-Fraumeni syndrome (LFS). We conducted whole-genome sequencing on blood samples collected from parents and offspring of individuals with LFS to assess whether TP53 dysregulation in germline cells of either maternal or paternal origin influences clonal dynamics and impacts the number of germline de novo mutations in their offspring. To explore this further, we utilised NanoSeq, a highly accurate method for detecting mutations, to analyse buccal samples from index individuals and their parents, enabling us to investigate clonal dynamics in tissues beyond blood. Additionally, we performed sperm sequencing from fathers of LFS index cases to assess whether TP53 mutations confer a selective advantage in germ cells. Our study is now complete, and we are just months away from publication. Our findings provide important insights into the role of TP53 in reproductive tissues: TP53 does not provide a selective advantage in parental germ cells, making it unlikely to undergo clonal expansion in reproductive tissues. As a result, the recurrence risk for de novo germline TP53 mutations is very low. However, when TP53 mutations occur early in development, prior to the separation of soma and germline or around primordial germ cell specification, the recurrence risk increases significantly. In cases where a de novo TP53 mutation arises in one of the parental germ cells, we found no impact on the overall germline and somatic mutational burdens in offspring. These findings have important implications for genetic counselling and recurrence risk assessment in families affected by LFS. |
| Collaborator Contribution | Our collaboration with team at Great Ormond Street Hospital (GOSH) has been instrumental in advancing our research on Li-Fraumeni syndrome (LFS). Their contributions have been critical in several key areas: the GOSH team has played a pivotal role in identifying, recruiting, and collecting samples from LFS patients and their relatives. Their efforts have ensured a diverse and well characterised cohort, providing essential material for our analyses. Alongside sample collection, they have gathered detailed phenotypic information, which has been crucial for correlating genotypic findings with clinical outcomes. Their involvement has also helped streamline ethical approvals and clinical protocols, allowing for a smooth and compliant research process. This partnership has significantly enriched our study, enabling us to generate comprehensive insights into the genetic and phenotypic aspects of LFS. As our project reaches completion, their continued collaboration remains invaluable in ensuring the clinical relevance and impact of our findings. |
| Impact | Our investigation is now complete, and we are in the final stages of preparing our findings for publication in a high impact journal. This collaboration has resulted in several key outputs that will contribute to the broader scientific community: We have generated a comprehensive sequencing dataset from the parents and offspring of individuals with Li-Fraumeni syndrome (LFS). Once published, this dataset will be made accessible to other researchers through the European Genome-Phenome Archive (EGA), supporting future studies on germline and somatic mutational processes. The analysis pipeline we developed for this study will be shared via GitHub, allowing researchers to apply and adapt it for similar investigations into germline and somatic mutation dynamics. We are currently months away from submission, with plans to publish our findings in a high-impact journal. This will help advance the understanding of TP53-driven mutagenesis, germline mutation recurrence risks, and clonal selection dynamics in reproductive tissues. This project is inherently multi-disciplinary, bringing together expertise from: genetics & genomics, bioinformatics, computational biology, clinical oncology, genetic Counselling. By combining these disciplines, this collaboration has provided critical insights into germline TP53 mutations and their clinical implications, paving the way for improved risk assessment and genetic counselling strategies for individuals with LFS. |
| Start Year | 2022 |
| Description | Unravelling the evolutionary trajectory of adrenocortical carcinomas in hereditary cancer Predisposition syndromes |
| Organisation | Great Ormond Street Hospital (GOSH) |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition disorder caused by germline TP53 mutations, which significantly increase the risk of developing various cancers, including sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas (ACCs). Individuals with LFS face a lifetime cancer risk of approximately 80% for men and nearly 100% for women. As part of this collaboration, our research team has been focusing on characterising the mutational landscape of ACCs, with a specific emphasis on identifying key driver events, determining their temporal occurrence, and mapping the evolutionary trajectories of ACCs across different germline backgrounds. A major aspect of our work involves comparative analyses of ACCs in individuals with LFS, Beckwith-Wiedemann syndrome (BWS), and those with sporadic ACCs, aiming to uncover molecular distinctions between these groups. Since our last update, we have generated data from over 20 patients, significantly expanding our dataset. We are now integrating all mutational types, including single nucleotide variants (SNVs) and copy number variations (CNVs), to identify markers that distinguish inherited cancer predisposition syndromes from sporadic cases. Additionally, we are leveraging AI algorithms to analyse the mutational landscape in conjunction with histological features, aiming to develop more accurate predictive tools for clinical applications. Our work is paving the way for improved risk stratification and early detection strategies, ultimately contributing to better clinical management and personalised treatment approaches for ACC patients across different genetic backgrounds. My team is actively generating sequencing data of ACC samples with diverse genetic background. Currently we are analysing mutational landscapes and signatures using whole-genome sequencing (WGS) data obtained from laser-captured microbiopsies of tumours. The project's outcomes are set to provide a nuanced understanding of fundamental differences in ACC, with direct implications for improving patient care in a disease with significant unmet clinical needs. |
| Collaborator Contribution | We have acquired ACC samples through collaborations with biobanks and clinicians. Their cooperation has been invaluable to our research efforts on ACC tumors, as they have provided access to a substantial number of samples essential for our study. Their contribution has greatly enriched our understanding of ACC and has been pivotal in advancing our research in this area. |
| Impact | This project remains ongoing, and we have now successfully generated data from over 20 patients, significantly expanding our dataset. Our latest analyses are integrating multiple mutational types, including SNVs and CNVs, to identify markers that distinguish inherited cancer predisposition syndromes from sporadic ACC cases. Initial results from the first phase of analysis have been highly promising, with potential implications for the clinical management of individuals with cancer predisposition syndromes who develop ACC tumours. In addition, we are now applying AI algorithms to correlate mutational landscapes with histological features, aiming to develop predictive tools for improved diagnosis and risk stratification in clinical settings. This project is inherently multi-disciplinary, drawing expertise from oncology, genetics, genomics, bioinformatics, and computational pathology. By integrating clinical, molecular, and computational approaches, we are ensuring a comprehensive understanding of the evolutionary trajectories of ACCs across different germline backgrounds. This collaborative effort continues to drive forward critical insights with potential translational applications in precision medicine. |
| Start Year | 2023 |
| Description | Unravelling the evolutionary trajectory of adrenocortical carcinomas in hereditary cancer Predisposition syndromes |
| Organisation | Newcastle upon Tyne Hospitals NHS Charity |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition disorder caused by germline TP53 mutations, which significantly increase the risk of developing various cancers, including sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas (ACCs). Individuals with LFS face a lifetime cancer risk of approximately 80% for men and nearly 100% for women. As part of this collaboration, our research team has been focusing on characterising the mutational landscape of ACCs, with a specific emphasis on identifying key driver events, determining their temporal occurrence, and mapping the evolutionary trajectories of ACCs across different germline backgrounds. A major aspect of our work involves comparative analyses of ACCs in individuals with LFS, Beckwith-Wiedemann syndrome (BWS), and those with sporadic ACCs, aiming to uncover molecular distinctions between these groups. Since our last update, we have generated data from over 20 patients, significantly expanding our dataset. We are now integrating all mutational types, including single nucleotide variants (SNVs) and copy number variations (CNVs), to identify markers that distinguish inherited cancer predisposition syndromes from sporadic cases. Additionally, we are leveraging AI algorithms to analyse the mutational landscape in conjunction with histological features, aiming to develop more accurate predictive tools for clinical applications. Our work is paving the way for improved risk stratification and early detection strategies, ultimately contributing to better clinical management and personalised treatment approaches for ACC patients across different genetic backgrounds. My team is actively generating sequencing data of ACC samples with diverse genetic background. Currently we are analysing mutational landscapes and signatures using whole-genome sequencing (WGS) data obtained from laser-captured microbiopsies of tumours. The project's outcomes are set to provide a nuanced understanding of fundamental differences in ACC, with direct implications for improving patient care in a disease with significant unmet clinical needs. |
| Collaborator Contribution | We have acquired ACC samples through collaborations with biobanks and clinicians. Their cooperation has been invaluable to our research efforts on ACC tumors, as they have provided access to a substantial number of samples essential for our study. Their contribution has greatly enriched our understanding of ACC and has been pivotal in advancing our research in this area. |
| Impact | This project remains ongoing, and we have now successfully generated data from over 20 patients, significantly expanding our dataset. Our latest analyses are integrating multiple mutational types, including SNVs and CNVs, to identify markers that distinguish inherited cancer predisposition syndromes from sporadic ACC cases. Initial results from the first phase of analysis have been highly promising, with potential implications for the clinical management of individuals with cancer predisposition syndromes who develop ACC tumours. In addition, we are now applying AI algorithms to correlate mutational landscapes with histological features, aiming to develop predictive tools for improved diagnosis and risk stratification in clinical settings. This project is inherently multi-disciplinary, drawing expertise from oncology, genetics, genomics, bioinformatics, and computational pathology. By integrating clinical, molecular, and computational approaches, we are ensuring a comprehensive understanding of the evolutionary trajectories of ACCs across different germline backgrounds. This collaborative effort continues to drive forward critical insights with potential translational applications in precision medicine. |
| Start Year | 2023 |
| Description | Li-Fraumeni Syndrome (LFS) patient & family research workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | This annual workshop brings together Li-Fraumeni Syndrome (LFS) patients, their families, clinicians, and researchers to foster discussion, enhance patient involvement, and raise awareness about the latest scientific advancements in LFS research. Each year, we present our latest findings, including insights into germline TP53 mutations, cancer risk assessment, and new discoveries in genetic predisposition and surveillance strategies. The workshop provides a platform for patients and families to engage directly with researchers, ask questions, and share their experiences, ensuring that our research remains patient-centered and clinically relevant. By maintaining this ongoing engagement for consecutive years, we aim to strengthen patient involvement, improve understanding of LFS, and support more informed decision-making for individuals and families affected by the condition. This initiative continues to have a meaningful impact, promoting collaborative dialogue between the research and patient communities while guiding future research directions. |
| Year(s) Of Engagement Activity | 2023,2024,2025 |
| URL | http://www.tp53.co.uk/lfs-uk-2023/ |