Title: Pathogenic variants and clonal dynamics in normal and cancerous testes and their role in cancer predisposition
Funder: Cancer Research UK

Abstract: Inherited cancers play a major role in about 5 to 10 percent of all cancers. It is increasingly apparent that many inherited cancer syndromes arise through new mutations acquired most likely in germline of fathers. Most of the burden of high-penetrance germline predisposition to cancer arises through mutations acquired during spermatogenesis. However, little is known about mutagenesis within the hierarchy of spermatogenesis or factors that influence rates of mutation in the testes. It is likely that mutations in spermatogonia stem cells that confer weaker selective advantage and generate smaller clonal expansions in the testes, become enrich in sperms and transmit to the next generations. However, due to the low sensitivity of standard genomic approaches, subclonal mutations that may only be present in small contiguous areas within testes have been poorly investigated. This proposal aims to provide a detailed description of the genetic changes in normal and precancerous in testicular tissue, and to understand how mutations acquired during spermatogenesis contribute to the germline predisposition to cancer for future offspring. Specifically, it aims to: (1) Construct the clonal dynamics in normal and cancerous testes and identifying factors that affect clonal structures. (2) Measure the mutational burden of pathogenic variants in sperms and to identify the processes that underlie their acquisition. (3) Provide an accurate estimate the recurrence risk of cancer-predisposition. This study, will use the state-of-the-art laser capture microdissection combined with sequencing methodologies (duplex and single cell sequencing) to generate a comprehensive overview of mutational landscape and clonal dynamics in testicular tissues. It will measure the heritability risk of pathogenic variants by screening sperms from normal donors and men with children diagnosed with germline de novo mutations (DNMs) cancer predisposition syndrome and early childhood cancers The outcome will identify the factors that influence the acquisition of DNMs during spermatogenesis, which are important for understanding inherited cancers. This work will address fundamental questions; for example, whether TP53 mutations in spermatogonia stem cells can lead to clonal expansion producing sperms that could cause LFS in the next generation. The results of this work will determine the recurrence risk of cancer-predisposing mutations in families with different genetic and environmental-exposure backgrounds. The outcome holds the promise of discovering fundamental oncogenic pathways and can have a great and broader clinical applications for developing screening tests for inherited cancer.

Lay abstract: Inherited cancers play a major role in about 5 to 10 percent of all cancers. It is increasingly apparent that many inherited cancer syndromes arise through new mutations acquired most likely in germline of fathers. Most of the burden of high-penetrance germline predisposition to cancer arises through mutations acquired during spermatogenesis. However, little is known about mutagenesis within the hierarchy of spermatogenesis or factors that influence rates of mutation in the testes. It is likely that mutations in spermatogonia stem cells that confer weaker selective advantage and generate smaller clonal expansions in the testes, become enrich in sperms and transmit to the next generations. However, due to the low sensitivity of standard genomic approaches, subclonal mutations that may only be present in small contiguous areas within testes have been poorly investigated. This proposal aims to provide a detailed description of the genetic changes in normal and precancerous in testicular tissue, and to understand how mutations acquired during spermatogenesis contribute to the germline predisposition to cancer for future offspring. Specifically, it aims to: (1) Construct the clonal dynamics in normal and cancerous testes and identifying factors that affect clonal structures. (2) Measure the mutational burden of pathogenic variants in sperms and to identify the processes that underlie their acquisition. (3) Provide an accurate estimate the recurrence risk of cancer-predisposition. This study, will use the state-of-the-art laser capture microdissection combined with sequencing methodologies (duplex and single cell sequencing) to generate a comprehensive overview of mutational landscape and clonal dynamics in testicular tissues. It will measure the heritability risk of pathogenic variants by screening sperms from normal donors and men with children diagnosed with germline de novo mutations (DNMs) cancer predisposition syndrome and early childhood cancers The outcome will identify the factors that influence the acquisition of DNMs during spermatogenesis, which are important for understanding inherited cancers. This work will address fundamental questions; for example, whether TP53 mutations in spermatogonia stem cells can lead to clonal expansion producing sperms that could cause LFS in the next generation. The results of this work will determine the recurrence risk of cancer-predisposing mutations in families with different genetic and environmental-exposure backgrounds. The outcome holds the promise of discovering fundamental oncogenic pathways and can have a great and broader clinical applications for developing screening tests for inherited cancer.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS