Project description:Somatic mutations (burdens and signatures) and clonal dynamics in normal human tissues from the gastrointestinal tract of individuals with tumour predisposition syndromes and DNA damage repair defects.
Project description:Somatic mutations (burdens and signatures) and clonal dynamics in normal human tissues from the gastrointestinal tract of individuals with tumour predisposition syndromes and DNA damage repair defects.
Project description:Repetitive sequences are hotspots of evolution at multiple levels. However, due to technical difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content of proteomes and genomes, directly from proteomic and genomic raw sequence data, and applied it to analyze a wide range of tumors and normal tissues. We identify high similarity between the repeat-instability in tumors and their patient-matched normal tissues, but also tumor-specific signatures, both in protein expression and in the genome, that strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We find an inverse relationship between repeat-instability and point mutation load, within and across patients, and independently of other somatic aberrations. Thus, repeat-instability is a distinct, transient and compensatory adaptive mechanism in tumor evolution.
Project description:To identify aberrantly expressed long intergenic noncoding RNAs (lincRNAs) in muscle-invasive bladder cancer tissues compared with normal adjacent tissues, we have employed microarray expression profiling as a discovery platform to identify lincRNAs that may play important roles in bladder cancer progression. Samples of fresh frozen cancer tissues, together with normal adjacent tissues (3 cm away from the tumor), were obtained during surgical resection, and total RNA was extracted for microarray analysis.
Project description:To identify aberrantly expressed long intergenic noncoding RNAs (lincRNAs) in bladder cancer tissues compared with normal adjacent tissues, we have employed microarray expression profiling as a discovery platform to identify lincRNAs that may play important roles in bladder cancer origin and progression. Samples of fresh frozen cancer tissues, together with normal adjacent tissues (3 cm away from the tumor), were obtained during surgical resection, and total RNA was extracted for microarray analysis.
Project description:This study aims to characterise the mutation burdens and signatures of adult stem cells derived from different regions of the stomach in order to gain insight into the causes and preclinical evolution of the diverse cancer subtypes. Clonal populations of cells from different anatomical locations of the stomach will be derived through organoid culture and/or laser microdissection and interrogated by whole genome sequencing and/or targeted pulldown. A total of circa 300 samples from 20 – 30 donors (cancer and non-cancer patients undergoing total/partial gastrectomy) will be analysed for mutational burden and signatures and genomic findings correlated with topology, age, risk factors and different stages of pre-neoplastic or neoplastic progression.