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:Mutational signatures' association with replication timing (RT) has been studied in cancer samples, but the RT distribution of somatic mutations in non-cancerous cells was only minimally explored. Here, we performed comprehensive analyses of mutational signatures in 2.9 million somatic mutations across multiple non-cancerous tissues, stratified by early and late RT regions. We found that many mutational processes are active mainly or solely in early RT, such as SBS16 in hepatocytes and SBS88 in the colon, or in late RT, such as SBS4 in lung and hepatocytes, and SBS18 across many tissues. The two ubiquitous signatures, SBS1 and SBS5, showed late and early bias, respectively, across multiple tissues and in mutations representing germ cells. We also performed a direct comparison with cancer samples in 4 matched tissue-cancer types. Unexpectedly, while for most signatures the RT bias was consistent in normal tissue and in cancer, we found that SBS1's late RT bias is lost in cancer.
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.