MAESTRO 8 [2016/22/A/NZ2/00184]

Analysis of somatic mutations in miRNA and miRNA-biogenesis genes to identify new therapeutic targets and biomarkers of cancer

Cancer encompasses a broad spectrum of diseases (>100) arising from the accumulation of somatically acquired mutations. These mutations provide a growth advantage to a tumor cell, resulting in clonal expansion leading to cancer progression. Among cancer-related mutations are loss-of-function mutations in tumor suppressor genes and gain-of-function mutations in oncogenes. Both tumor suppressor genes and oncogenes may be regulated by a class of short (~21 nt long) single-stranded noncoding RNAs known as microRNAs (miRNAs), that are intensively studied in cancer. They act predominantly by binding to the target mRNA 3’ UTR sequence. Although miRNAs are intensively studied in cancer and many miRNAs playing important roles in cancer have been already identified, the cancer somatic mutations in miRNA genes have been never studied before. It can be assumed that mutations in miRNA or its precursor sequence may alter the folding of the miRNA precursor structure, efficiency, and specificity of miRNA-biogenesis and the sequence of the miRNA itself, thus altering the spectrum of target mRNAs. The somatic mutations may both disrupt naturally occurring miRNAs and create new miRNAs that recognize targets completely different from the original ones, which may result in cancer development associated with gain- or loss-of-function of a specific MIRNA gene.  

Therefore, the main objective of the project is to identify cancer-driving somatic mutations in miRNA and miRNA-biogenesis genes.   

it’s hard to believe that at least part of genetic variation driving cancer is not hidden in the non-coding genome, especially in elements playing an important role in cancer, such as miRNA genes