ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability人类ultraconserved地区超深测序揭示体细胞和宪法的基因组不稳定性.pdf

Ultradeep Sequencing of a Human Ultraconserved Region Reveals Somatic and Constitutional Genomic Instability 1 1 1 2 3 2,4 Anna De Grassi , Cinzia Segala , Fabio Iannelli , Sara Volorio , Lucio Bertario , Paolo Radice , Loris 1 1 Bernard , Francesca D. Ciccarelli * 1 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy, 2 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, IFOM-IEO Campus, Milan, Italy, 3 Hereditary Colorectal Tumor Registry; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 4 Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Abstract Early detection of cancer-associated genomic instability is crucial, particularly in tumour types in which this instability represents the essential underlying mechanism of tumourigenesis. Currently used methods require the presence of already established neoplastic cells because they only detect clonal mutations. In principle, parallel sequencing of single DNA filaments could reveal the early phases of tumour initiation by detecting low-frequency mutations, provided an adequate depth of coverage and an effective control of the experimental error. We applied ultradeep sequencing to estimate the genomic instability of individuals with hereditary non-polyposis colorectal cancer (HNPCC). To overcome the experimental error, we used an ultraconserved region (UCR) of the human genome as an internal control. By comparing the mutability outside and inside the UCR, we observed a tendency of the ultraconserved element to accumulate significantly fewer mutations than the flanking segm