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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,12,3]]},"abstract":"<jats:p>\n                    The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell SEs at single-nucleotide resolution from 10 healthy individuals across diverse ethnicities. We detected a total of approximately 9,000 subclonal mutations (allele frequencies &lt;0.1%); of these, approximately 8,000 are present in the\n                    <jats:italic>BCL6<\/jats:italic>\n                    SE alone. Within the\n                    <jats:italic>BCL6<\/jats:italic>\n                    SE, we identified 3 regions of clustered mutations in which the mutation frequency is \u223c7 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    . Mutational spectra show a predominance of C &gt; T\/G &gt; A and A &gt; G\/T &gt; C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase \u03b7, respectively, in mutagenesis in normal B cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signatures SBS85, SBS37, and SBS39 were found in the\n                    <jats:italic>BCL6<\/jats:italic>\n                    SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1914163116","type":"journal-article","created":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T19:54:14Z","timestamp":1574279654000},"page":"24779-24785","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["A high-resolution landscape of mutations in the\n                    <i>BCL6<\/i>\n                    super-enhancer in normal human B cells"],"prefix":"10.1073","volume":"116","author":[{"given":"Jiang-Cheng","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini S.","family":"Kamath-Loeb","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-2131","authenticated-orcid":false,"given":"Brendan F.","family":"Kohrn","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith R.","family":"Loeb","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"},{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley D.","family":"Preston","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6291-4498","authenticated-orcid":false,"given":"Lawrence A.","family":"Loeb","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195;"},{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,11,20]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nri2217","article-title":"Germinal centres: Role in B cell physiology and malignancy","volume":"8","author":"Klein U.","year":"2008","unstructured":"U. 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