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Research Article

A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells

Jiang-Cheng Shen, Ashwini S. Kamath-Loeb, View ORCID ProfileBrendan F. Kohrn, Keith R. Loeb, Bradley D. Preston, and View ORCID ProfileLawrence A. Loeb
PNAS December 3, 2019 116 (49) 24779-24785; first published November 20, 2019 https://doi.org/10.1073/pnas.1914163116
Jiang-Cheng Shen
aDepartment of Pathology, University of Washington, Seattle, WA 98195;
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Ashwini S. Kamath-Loeb
aDepartment of Pathology, University of Washington, Seattle, WA 98195;
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Brendan F. Kohrn
aDepartment of Pathology, University of Washington, Seattle, WA 98195;
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  • ORCID record for Brendan F. Kohrn
Keith R. Loeb
aDepartment of Pathology, University of Washington, Seattle, WA 98195;bClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
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Bradley D. Preston
aDepartment of Pathology, University of Washington, Seattle, WA 98195;
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Lawrence A. Loeb
aDepartment of Pathology, University of Washington, Seattle, WA 98195;cDepartment of Biochemistry, University of Washington, Seattle, WA 98195
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  • ORCID record for Lawrence A. Loeb
  • For correspondence: laaloeb@gmail.com
  1. Edited by James E. Cleaver, University of California San Francisco Medical Center, San Francisco, CA, and approved October 28, 2019 (received for review August 14, 2019)

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Significance

We used duplex sequencing to detect low-frequency mutations in the BCL6 super-enhancer locus in normal human B cells. The landscape of preexisting mutations is remarkably conserved across different ethnicities and reveals clustered mutational hotspots that correlate with reported sites of clonal mutations and translocation breakpoints in human B cell lymphomas. This high-resolution genomic landscape revealed by duplex sequencing offers accurate and thorough profiling of low-frequency preexisting mutations in normal individuals along with the potential for early detection of neoplastic alterations.

Abstract

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 <0.1%); of these, approximately 8,000 are present in the BCL6 SE alone. Within the BCL6 SE, we identified 3 regions of clustered mutations in which the mutation frequency is ∼7 × 10−4. Mutational spectra show a predominance of C > T/G > A and A > G/T > C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase η, 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 BCL6 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.

  • duplex sequencing
  • somatic hypermutation
  • BCL6
  • super-enhancer
  • mutational signatures

Footnotes

  • ↵1To whom correspondence may be addressed. Email: laaloeb{at}gmail.com.
  • Author contributions: J.-C.S., B.D.P., and L.A.L. designed research; J.-C.S. and A.S.K.-L. performed research; B.F.K. and K.R.L. contributed new reagents/analytic tools; J.-C.S., A.S.K.-L., B.F.K., K.R.L., B.D.P., and L.A.L. analyzed data; and J.-C.S., A.S.K.-L., and L.A.L. wrote the paper.

  • Competing interest statement: L.A.L. is a founder and equity holder at TwinStrand Biosciences.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data in this paper have been uploaded to NCBI BioProject (accession no. PRJNA574179).

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1914163116/-/DCSupplemental.

Published under the PNAS license.

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A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells
Jiang-Cheng Shen, Ashwini S. Kamath-Loeb, Brendan F. Kohrn, Keith R. Loeb, Bradley D. Preston, Lawrence A. Loeb
Proceedings of the National Academy of Sciences Dec 2019, 116 (49) 24779-24785; DOI: 10.1073/pnas.1914163116

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A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells
Jiang-Cheng Shen, Ashwini S. Kamath-Loeb, Brendan F. Kohrn, Keith R. Loeb, Bradley D. Preston, Lawrence A. Loeb
Proceedings of the National Academy of Sciences Dec 2019, 116 (49) 24779-24785; DOI: 10.1073/pnas.1914163116
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