High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis by Katharine A. Lombardo, David G. Coffey,

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High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis by Katharine A. Lombardo, David G. Coffey, Alicia J. Morales, Christopher S. Carlson, Andrea M. H. Towlerton, Sarah E. Gerdts, Francis K. Nkrumah, Janet Neequaye, Robert J. Biggar, Jackson Orem, Corey Casper, Sam M. Mbulaiteye, Kishor G. Bhatia, and Edus H. Warren BloodAdv Volume 1(9):535-544 March 28, 2017 ©2017 by American Society of Hematology

Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology

HTS of gDNA and RNA from Ugandan BL tumors identifies the repertoire of Ig rearrangements and sequence variants in tumor cells. HTS of gDNA and RNA from Ugandan BL tumors identifies the repertoire of Ig rearrangements and sequence variants in tumor cells. (A-B) Cumulative frequency plots of all unique IGH (A) or IGK/IGL (B) sequences identified by HTS of gDNA from the Ugandan BL cohort. Each segment in the bar plots represents a unique nucleotide sequence, and the color indicates the type of Ig rearrangement. Black lines separate the unique sequences, so highly polyclonal regions appear black in the figure. *Indicates that the tumor sample was EBV-negative; †indicates that the repertoire was classified as polyclonal. (C) Normalized c-MYC expression for each of the 18 Ugandan tumors on which RNAseq analysis was performed. RNAseq was not performed on sample 009-0210 due to poor quality RNA. (D) Genes with at least 1 single nucleotide variant (SNV) detected in RNAseq and predicted to be pathologic in each of the 18 Ugandan BL tumors. A red box indicates the presence of at least 1 SNV. Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology

HTS of gDNA from Ghanaian BL tumors identifies the repertoire of Ig rearrangements in tumor cells. HTS of gDNA from Ghanaian BL tumors identifies the repertoire of Ig rearrangements in tumor cells. (A-B) Cumulative frequency plots of all unique IGH (A) or IGK/IGL (B) sequences identified by HTS of gDNA from the Ghanaian BL cohort. Each segment in the bar plots represents a unique nucleotide sequence, and the color indicates the type of Ig rearrangement. Black lines separate the unique sequences, so polyclonal regions appear black in the figure. *Indicates that the tumor sample was EBV-negative; †indicates that the repertoire was classified as polyclonal. Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology

HTS of IGH in BL tumors reveals large families of closely related sequences. HTS of IGH in BL tumors reveals large families of closely related sequences. (A) Phylogenetic tree of all IGH sequences observed in a representative BL tumor sample. Unique IGH VDJ gene rearrangements are indicated by node color. The red arrow indicates the dominant unique sequence identified in the tumor. (B-G) Density plots of nucleotide edit distance (the number of nucleotide differences between a given unique sequence and the most frequent sequence in the tumor) for all sequences identified in all BL IGH samples (B), BL IGK/IGL samples (C), BL TRB samples (D), nonmalignant bone marrow and PBMC IGH control samples (E), bone marrow control IGK/IGL samples (F), and for CD8+ T-cell clones (G). (H) Clonal relatedness scores for each of the sample populations listed above (defined as the total number of distinct unique sequences with an edit distance <10 from the most frequent sequence, divided by the total number of unique sequences). Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology

Biased IGHV gene utilization observed in BL tumors. Biased IGHV gene utilization observed in BL tumors. (A) Heat map illustrating IGHV gene usage in the 30 endemic BL samples from our cohorts, 40 published endemic BL samples, and 61 published sporadic BL samples, as compared with 42 healthy controls. Highly enriched IGHV genes are indicated in red, and genes with significant differential utilization (P < .05) in BL tumor and control B cells are indicated by an asterisk. Both IGHV gene utilization and all samples are clustered by similarity. (B) Frequency of IGHV gene utilization in the 5 significantly differentially used IGHV genes. IGHV gene frequencies in BL tumors are plotted in red, and IGHV gene frequencies of healthy controls are plotted in blue. Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology

Nonsynonymous sites of SHM and SHM-induced NLGS are enriched in CDRs Nonsynonymous sites of SHM and SHM-induced NLGS are enriched in CDRs. Analyses were performed on all clonal BL tumors for which the complete V region of the most frequent sequence could be determined by capillary sequencing (n = 29). Nonsynonymous sites of SHM and SHM-induced NLGS are enriched in CDRs. Analyses were performed on all clonal BL tumors for which the complete V region of the most frequent sequence could be determined by capillary sequencing (n = 29). (A) Sites of nonsynonymous SHM plotted per amino acid residue in each IGH gene region. Statistically significant differences in SHM incidence are indicated by asterisks. (B) Sites of nonsynonymous (NS) and synonymous (S) SHM plotted per nucleotide residue in EBV+ and EBV– tumors by CDR or FR. (C) A schematic of an IGH or IGK/IGL gene rearrangement is shown and the location of all NLGS (Asn-X-Ser/Thr amino acid motifs) identified within a complete clonal BL tumor IGH and IGK/IGL sequences are indicated by red circles. Katharine A. Lombardo et al. Blood Adv 2017;1:535-544 ©2017 by American Society of Hematology