American Society of Hematology

Figure 7.

$Figure 7. Significantly different distributions of CREBBP mutations in human FL compared with DLBCL. (A) CREBBP mutation data were obtained for a total of 310 FL and 274 DLBCL in which both diseases were interrogated in the same study using the same approach. Mutations in CREBBP were identified in 151 FL and 51 DLBCL, and the relative representation of the position of these mutations are expressed as a fraction of all CREBBP mutations in that disease, relative to the protein position of CREBBP isoform 1. The KAT domain is shaded in green and defined as amino acids 1342 to 1649. Larger peaks, indicative of a higher fraction of all CREBBP mutations, are seen upstream of the KAT domain in DLBCL compared with FL. In addition, a dominant hotspot can be seen at arginine 1446 in FL that is significantly reduced in DLBCL. In contrast, other hotspots at tyrosine 1482 and 1503 are present at relatively similar frequencies in both FL and DLBCL. (B) Pie graphs show that 78% (118/151) of CREBBP mutations fall within the KAT domain in FL, as compared with only 43% (22/51) in DLBCL (Fisher’s exact test, P < .001). (C) Pie graphs show that only 17% (25/151) of CREBBP mutations in FL create a frameshift of premature stop codon, while the remainder creates single-amino-acid substitutions or insertion/deletions. In contrast, missense/frameshift mutations are present at greater than twice this frequency, 39% (20/51), in DLBCL (Fisher’s exact test, P = .0016). (D) Gene expression microarray data from DLBCL tumors with previously determined CREBBP mutational status were used to evaluate MYC expression. There was a significantly higher expression of MYC in tumors with CREBBP mutation compared with those with no CREBBP mutation (1-tailed Student t test, P = .026). This is despite the unknown MYC translocation status that may alter the expression of MYC in a subset of cases. (E) MYC translocation status was available for 54 cases with known CREBBP mutation status. We observed no overlap in CREBBP mutation and MYC translocation, although this was not statistically significant.$

Significantly different distributions of CREBBP mutations in human FL compared with DLBCL. (A) CREBBP mutation data were obtained for a total of 310 FL and 274 DLBCL in which both diseases were interrogated in the same study using the same approach. Mutations in CREBBP were identified in 151 FL and 51 DLBCL, and the relative representation of the position of these mutations are expressed as a fraction of all CREBBP mutations in that disease, relative to the protein position of CREBBP isoform 1. The KAT domain is shaded in green and defined as amino acids 1342 to 1649. Larger peaks, indicative of a higher fraction of all CREBBP mutations, are seen upstream of the KAT domain in DLBCL compared with FL. In addition, a dominant hotspot can be seen at arginine 1446 in FL that is significantly reduced in DLBCL. In contrast, other hotspots at tyrosine 1482 and 1503 are present at relatively similar frequencies in both FL and DLBCL. (B) Pie graphs show that 78% (118/151) of CREBBP mutations fall within the KAT domain in FL, as compared with only 43% (22/51) in DLBCL (Fisher’s exact test, P < .001). (C) Pie graphs show that only 17% (25/151) of CREBBP mutations in FL create a frameshift of premature stop codon, while the remainder creates single-amino-acid substitutions or insertion/deletions. In contrast, missense/frameshift mutations are present at greater than twice this frequency, 39% (20/51), in DLBCL (Fisher’s exact test, P = .0016). (D) Gene expression microarray data from DLBCL tumors with previously determined CREBBP mutational status were used to evaluate MYC expression. There was a significantly higher expression of MYC in tumors with CREBBP mutation compared with those with no CREBBP mutation (1-tailed Student t test, P = .026). This is despite the unknown MYC translocation status that may alter the expression of MYC in a subset of cases. (E) MYC translocation status was available for 54 cases with known CREBBP mutation status. We observed no overlap in CREBBP mutation and MYC translocation, although this was not statistically significant.

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