Figure 1.
Integrative comutation patterns in MDS and implications for genotype-phenotype analysis. (A) Proportion and number of patients with or without gene mutations (mut.), cytogenetic alterations, and cnLOH events. (B) Number of patients with cnLOH at the most recurrent loci and co-occurrence of gene mutations in cis. The most recurrent cnLOH loci were 4/4q (2.6%), 17/17p (2.3%), and 7/7q (1.6%). Mutations in TET2, TP53, and EZH2 occurred in 94% (78/83), 96% (75/78), and 79% (42/53) of cases with cnLOH at the 4/4q, 17/17p, and 7/7q loci, respectively. (C) Heat map representing mutual exclusivity (brown) or co-occurrence (green) between gene mutations and loci with haploid LOH or cnLOH. Apart from the strong cnLOH–gene mutation interaction in cis (black thick line), focal deletions at the TET2 locus (4q24) also co-occurred with TET2 mutations (OR, 2.4; P = .0007). P values are from Fisher exact test with Benjamini-Hochberg (BH) multiple testing correction. (D) Comparison of comutation frequencies between cases with cnLOH (blue) or haploid LOH (gold) at 7/7q in the absence of CK. For example, mutations in EZH2 were enriched in the 53 cases with cnLOH at 7/7q (79%) compared with the 125 cases with isolated haploid LOH at 7/7q (10%). Conversely, haploid LOH at 7/7q was significantly enriched for U2AF1 and DNMT3A mutations (28% and 20%) compared with cnLOH at 7/7q (9% and 2%). P values are from Fisher exact test with BH multiple testing correction. ∗∗∗P < .001; ∗∗P < .01; ∗P < .05. (E) Comparison of the distributions of blood counts and of the percentage of BM blasts between cases classified as TET2 biallelic (blue) or TET2 other (ie, likely monoallelic, gold). P values are from the Wilcoxon rank-sum test. ∗∗∗∗P < .0001; ∗∗∗P < .001. (F) Comparison of comutation frequencies between cases with U2AF1 Q157 or S34 hot spot mutations. For example, ASXL1 mutations were present in 65% and 20% of patients with U2AF1 Q157 and S34 mutations, respectively (OR, 7.3; P < .0001). Mutations in CUX1, EZH2, PHF6, SETBP1, TP53, and monosomy 7 were also significantly more frequent in the Q157 subset. Conversely, BCOR mutations and del(20q) were more common in patients with S34 (26%) compared with Q157 (3%) mutations (P < .0001). P values are from Fisher exact test with BH multiple testing correction. ∗∗∗P < .001; ∗∗P < .01. FDR, false discovery rate; PTD, partial tandem duplication.

Integrative comutation patterns in MDS and implications for genotype-phenotype analysis. (A) Proportion and number of patients with or without gene mutations (mut.), cytogenetic alterations, and cnLOH events. (B) Number of patients with cnLOH at the most recurrent loci and co-occurrence of gene mutations in cis. The most recurrent cnLOH loci were 4/4q (2.6%), 17/17p (2.3%), and 7/7q (1.6%). Mutations in TET2, TP53, and EZH2 occurred in 94% (78/83), 96% (75/78), and 79% (42/53) of cases with cnLOH at the 4/4q, 17/17p, and 7/7q loci, respectively. (C) Heat map representing mutual exclusivity (brown) or co-occurrence (green) between gene mutations and loci with haploid LOH or cnLOH. Apart from the strong cnLOH–gene mutation interaction in cis (black thick line), focal deletions at the TET2 locus (4q24) also co-occurred with TET2 mutations (OR, 2.4; P = .0007). P values are from Fisher exact test with Benjamini-Hochberg (BH) multiple testing correction. (D) Comparison of comutation frequencies between cases with cnLOH (blue) or haploid LOH (gold) at 7/7q in the absence of CK. For example, mutations in EZH2 were enriched in the 53 cases with cnLOH at 7/7q (79%) compared with the 125 cases with isolated haploid LOH at 7/7q (10%). Conversely, haploid LOH at 7/7q was significantly enriched for U2AF1 and DNMT3A mutations (28% and 20%) compared with cnLOH at 7/7q (9% and 2%). P values are from Fisher exact test with BH multiple testing correction. ∗∗∗P < .001; ∗∗P < .01; ∗P < .05. (E) Comparison of the distributions of blood counts and of the percentage of BM blasts between cases classified as TET2 biallelic (blue) or TET2 other (ie, likely monoallelic, gold). P values are from the Wilcoxon rank-sum test. ∗∗∗∗P < .0001; ∗∗∗P < .001. (F) Comparison of comutation frequencies between cases with U2AF1 Q157 or S34 hot spot mutations. For example, ASXL1 mutations were present in 65% and 20% of patients with U2AF1 Q157 and S34 mutations, respectively (OR, 7.3; P < .0001). Mutations in CUX1, EZH2, PHF6, SETBP1, TP53, and monosomy 7 were also significantly more frequent in the Q157 subset. Conversely, BCOR mutations and del(20q) were more common in patients with S34 (26%) compared with Q157 (3%) mutations (P < .0001). P values are from Fisher exact test with BH multiple testing correction. ∗∗∗P < .001; ∗∗P < .01. FDR, false discovery rate; PTD, partial tandem duplication.

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