The genetic landscape of 207 patients with TBD. (A) An OncoPrint plot of somatic alterations detected in 207 patients with TBD based on patients’ clinical characteristics at the time of diagnosis or first visit. The number of mutations in each gene is shown on the left side of the graph. Most patients were symptomatic, but 35 patients were asymptomatic, including 2 who had isolated findings that did not meet the criteria for disease categories used in the study (isolated mucocutaneous findings and esophageal cancer). (B) The number of PGVs in TBD-related genes based on disease status. The frequency of mutations is also shown according to the affected gene. (C) CH in patients with TBD (n = 207). The top mutated genes and frequency of mutations, the type of mutation allelic transition, and the number of mutations per patient are shown in the figure. Somatic variants were primarily missense, median number of variants per patient was 1, and mutational signatures were mainly C→T/A. Clonal profiles were derived from symptomatic patients (only 1 asymptomatic patient had CH involving PPM1D and TERTp). (D) Somatic and germ line gene-gene interactions showing the mutually exclusive or co-occurring set of mutated genes. Significant interactions by the pair-wise Fisher exact test are depicted by asterisks (P < .05). Both somatic mutations and PGVs were found in POT1 and TINF2; POT1Δ and TINF2Δ refer to sets of somatic mutations in these genes. Genomic plots were generated using the Maftools package. (E) VAF of somatic mutations identified in PB. Boxes indicate VAF frequencies and ranges relative to each mutated gene. Centerline, median; box limits, upper and lower quartiles. PPM1D, TERTp, and POT1 mutations were mostly found at a median VAF of 1% (range, 0.5%-18%), 4% (range, 0.8%-32%), and 2% (range, 0.5%-39%), respectively. In contrast, U2AF1 and other MDS/AML-related mutations, mostly in splicing factors, were found at a median VAF of 11% (range, 0.8%-46%) and 4% (range, 0.5%-31%), respectively. Somatic mutations identified in patients with MDS/AML are highlighted in red. (F) Linear representations of signature CH genes mutated in our cohort. Blue and red circles represent missense and nonsense/frameshifts or splicing variants, respectively.

The genetic landscape of 207 patients with TBD. (A) An OncoPrint plot of somatic alterations detected in 207 patients with TBD based on patients’ clinical characteristics at the time of diagnosis or first visit. The number of mutations in each gene is shown on the left side of the graph. Most patients were symptomatic, but 35 patients were asymptomatic, including 2 who had isolated findings that did not meet the criteria for disease categories used in the study (isolated mucocutaneous findings and esophageal cancer). (B) The number of PGVs in TBD-related genes based on disease status. The frequency of mutations is also shown according to the affected gene. (C) CH in patients with TBD (n = 207). The top mutated genes and frequency of mutations, the type of mutation allelic transition, and the number of mutations per patient are shown in the figure. Somatic variants were primarily missense, median number of variants per patient was 1, and mutational signatures were mainly C→T/A. Clonal profiles were derived from symptomatic patients (only 1 asymptomatic patient had CH involving PPM1D and TERTp). (D) Somatic and germ line gene-gene interactions showing the mutually exclusive or co-occurring set of mutated genes. Significant interactions by the pair-wise Fisher exact test are depicted by asterisks (P < .05). Both somatic mutations and PGVs were found in POT1 and TINF2; POT1Δ and TINF2Δ refer to sets of somatic mutations in these genes. Genomic plots were generated using the Maftools package. (E) VAF of somatic mutations identified in PB. Boxes indicate VAF frequencies and ranges relative to each mutated gene. Centerline, median; box limits, upper and lower quartiles. PPM1D, TERTp, and POT1 mutations were mostly found at a median VAF of 1% (range, 0.5%-18%), 4% (range, 0.8%-32%), and 2% (range, 0.5%-39%), respectively. In contrast, U2AF1 and other MDS/AML-related mutations, mostly in splicing factors, were found at a median VAF of 11% (range, 0.8%-46%) and 4% (range, 0.5%-31%), respectively. Somatic mutations identified in patients with MDS/AML are highlighted in red. (F) Linear representations of signature CH genes mutated in our cohort. Blue and red circles represent missense and nonsense/frameshifts or splicing variants, respectively.

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