Telomere content is increased in TP53-mutated myeloid malignancies. (A) Telomere content in units of telomeric reads per GC content–matched million reads (TRPM) was quantified in WGS from tumor specimens (orange) and paired germ line control tissues (skin or buccal DNA, blue) for CBF AML and TP53-mutated myeloid malignancies. Significant telomere shortening in the CBF sample subset, with a mean shortening of 226 telomeric reads per GC content–matched million reads (TRPM; P = 8.3 × 10−7; 2-sided, paired t test) but not in the TP53-mutant subset (mean difference of −2.5 TRPM between tumor and normal). (B) Ratio of telomere content for tumor compared with normal tissue. TP53-mutated myeloid malignancies have significantly higher telomere content compared with CBF AML (P = 1.7 × 10−5, 2-sided t test). (C) Relative abundance of telomere variant repeats (TVR) in singleton context. Log2 tumor-to-normal ratio of singleton TVR repeats in TP53-mutant and CBF subtypes. The relative abundance of singleton TTTGGG repeats is significantly higher in TP53-mutated myeloid malignancies compared with CBF AML (P = 1.4 × 10−7, 2-sided t test). (D) Example of intrachromosomal insertion of t-type telomeric hexamer sequences seen in the tumor but not the paired normal sequence data from a TP53-mutated case (UPN 387082). (E) Fractions of patients with TP53-mutated myeloid malignancies (n = 42) and CBF AML (n = 18) with detectable interstitial (nontelomere) telomeric repeat variants (P = .006, Fisher exact test). (F) TP53-mutated cases with detectable interstitial insertions of telomeric variant repeats have higher SV counts (P = .0033, Wilcoxon ranked-sums test). (G) Fraction of TP53-mutated cases with detectable interstitial insertions of telomeric variant repeats in sample with (n = 25) and without (n = 17) chromothripsis (P value, not significant; odds ratio, 3.03; 95% confidence interval, 0.61-20.7; Fisher exact test).
