17p cytogenetic changes in TP53-mutated AML

Abstract Background In acute myeloid leukemia (AML), chromosomal rearrangements and point mutations involving the tumor suppressor gene TP53 confer adverse outcomes. We conducted a comprehensive analysis of 17p rearrangements in patients with TP53-mutated AML to assess their frequencies, patterns, and correlations with clinical outcomes. Methods We retrospectively reviewed AML cases diagnosed between 2019 and 2024 with both TP53 point mutations and 17p cytogenetic changes, identified via next-generation sequencing (NGS), karyotyping, and fluorescence in-situ hybridization (FISH). Cases lacking either NGS or cytogenetic studies were excluded. Survival outcomes were measured by Kaplan-Meier analysis with log-rank testing. Results Of 957 AML patients identified between 2019 and 2024, 104 had a TP53 mutation and/or 17p a cytogenetic abnormality at diagnosis. 12 patients were excluded due to incomplete NGS or cytogenetic studies, leaving 92 evaluable cases. The median age of diagnosis was 73 years (35 - 92 years). AML categories included: de novo (n = 58: 63.0%), history of prior myeloid neoplasm (n = 15: 16.3%), and history of prior cytotoxic chemotherapy and/or radiation (n = 19; 20.7%). The frequency of 17p cytogenetic changes did not significantly differ among AML categories (χ2 = 0.028). The majority of patients received induction therapy with a hypomethylating agent and venetoclax (HMA/venetoclax) with only 4 patients receiving anthracycline/cytarabine-based intensive induction therapy. 85.9% (n = 79) had ≥1 TP53 point mutation by NGS. 70.7% (n = 65) had ≥1 chromosomal abnormality involving 17p. Among those with a 17p structural abnormality, 80.0% (n = 52) also had ≥1 TP53 point mutation. 61 discrete cytogenetic rearrangements involving 17p were identified by karyotyping with del(17) being the most common (52.5%). Other rearrangements included additions (19.7%), deletions (11.5%), translocations (8.2%), pseudodicentric chromosomes (4.9%), and isochromosomes (3.3%) involving 17p. Among rearrangements with clearly defined breakpoints (n = 22), 68.2% involved 17p11.2. Of these, 80.0% co-occurred with at least one TP53 point mutation. No breakpoints were identified distal to TP53 at 17p13.1. 7 patients were found to have a 17p change by FISH but not with karyotyping. Although patients with 17p11.2 breakpoint mutations had the lowest survival (median OS of 5.2 mos), there was no significant difference between patients with del(17) (mOS 7.9 mos), or those with neither cytogenetic abnormality (mOS 12.7 mos; p = 0.49). Discussion In our cohort of patients with TP53-mutated AML, structural abnormalities involving 17p were common and often co-occurred with TP53 point mutations. No specific 17p abnormality, including del(17) or rearrangements with 17p11.2 breakpoints, were associated with improved overall survival. To our knowledge, this is the first report of recurrent breakpoint clustering at 17p11.2 in TP53-mutated AML; a region enriched for low-copy repeats (LCRs) known to mediate genomic instability (Zhang et al., 2005; Bi et al., 2002). Given that TP53 loss promotes chromosomal instability, and that most cases with a 17p11.2 breakpoint also harbored TP53 point mutations, it is plausible that LCRs at 17p11.2 contribute to aberrant repair of double-strand DNA breaks in the setting of impaired p53 function. This supports further investigation into LCR-driven instability as a mechanism of TP53 dysfunction and a potential target for genomic profiling or therapeutic intervention.