Additional sex combs-like 1 variants in an acute myeloid leukaemia and a general elderly cohort in central South Africa.

BACKGROUND

In patients with acute myeloid leukaemia (AML), pathogenic variants in the additional sex combs-like 1 (ASXL1) gene confer poor prognosis and are frequently involved in clonal haematopoiesis of indeterminate potential, with increasing prevalence with advancing age.

OBJECTIVE

We determined the prevalence of ASXL1 variants in an AML cohort and general elderly population in central South Africa.

METHODS

The study included 40 participants with de novo AML and 100 elderly participants (≥ 65 years). Polymerase chain reactions and Oxford nanopore sequencing of ASXL1 exon 12 were performed on all samples between 01 October 2023 and 30 September 2024.

RESULTS

Of the 40 AML participants, 25 (62.5%) were women, with a median age of 42 years. ASXL1 mutations were detected in 5%. In total, 248 ASXL1 variants were detected in 68 of the 100 elderly participants aged 65-88 years (mean 71 years). Variants in the coding regions included synonymous (58.4%) and missense (41.6%) variants. Benign variants were detected in 29% of the elderly participants, while variants of uncertain significance were present in 2%, each with a variant allele frequency of ≥ 20%. No pathogenic or likely pathogenic variants were identified.

CONCLUSION

The prevalence of ASXL1 exon 12 variants in our AML cohort was consistent with international data. Variants in the elderly population were very prevalent; however, with no actionable variants capable of driving clonal expansion, clonal haematopoiesis of indeterminate potential was not detected. The variants of uncertain significance at allele frequencies of ≥ 2% likely suggest a clonal haematopoietic process.

WHAT THIS STUDY ADDS: Routine ASXL1 testing in all AML patients is not recommended in our resource-limited setting. Testing should be individualised according to its potential clinical impact, using high-throughput sequencing with clinically relevant variant classification.