High-risk Shadows in a Favorable-risk Disease: The Indian Genomic Landscape of CBF-AML

Abstract

Background: Core-binding factor AML (CBF-AML), defined by RUNX1::RUNX1T1 and CBFB::MYH11 fusions, is conventionally classified as favorable-risk. Genomic data from low- and middle-income countries such as India remain limited. Aims: This study aimed to characterise the co-mutational and cytogenetic landscape of Indian CBF-AML and compare co-mutation frequencies with the TCGA CBF-AML cohort. Methods: This retrospective study analysed 165 Indian CBF-AML cases from two tertiary-care centres using targeted next-generation sequencing and, where available, cytogenetic analysis. Only Tier I/II pathogenic or likely pathogenic somatic variants with a variant allele fraction of ≥5% were counted as co-mutations; variants of uncertain significance were catalogued separately. Co-mutation frequencies were compared with 18 CBF-AML cases from The Cancer Genome Atlas using Fisher’s exact tests. Results: Median age was 33.4 years (range 16–45; M:F = 3.1:1). RUNX1::RUNX1T1 predominated (70%; 116/165) and CBFB::MYH11 accounted for 30% (49/165). At least one co-mutation was present in 70% of RUNX1::RUNX1T1 and 80% of CBFB::MYH11 cases. NRAS was the most common co-mutation (32%). Compared with t(8;21), inv(16) cases showed significantly more spliceosome (p=0.028) and WT1 (p=0.021) mutations. Two cases carried complex-karyotype TP53 mutations. Among 62 karyotyped cases, at least one additional cytogenetic abnormality was seen in 32, most commonly trisomy 8 and trisomy 22. Conclusion: Indian CBF-AML shares the core biology of Western cohorts but shows a higher co-mutational burden and enrichment of WT1 and spliceosome mutations in the inv(16) subtype. These descriptive findings, together with limited access to gemtuzumab ozogamicin in India, are hypothesis-generating and support prospective, outcome-linked evaluation of whether a uniform favorable-risk label is appropriate in this setting. No survival, MRD, or treatment data are presented; prognostic conclusions cannot be drawn.