High-risk Shadows in a Favorable-risk Disease: The Indian Genomic Landscape of CBF-AML
Bhargava Rahul *
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Nathany Shrinidhi
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Surange Devyani
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Swaminathan Anusha
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Dua Vikas
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Bhurani Dinesh
Hematology and BMT, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.
K Nath Swarsat
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Makda Moin
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Panda Rastogi Neha
Infectious Diseases, Hematology and BMT, Fortis Memorial Research Insti- tute, Gurugram, India.
Arora Sunisha
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Chakraborty Sohini
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Garg Paritosh
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Verma Haristuti
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Shrivastava Harshu
Hematology and BMT, Fortis Memorial Research Institute, Gurugram, India.
Gupta Aastha
Hematopathology, Fortis Memorial Research Institute, Gurugram, India.
Raizada Niti
Hematology and BMT, Fortis Hospital BG Road, Bangalore, India.
Ahmed Rayaz
Hematology and BMT, Max Superspeciality Hospital, Saket, New Delhi, India.
Singh Reema
Hematology and BMT, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.
Singh Aakanksha
Hematology and BMT, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.
Pachauri Priyanshi
Hematology and BMT, Fortis Hospital Noida, India.
*Author to whom correspondence should be addressed.
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.
Keywords: Core-binding factor acute myeloid leukaemia, next-generation sequencing, co-mutation profile, cytogenetics, NRAS, WT1, spliceosome mutations, Indian cohort