Prognostic Genomic Biomarkers for Acute Myeloid Leukemia (AML) Based on French-American-British (FAB) Subtypes

Background: The FAB classification system divides AML into eight subtypes, M0-M7, based on the blast cell morphology and its degree of myeloid maturation. It's an older system to classify AML, but is still used in some treatment protocols. Some prognostic factors related to patient and tumor characteristics have been previously described for AML, including age, Karnofsky score, and karyotype etc. However, the prognostic genomic biomarkers for detailed FAB subtypes of AML are not well defined.

Design: Whole genome sequencing data were analyzed in 197 cases of AML. Twenty-four mutation genes and 38 copy number altered genes were selected based on change rate >=2% as a cutoff. Kaplan Meier Survival analysis for these genes was performed in five FAB subtypes (M0-M5). M6 and M7 are excluded from this study because of small sample size (M6, n=3; M7, n=3). All sequencing data and corresponding pathology information were from The Cancer Genome Atlas (Acute Myeloid Leukemia, TCGA provisional) and were analyzed via cBioPortal bioinformatics tool.

Result: Total of seven mutation genes and two copy number altered genes show prognostic values. TP53 gene mutation is associated with worse overall survival in M0 (n=18). DNMT3A gene mutation is associated with worse overall survival in M1 (n=44). Gene mutations of NPM1, FLT3, IDH1 and gene amplification of KMT2A are associated with worse overall survival in M2 (n=44). BRINP3 gene mutation is associated with worse overall survival in M3 (n=21). TP53 gene mutation and gene amplification of KMT2A and ERG are associated with worse overall survival in M4 (n=39). KRAS mutation is associated with worse overall survival in M5 (n=22). (Log-rank test, p<0.05 for all tests)

Conclusion: These data suggest that different FAB subtypes of AML could have unique prognostic genomic biomarkers. Compared with whole exome sequencing, targeted gene sequencing for these biomarkers may save time and money for patients. Further studies are necessary to understand the biological effects of these gene mutations/amplifications and confirm the above associations.