The understanding of the somatic driver mutations and genetic abnormalities in acute myeloid leukemia (AML) has enabled the discovery of actionable mutations and improved risk stratification; however, it is unclear how the distribution of molecular defined subsets varies within different populations. The median age of AML diagnosis in Mexico is younger than for other international cohorts; however, no mutational analysis has been performed to date. We thus sought to ascertain differences in somatic mutations in this population.
Methods: We created a collaborative research initiative to evaluate the frequency of recurrently mutated genes in 48 Mexican AML patients using a combination of whole-exome and targeted next-generation sequencing. We compared the prevalence to other reported Hispanic cohorts in the US and large international cohorts.
Results: The median age of diagnosis was 38 year (15-86). Somatic mutations were detected in 96% of patients, with a median of 2 mutated genes per patient (range 0-6). The most prevalent mutations in the cohort were FLT3 (29%) (with FLT3-TKD over-represented in 21% of the total cohort vs. 10% for FLT3-ITD and 6% harboring simultaneous ITD and TKD mutations), followed by CEBPA (21%), TET2 (19%), DNMT3A (19%), RUNX1 (15%) and NPM1 (12%). Fusion genes were detected in 21% of patients, with t(8;21)(AML-ETO) being the most commonly found (13%), followed by MLL rearrangements (4%) and inv(16)(CBFB-MYH11) (2%). When compared to international cohorts, CEBPA, RUNX1 GATA2, TET2, AML1-ETO, U2AF1, ASXL1 and KIT were found to be enriched in our cohort. In contrast, mutations in FLT3-ITD, DNMT3A, NPM1 and IDH2 were under-represented in the Mexican cohort. There was an over-representation of CEBPA mutated AML, with a characteristic mutational distribution and variant allele frequencies (VAF) in the 50% range that could be indicative of a greater incidence of germline predisposition in this population. The median overall survival for the cohort was 9 months. Adjustment for prognostic variables that tend to have better prognosis, such as lower age, higher prevalence of CEBPA and lower FLT3-ITD prevalence, did not attenuate the disparities in disease outcomes.
Conclusion: Mexican AML patients show a distinct genetic repertoire compared with other international cohorts that point to differences in host genetic susceptibility and environmental factors. Interestingly, some of the detected variants are targetable mutations that could influence management decisions. Despite some better prognostic risk groups such as younger age, lower FLT3-ITD and higher CEBPA, the outcomes for the cohort were overall poor, which correlates to reports of Hispanic minorities in the SEER database. Based on these findings, it is important to further investigate the true incidence of germline mutations in Mexican patients and other Hispanic patients and determine if there is a genetic susceptibility to develop AML that could explain some of the difference in age of onset and molecular findings.
Citation Format: Alexandra Gomez-Arteaga, Nuria Mencia-Trinchant, Adolfo Martinez Tovar, Irma Olarte Carrillo, Anel Garcia Laguna, Etta Rozen Fuller, Christian Ramos Penafiel, Monica L. Guzman, Duane C. Hassane. Molecular landscape of acute myeloid leukemia in Mexico [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C061.