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. 2021 Mar 19:11:642744.
doi: 10.3389/fonc.2021.642744. eCollection 2021.

Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome

Francianne G Andrade  1 , Suellen V M Feliciano  1 , Ingrid Sardou-Cezar  1 , Gisele D Brisson  1 , Filipe V Dos Santos-Bueno  1 , Danielle T Vianna  2 , Luísa V C Marques  1 , Eugênia Terra-Granado  1 , Ilana Zalcberg  2 , Marceli de O Santos  3 , Juliana T Costa  4 , Elda P Noronha  1 , Luiz C S Thuler  5 , Joseph L Wiemels  6 , Maria S Pombo-de-Oliveira  1 ; Brazilian Collaborative Study Group of Acute Leukemia
Collaborators, Affiliations

Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome

Francianne G Andrade et al. Front Oncol. .

Abstract

Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among the geographic regions with relatively higher percentages in the Latin American population. We aimed to explore the population burden of pediatric APL, gathering information from the population-based cancer registry (PBCR) and the diagnosis of APL obtained through incident cases from a hospital-based cohort. The homozygous deletion in glutathione S-transferases (GSTs) leads to a loss of enzyme detoxification activity, possibly affecting the treatment response. Mutations in the RAS pathway genes are also considered to be a key component of the disease both in the pathogenesis and in the outcomes. We have assessed mutations in a RAS-MAP kinase pathway (FLT3, PTPN11, and K-/NRAS) and GST variant predisposition risk in the outcome. Out of the 805 children and adolescents with acute myeloid leukemia (AML) who are registered in the PBCR, 35 (4.3%) were APL cases. The age-adjusted incidence rate (AAIR) was 0.03 per 100,000 person-years. One-hundred and sixty-three patients with APL were studied out of 931 AML cases (17.5%) from a hospital-based cohort. Mutations in FLT3, KRAS, and NRAS accounted for 52.1% of the cases. Patients with APL presented a 5-year probability of the overall survival (OS) of 67.3 ± 5.8%. A GST-theta 1 (GSTT1) null genotype conferred adverse prognosis, with an estimated hazard ratio of 2.8, 95% confidence interval (CI) 1.2-6.9. We speculate that the GSTT1 polymorphism is associated with therapeutics and would allow better OS of patients with APL with a GSTT1 null genotype.

Keywords: PML-RARA fusion gene; acute pediatric leukemia; childhood Incidence; glutathione S-transferase; prognosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Joinpoint analysis for age-adjusted incidence rate (AAIR) (0–19 years, standard world population) from acute promyelocytic leukemia (APL) in Brazilian population-based cancer registry (PBCR), 2000–2009. Solid circles indicate the data for observed age-adjusted rate and solid line indicates the data for modeled age-adjusted rate.
Figure 2
Figure 2
Overall survival (OS) of pediatric cases of APL. Probability of the OS, according to GSTT1 polymorphisms.
Figure 3
Figure 3
Study design. We gathered the information from a PBCR and the diagnosis of obtained through the incident cases from a hospital-based cohort. AAIR, age-adjusted incidence rate; ASIR, age-specific incident rate; ITD, internal tandem duplications; VAF, variant allelic frequency.
See this image and copyright information in PMC

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