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  • In this study we detected the PAX FOXO fusion


    In this study, we detected the PAX3/7–FOXO1 fusion Cetylpyridinium Chloride in 50% of the ARMS samples, 40% PAX3–FOXO1 and 10% PAX7–FOXO1. This detection confirmed the histological diagnosis and adds to its new information that can be useful in the prognosis evaluation of ARMS patients, since the patients with PAX3/7–FOXO1 positive tumors have worse prognosis than those with PAX3/7–FOXO1-negative tumors [8]. Also, we detected the EWS–FLI1 rearrangement in 60% of the cases of the ES tumors and we detected the SS18–SSX1/2 rearrangements in 90% of the SS tumors. In our study, the percentage of fusion gene detection in RMS and ES tumors samples was tightly smaller than that described in the literature. However, the sensitivity of RT-PCR for the detection of PAX3/7–FOXO1 and EWS–FLI1 rearrangements was 10 and 10, respectively. Additionally, about fusion gene detection in RMS and ES, most studies described in the literature are multicentric and involving several institutions and cooperative groups. Multicentric studies in RMS, involving RT-PCR rearrangement detection, work with a large number of samples, ranging from 59 to 91, with a percentage of PAX3–FOXO1 rearrangement ranging from 41 to 59%, and PAX7–FOXO1 rearrangement detection ranging from 8 to 22% [4], [22], [23], [24], [25]. Moreover, the percentage of samples without PAX3/7–FOXO1 was between 22 and 50% [4], [22], [25]. Multicentric studies in ES work with a large number of samples, from 99 to 578, with percentage of EWS–FLI1 rearrangement ranging from 65 to 90% [26], [27]. Our study was carried out in a single institution, Pediatric Oncology Institute-GRAACC/UNIFESP (Pediatric Oncology Institute-Support Group for Children and Adolescents with Cancer/Federal University of São Paulo), which is used as reference in the treatment and research of pediatric cancer, not only in South America, but also in Latin America. Additionally, our study is the only one that was conducted in Brazil, with pediatric sarcoma tumor samples, involving molecular detection of rearrangements and IGF2, IHH, PTCH1 and GLI1 gene expressions with clinical parameters. The IGF pathway has shown a significant involvement in the pathogenesis of various pediatric sarcomas, including RMS, SS and ES [28], [29]. We performed IGF2 gene expression quantification on 29 RMS samples; 25 of these samples were previously investigated [21]. We found a high expression of IGF2 compared to control (p<0.0001, cutoff=0.8317) (Fig. 2a). Also, we observed a high expression of IGF2 gene in ERMS (p=0.0024) and in ARMS compared to control (p=0.0273) (Fig. 2b). Although not significant, we find a difference in the IGF2 expression levels between PAX3/7–FOXO1-positive and PAX3/7–FOXO1-negative samples (p=0.9310). These findings corroborate recent records from the literature [29]. Some studies show a difference in the molecular characteristics of ARMS without PAX3/7–FOXO1 and ARMS positive of these rearrangements. Furthermore, these studies suggest a similarity between ERMS and ARMS negative tumors [29], [30]. Makawita et al. [29] performed immunohistochemistry in 24 ERMS and 8 ARMS to determine the expression patterns of the IGF family. However, only IGF2 showed a significant difference in the expression between the ERMS and ARMS subtypes, with higher levels of expression in ERMS (p=0.0003). Within the ARMS subtype, IGF2 positivity was limited to PAX/FOXO1 translocation-negative tumors. ERMS and translocation-negative ARMS cell lines showed a significantly higher mean IGF2 expression levels when compared to translocation-positive ARMS cell lines (p=0.0027). Stable introduction of PAX3/FOXO1 into an ERMS cell line also demonstrated a significant reduction in the IGF2 gene expression. The authors suggested that expression of the IGF2 ligand was associated with translocation-negative tumors and could serve as a diagnostic aid in distinguishing RMS subtypes.