Abstract
In the Ptch+/- mouse model for embryonal rhabdomyosarcoma (ERMS), we recently showed that oncogenic (onc) H-, K- or NRAS mutations do not influence tumor growth when induced at the advanced, full-blown tumor stage. However, when induced at the invisible ERMS precursor stage at 4 weeks of age, tumor development was enforced upon oncHRAS and oncKRAS but not by oncNRAS, which instead initiated tumor differentiation. These data indicate that oncRAS-associated processes differ from each other in dependency on the isoform and their occurrence during tumor development. Here, we investigated the outcome of oncNRAS induction at an earlier ERMS precursor stage at 2 weeks of age. In this setting, oncNRAS accelerates tumor growth because it significantly shortens the ERMS-free survival and increases the ERMS incidence. However, it does not seem to alter the differentiation of the tumors. It is also not involved in tumor initiation. Together, these data show that oncNRAS mutations can accelerate tumor growth when targeting immature ERMS precursors within a specific time window, in which the precursors are permissive to the mutation and show that oncNRAS-associated processes differ from each other in dependency on their occurrence during tumor development.
Highlights
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and comprises 4.5% of all childhood cancer with an annual incidence of 4.5 cases per million children
RMS is classified into embryonal RMS (ERMS), alveolar RMS (ARMS), pleomorphic, spindle cell and sclerosing tumors [1,2]
Relevant in etiology and the poorer prognosis of ARMS are chromosomal translocations resulting in PAX3FOXO1 or PAX7-FOXO1 fusion proteins that occur in approximately 80% of ARMS [3]
Summary
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and comprises 4.5% of all childhood cancer with an annual incidence of 4.5 cases per million children. Whereas KRAS and HRAS mutations were found in 9% and 8% of fusion-negative tumors, respectively, NRAS mutations were observed in 17% of cases [5] This demonstrates that oncNRAS is the most frequent mutation in ERMS, which has been shown in other studies [6,7,8]. We recently compared the effects of oncRAS mutations affecting codon 12 of all 3 RAS isoforms (i.e., oncK-, oncH- and oncNRAS) in the Ptch+/- mouse model for ERMS-like tumors. In this model, ERMS are initiated before birth and become palpable at the earliest around 7 weeks of age [11]. 2-week-old mice and analyzed the impact on incidence, growth, latency time, multiplicity and differentiation status of the tumors
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