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Background  Wilms tumor (WT) is the most common renal tumor in childhood. Among others,  MYCN  copy number gain and  MYCN  P44L and  MAX  R60Q mutations have been identified in WT.  MYCN  encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes.  MYCN  gain has been associated with adverse prognosis in different childhood tumors including WT. The  MYCN  P44L and  MAX  R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized.    Methods  We screened a large cohort of unselected WTs for  MYCN  and  MAX  alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes.    Results  Mutation screening revealed mutation frequencies of 3% for  MYCN  P44L and 0.9% for  MAX  R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for  MAX  R60Q, while the  MYCN  P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g.  PEG10 ,  YEATS2 ,  FOXK1 ,  CBLL1  and  MCRS1,  whose expression is correlated with  MYCN  in WT samples and several of these are known for their own oncogenic potential.    Conclusions  The strongly elevated risk of relapse associated with mutant  MYCN  and  MAX  or elevated  MYCN  expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12935-021-02259-2.

MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates