43. PAX5 partial tandem duplication in pediatric B-ALL: Incidence and clinical, morphologic and genetic correlations

      Gain of extra copies of the 5′ portion of the PAX5 gene (PAX5-partial tandem duplication or PAX5-PTD) has been proposed to define a specific genetic subgroup of B-ALL (PMID: 30842609), and has most recently been associated with the novel PAX5-alteration driven (PAX5alt) subtype of the disease (PMID: 30643249). We determined the incidence and clinical, morphologic and molecular correlations of PAX5-PTD in an unselected cohort of 228 B-ALL patients. PAX5-PTD was detected by Chromosomal microarray (CMA) analysis in 5/228 B-ALLs (2.1%). There were two extra copies (triplication) of a 38-51 kb region (exons 2-5), encoding the PAX5 DNA-binding domain. The triplications were 'in frame', predicted to result in an altered protein. Two PAX5-PTD cases were classified as Ph-like/CRLF2 positive, based on P2RY8-CRLF2 fusions and JAK mutations detected by NGS panel testing. Notably, occurrence of PAX5-PTD in CRLF2-positive B-ALL has been reported previously. Extensive genetic evaluation of the remaining three PAX5-PTD cases excluded other subtype-defining genetic drivers; the cases were positive for CDKN2A/2B deletions (3/3), IKZF1 loss (2/3), RAS pathway and epigenetic mutations, and negative for abnormalities of the second PAX5 allele. Clinically, 4/5 patients presented at a young age (<5 years), 2 with standard-risk (SR), and 3 with high-risk (HR) B-ALL. One patient with SR and one with HR ALL developed early relapse. Our findings suggest that, similar to other PAX5 alterations, PAX5-PTD acts both as the primary driver in PAX5alt B-ALL, as well as the secondary abnormality enriched in Ph-like/CRLF2 positive B-ALL cases.
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