Gene Expression Signature Associated with Clinical Outcome in ALK-Positive Anaplastic Large Cell Lymphoma

Abstract

Anaplastic large cell lymphomas associated with ALK translocation have a good outcome after CHOP treatment; however, the 2-year relapse rate remains at 30%. Microarray gene-expression profiling of 48 samples obtained at diagnosis was used to identify 47 genes that were differentially expressed between patients with early relapse/progression and no relapse. In the relapsing group, the most significant overrepresented genes were related to the regulation of the immune response and T-cell activation while those in the non-relapsing group were involved in the extracellular matrix. Fluidigm technology gave concordant results for 29 genes, of which FN1, FAM179A, and SLC40A1 had the strongest predictive power after logistic regression and two classification algorithms. In parallel with 39 samples, we used a Kallisto/Sleuth pipeline to analyze RNA sequencing data and identified 20 genes common to the 28 genes validated by Fluidigm technology—notably, the FAM179A and FN1 genes. Interestingly, FN1 also belongs to the gene signature predicting longer survival in diffuse large B-cell lymphomas treated with CHOP. Thus, our molecular signatures indicate that the FN1 gene, a matrix key regulator, might also be involved in the prognosis and the therapeutic response in anaplastic lymphomas.

Anaplastic large cell lymphoma with ALK::ATIC fusion mimicking a histiocytic sarcoma debuting as an anterior thoracic soft tissue tumor with exceptional clinicopathological, morphological and molecular features

“…Interestingly, certain patterns have an association with their molecular background; in our case we observed a mixed pattern with compound and lymphohistiocytic morphologies which in contrast to the clinical and immunohistochemical features initially oriented towards the diagnosis of an HS since it shows a similar immunophenotypic profile as ALK + ALCL and led to a misdiagnosis 1,2 . ALK shows a wide variety of fusion partners (more than 25 described) with NPM1 being the most common; the ATIC partner found in our case has been described in less than 1% of ALCL 1,3 . The aggressive behavior of this neoplasm is consistent with its molecular background, which could explain the unusual histology, clinical presentation and biological behavior.…”

“…1,2 ALK shows a wide variety of fusion partners (more than 25 described) with NPM1 being the most common; the ATIC partner found in our case has been described in less than 1% of ALCL. 1,3 The aggressive behavior of this neoplasm is consistent with its molecular background, which could explain the unusual histology, clinical presentation and biological behavior. It is therefore important in the context of challenging cases with small biopsies not to overlook the diagnostic pearls and fine details despite having ruled out the most frequent morphological mimickers.…”

“…[1][2][3] NPM1 was the first fusion partner described in ALK + ALCL in the 1990s, and to date a large number of fusion partners have been reported, some of them with very low frequency rates described. 1,3…”

“…Recent studies have shown that ALK‐positive ALCL (ALK + ALCL) exhibit constitutive activation of signaling pathways that dysregulate essential canonical events in T‐cell activation, affect epigenetic regulation, lead to immune evasion, and dysregulate metabolic pathways 1 . This type of lymphoma has a wide variety of clinicopathologic features described and many times when clinical data, histology and immunophenotypic profile are inconclusive other rare exclusion diagnoses should be considered because the may mimic this type of lymphoma and to rule them out it is necessary to have access to more advanced molecular studies, making ALK ALCL an extremely challenging diagnosis 1–3 . NPM1 was the first fusion partner described in ALK + ALCL in the 1990s, and to date a large number of fusion partners have been reported, some of them with very low frequency rates described 1,3 …”

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma

“…Gene set enrichment analysis (GSEA) demonstrated that MYC targets and negative regulation of genes involved in the inflammatory response pathways are enriched in the relapsed samples (Supplementary Figure 6A-B). While the relapse-associated genes from Camille et al 73 were not consistently upregulated in our cohort of relapsed RNAseq samples (Supplementary Figure 6C-D), diagnosis-associated genes were consistently up-regulated in our cohort of diagnosis ALK+ ALCL, which were enriched for genes involved in the extracellular matrix region (Supplementary Figure 6E-F). To evaluate the relationship between relapse gene signature and clinical outcome, we developed a relapse signature score by single-sample GSEA and analyzed the RNA sequencing data from our pediatric ALCL cohort (Supplementary Table S12).…”