Three-gene diagnostic classifier for ALK negative ALCL

Anaplastic Large Cell Lymphomas (ALCL) comprise approximately 12% of all T-cell Non-Hodgkin's lymphomas (T-NHL), representing a heterogeneous group whose definition, origin andrelationship with other T-NHL remains controversial. The notion that ALCL strongly expressCD30, and display recurrent chromosomal translocations involving the Anaplastic LymphomaKinase (ALK) gene, led to recognition of two subsets, according to ALK expression. AlthoughALK positive ALCL can be readily diagnosed, ALK negative ALCL still lack unique geneticfeatures and their distinction from other CD30 positive Peripheral T-Cell Lymphomas (PTCL) isnot trivial. To unravel the regulatory network underlying lymphomagenesis of ALCL, and todiscover new genomic classifiers for the recognition of ALK-positive and ALK-negative ALCLpatients, we undertook a systematic approach of pathway discovery through a gene expressionprofiling meta-analysis of 309 cases, using data generated by five sets of experiments. Inagreement with previous studies, unsupervised analyses were not able to distinguish ALCL fromthe other T-NHL categories. However, pathway discovery and prediction analyses defined aminimum set of genes useful for the stratification of ALK negative ALCL and strengthened thehypothesis that ALCL correspond to a distinctive pathological subgroup within T-NHL. Applicationof RT-qPCR in independent data sets of cryo-preserved and formalin-fixed paraffin embeddedsamples confirmed the gene expression profiling predictions and validated a simple model basedon the measurement of three genes. These data suggest the possibility to translate RT-qPCRprotocols to routine clinical settings as a new approach to precisely define T-NHL and to selectmore appropriate therapeutic protocols.