The Ϸ1-Mb leukocyte receptor complex at 19q13.4 is a key polymorphic immunoregion containing all of the natural killer-receptor KIR and related ILT genes. When the organization of the leukocyte receptor complex was compared from two haplotypes, the gene content in the KIR region varied dramatically, with framework loci flanking regions of widely variable gene content. The ILT genes were more stable in number except for ILT6, which was present only in one haplotype. Analysis of Alu repeats and comparison of KIR gene sequences, which are over 90% identical, are consistent with a recent origin. KIR genesis was followed by extensive duplication͞deletion as well as intergenic sequence exchange, reminiscent of MHC class I genes, which provide KIR ligands.

A subgroup of small-round-cell tumors identified as belonging to the Ewing family of tumors can be defined according to a specific molecular genetic lesion that is detectable by a rapid, reliable, and efficient method. This approach can be applied to small specimens obtained by fine-needle biopsies.

Balanced translocations involving band q12 of human chromosome 22 are the most frequent recurrent translocations observed in human solid tumours. It has been shown recently that this region encodes EWS, a protein with an RNA binding homologous domain. In Ewing's sarcoma and malignant melanoma of soft parts, translocations of band 22q12 to chromosome 11 and 12 result in the fusion of EWS with the transcription factors FLI‐1 and ATF1, respectively. The present analysis of 89 Ewing's sarcomas and related tumours show that in addition to the expected EWS‐FLI‐1 fusion, the EWS gene can be fused to ERG, a transcription factor closely related to FLI‐1 but located on chromosome 21. The position of the chromosome translocation breakpoints are shown to be restricted to introns 7‐10 of the EWS gene and widely dispersed within introns 3‐9 of the Ets‐related genes. This heterogeneity generates a variety of chimeric proteins that can be detected by immuno‐precipitation. On rare occasions, they may be associated with a truncated EWS protein arising from alternate splicing. All 13 different fusion proteins that were evidenced contained the N‐terminal domain of EWS and the Ets domain of FLI‐1 or ERG suggesting that oncogenic conversion is achieved by the linking of the two domains with no marked constraint on the connecting peptide.

We report genetic aberrations that activate the ERK/MAP kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency of gene fusions between KIAA1549 and BRAF among these tumours. These fusions were identified from analysis of focal copy number gains at 7q34, detected using Affymetrix 250K and 6.0 SNP arrays. PCR and sequencing confirmed the presence of five KIAA1549-BRAF fusion variants, along with a single fusion between SRGAP3 and RAF1. The resulting fusion genes lack the auto-inhibitory domains of BRAF and RAF1, which are replaced in-frame by the beginning of KIAA1549 and SRGAP3, respectively, conferring constitutive kinase activity. An activating mutation of KRAS was identified in the single pilocytic astrocytoma without a BRAF or RAF1 fusion. Further fusions and activating mutations in BRAF were identified in 28% of grade II astrocytomas, highlighting the importance of the ERK/MAP kinase pathway in the development of paediatric low-grade gliomas.