Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors.

We have identified a new t(1;21)(p32;q22) chromosomal translocation in a MDS/AML patient that results in expression of an aberrant C-terminally truncated RUNX1 protein lacking several regulatory domains. As similar truncated RUNX1 proteins are generated by genetic aberrations including chromosomal translocations and point mutations, we used the t(1;21)(p32;q22) chromosomal translocation as a model to explore whether C-terminally truncated RUNX1 proteins trigger effects similar to those induced by well-characterized leukemogenic RUNX1 fusion genes. In vitro analysis of transduced human hematopoietic/progenitor stem cells showed that truncated RUNX1 proteins increase proliferation and self-renewal and disrupt the differentiation program by interfering with RUNX1b. These effects are similar to but milder than those induced by the RUNX1/ETO fusion protein. GSEA analysis confirmed similar altered gene expression patterns in the truncated RUNX1 and RUNX1/ETO models, with both models showing alterations in genes involved in self-renewal and leukemogenesis, including homeobox genes, primitive erythroid genes and leukemogenic transcription factors. We propose that C-terminally truncated RUNX1 proteins can contribute to leukemogenesis in a similar way to RUNX1 fusion genes but through a milder phenotype.

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.

Dermatofibrosarcoma protuberans mixoide infantil / Myxoid Dermatofibrosarcoma Protuberans in Childhood

El dermatofibrosarcoma protuberans (DFSP) es un tumor cutáneo, localmente agresivo, que afecta a adultos jóvenes o de edad media. Se han descrito diferentes formas histológicas, siendo la mixoide una de las más infrecuentes. Microscópicamente está constituido por una neoformación que ocupa la dermis e hipodermis, de predominio mixoide, con áreas periféricas conformadas por haces de células fusiformes, de crecimiento infiltrativo, que expresan el marcador inmunohistoquímico CD34 de forma difusa. Presentamos por primera vez un DFSP mixoide en un dedo de la mano izquierda de una niña de 14 años, de más de 10 años de evolución. Se trata del primer caso infantil de DFSP mixoide en dicha localización. Este subtipo histológico se ha descrito fundamentalmente en las extremidades de adultos, siendo excepcional en niños. Se comenta el diagnóstico diferencial con otros tumores mesenquimales mixoides CD34 positivos (AU)

Dermatofibrosarcoma protuberans is a locally aggressive skin tumor that affects young and middle-aged adults. A number of histological variants have been described, the myxoid type being one of the least common. Microscopically it is formed of a neoplastic growth that is located in the dermis and hypodermis and has a predominant myxoid component. Peripherally there are infiltrating bundles of spindle-shaped cells that are diffusely positive for the CD34 immunohistochemical marker. We report a case of myxoid dermatofibrosarcoma protuberans on a finger of the left hand of a 14-year-old girl. The tumor had been present for at least 10 years. This is the first pediatric case of myxoid dermatofibrosarcoma protuberans at this site. This histological subtype has mainly been described on the extremities in adults and is very rare in children. We discuss the differential diagnosis with other CD34+ myxoid mesenchymal tumors (AU)

[Myxoid dermatofibrosarcoma protuberans in childhood]. / Dermatofibrosarcoma protuberans mixoide infantil.

Dermatofibrosarcoma protuberans is a locally aggressive skin tumor that affects young and middle-aged adults. A number of histological variants have been described, the myxoid type being one of the least common. Microscopically it is formed of a neoplastic growth that is located in the dermis and hypodermis and has a predominant myxoid component. Peripherally there are infiltrating bundles of spindle-shaped cells that are diffusely positive for the CD34 immunohistochemical marker. We report a case of myxoid dermatofibrosarcoma protuberans on a finger of the left hand of a 14-year-old girl. The tumor had been present for at least 10 years. This is the first pediatric case of myxoid dermatofibrosarcoma protuberans at this site. This histological subtype has mainly been described on the extremities in adults and is very rare in children. We discuss the differential diagnosis with other CD34(+) myxoid mesenchymal tumors.

Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma.

Ewing's sarcoma (ES) is characterized by specific chromosome translocations, the most common being t(11;22)(q24;q12). Additionally, other type of genetic abnormalities may occur and be relevant for explaining the variable tumour biology and clinical outcome. We have carried out a high-resolution array CGH and expression profiling on 25 ES tumour samples to characterize the DNA copy number aberrations (CNA) occurring in these tumours and determine their association with gene-expression profiles and clinical outcome. CNA were observed in 84% of the cases. We observed a median number of three aberrations per case. Besides numerical chromosome changes, smaller aberrations were found and defined at chromosomes 5p, 7q and 9p. All CNA were compiled to define the smallest overlapping regions of imbalance (SORI). A total of 35 SORI were delimited. Bioinformatics analyses were conducted to identify subgroups according to the pattern of genomic instability. Unsupervised and supervised clustering analysis (using SORI as variables) segregated the tumours in two distinct groups: one genomically stable (< or =3 CNA) and other genomically unstable (>3 CNA). The genomic unstable group showed a statistically significant shorter overall survival and was more refractory to chemotherapy. Expression profile analysis revealed significant differences between both groups. Genes related with chromosome segregation, DNA repair pathways and cell-cycle control were upregulated in the genomically unstable group. This report elucidates, for the first time, data about genomic instability in ES, based on CNA and expression profiling, and shows that a genomically unstable group of Ewing's tumours is correlated with a significant poor prognosis.

Interpretation of expression-profiling results obtained from different platforms and tissue sources: examples using prostate cancer data.

The analysis of expression signatures is a powerful tool for the classification of cancer and other tissue samples. Several protocols and platforms are available on the market, and these lead to both confirmatory and complementary results. We review the main processing techniques for cross-platform comparisons and the different tissue sources for cancer profiling. Some examples and the cross-interpretation of bibliographic data related to prostate cancer are also presented.