Unknown,Transcriptomics,Genomics,Proteomics

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Truncating mutations of STAG2 define a molecular subgroup of aneuploid bladder cancers with poor prognosis.

ABSTRACT: Aneuploidy is among the most common hallmarks of cancer, yet the underlying genetic mechanisms are still poorly defined. We have recently identified STAG2 as a gene that is mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy. However, no single tumor type has yet been identified in which inactivation of a cohesin subunit represents a predominant mutational event. Here we used immunohistochemistry to screen a panel of 2,214 tumors from each of the major human tumor types to identify additional tumor types harboring somatic loss of STAG2. Strikingly, STAG2 expression was completely absent in 18% of urothelial carcinomas, the most common type of bladder cancer and the fifth most common cancer in the United States. DNA sequencing revealed that somatic mutations of STAG2 were present in 21% of urothelial carcinomas, which were found to be a group of highly aneuploid tumors. The acquisition of STAG2 mutations was shown to be an early event in the pathogenesis of urothelial carcinoma. STAG2 loss was significantly associated with lymph node invasion, increased disease recurrence, and reduced cancer-specific survival. These results identify STAG2 as one of the most commonly mutated genes in bladder cancer discovered to date, and demonstrate that STAG2 inactivation defines an aggressive subtype of bladder cancer with particularly poor prognosis. Affymetrix CytoScan HD Arrays were performed according to the manufacturer's directions on genomic DNA extracted directly from snap-frozen human urothelial carcinoma primary tumors. Copy number analysis using Affymetrix CytoScan HD Arrays was performed for 12 human urothelial carcinomas of the bladder with truncating mutations of the STAG2 gene.

ORGANISM(S): Homo sapiens

SUBMITTER: David Solomon

PROVIDER: E-GEOD-41581 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described more than 30 years ago, the phenotype of MM-CSC is still a matter of debate, especially with respect to the expression of syndecan- 1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 surface expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are also phenotypically interconvertible. Overall, our results differ from previously published data which attribute a B-cell phenotype to MM-CSC and urge the need to explore more reliable markers to discriminate true clonogenic myeloma cells. To compare the Copy Number Abnormalities of the subpopulations CD138++ and CD138low within the MM cell line, RPMI-8226. DNA was isolated from CD138++ (n=3) and CD138low (n=3) RPMI-8226 cells. The detection of CNA was investigated using the CytoScan HD array (Affymetrix, Santa Clara, CA, USA) which includes more than 2.6 million copy number markers and 750.000 SNPs. Briefly, genomic DNA was digested with Nsp I restriction endonuclease, ligated to adaptors that recognize the cohesive four base pair overhangs and amplified by PCR. PCR product was purified and fragmented with DNAse I and then end-labeled using terminal deoxynucleotidyl transferase and hybridized to the CytoScan HD array. The arrays were processed using the Fluidics Station 450, GeneChip Scanner 3000 7 G and AGCC (AffymetrixGeneChip Command Console Software). For the analysis we employed the AffymetrixM-BM-. Chromosome Analysis Suite (ChAS) Software v2.0 and Nexus Copy Number Software Version 7.0 (BioDiscovery, El Segundo, CA, USA). The complete data set was analyzed by visual inspection using ChAS software. CNA were reported when the three following criteria were achieved: minimum of 50 markers per segment, 200 Kb minimum genomic sizes and 50% overlap with known copy number variants (Database of Genomic Variants).

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Truncating mutations of STAG2 define a molecular subgroup of aneuploid bladder cancers with poor prognosis.

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