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In Biology of Genomes Talk, Single-cell Analysis Offers Refined View of Medulloblastoma

COLD SPRING HARBOR, NY (GenomeWeb News) – Through whole-exome sequencing of single cells from a medulloblastoma tumor, researchers were able to identify distinct cancer cell types within the tumor that otherwise may have been overlooked, work presented by Stanford University's Sofia Kyriazopoulou-Panagiotopoulou at Biology of Genomes here indicated.

Medulloblastoma, a brain tumor that mainly arises in children, falls into different subtypes, but Kyriazopoulou-Panagiotopoulou noted that the borders between the subtypes are fuzzy, with some mutations shared across the different types. The various groupings of the cancer are also linked to different prognoses.

Further, tumors themselves typically are heterogeneous collections of cancer cells, which may contain different mutations and have different characteristics. However, many approaches for studying cancer look at the tumor as a whole, potentially overshadowing such differences.

Instead, Kyriazopoulou-Panagiotopoulou and her colleagues examined single medulloblastoma cells to better understand the heterogeneity of such cancers and their evolution.

They performed whole-exome sequencing of 30 cells from a medulloblastoma tumor from a nine-year-old girl as well as single peripheral lymphocytes as controls. They also looked at the whole genome of the bulk tumor and a recurrent tumor.

Their analyses indicated that the primary medulloblastoma consisted of distinct cell types, and there was strong evidence that copy number variation played a role in the tumor. Kyriazopoulou-Panagiotopoulou noted that there were widespread CNV changes in the bulk tumor samples while the control blood samples had constant CNV levels.

Additionally, such changes could distinguish tumor and normal cells.

Further, a subset of the cells from the primary medulloblastoma appeared to then become more common in the recurrent tumor. "Without single-cell analysis, it's almost impossible to find overlap between the primary and recurrent tumors," Kyriazopoulou-Panagiotopoulou said.

Using copy-number variants, Kyriazopoulou-Panagiotopoulou and her colleagues worked out the phylogenetic relationship of the tumor cell subtypes and what mutations occurred early on and which ones were more cohort specific.

For example, two groups of cells contained regions of hypermutation with evidence of copy number gains. The regions were also enriched for genes already associated with tumorigenesis and medulloblastoma like PDGFA. She added that such regions might confer a fitness advantage to growing tumors.

A single-cell analysis approach, Kyriazopoulou-Panagiotopoulou added, offered a more refined view of the tumor.

Bulk analysis of the medulloblastoma indicated that that it belonged to one of the medulloblastoma subtypes, while the analysis of the single cells indicated that the tumor actually shared variants with multiple tumor types, underscoring, she said, the caveats of bulk analysis.

Better understanding the subtypes of cells of the tumor, Kyriazopoulou-Panagiotopoulou added, could lead to better treatment strategies.