ABSTRACT
SUMMARY: Given the rarity of cancer in childhood, it should be even more uncommon for pediatric cancer survivors to develop a second, independent malignancy, yet they incur a greatly elevated risk after initial remission. In this issue of Cancer Discovery, Sánchez-Guixé and colleagues unpick the origins of second tumours in four children, and the potential role platinum-based chemotherapy may play in subsequent tumorigenesis. See related article by Sánchez-Guixé et al., p. 953 (8).
Subject(s)
Neoplasms, Second Primary , Humans , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/epidemiology , Child , Cancer Survivors , Neoplasms/drug therapyABSTRACT
A fundamental step of tumour single cell mRNA analysis is separating cancer and non-cancer cells. We show that the common approach to separation, using shifts in average expression, can lead to erroneous biological conclusions. By contrast, allelic imbalances representing copy number changes directly detect the cancer genotype and accurately separate cancer from non-cancer cells. Our findings provide a definitive approach to identifying cancer cells from single cell mRNA sequencing data.
Subject(s)
Neoplasms , Transcriptome , Allelic Imbalance/genetics , Genotype , Humans , Neoplasms/diagnosis , Neoplasms/genetics , Polymorphism, Single Nucleotide , RNA, Messenger/geneticsABSTRACT
Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.
Subject(s)
Neural Stem Cells , Neuroblastoma , Child , Humans , Neural Crest/metabolism , Neural Stem Cells/metabolism , Neuroblastoma/genetics , Neuroblastoma/metabolism , Neuroblastoma/pathology , RNA, Messenger/genetics , TranscriptomeABSTRACT
Transposable elements (TEs) are interspersed repeat sequences that make up much of the human genome. Their expression has been implicated in development and disease. However, TE-derived RNA-seq reads are difficult to quantify. Past approaches have excluded these reads or aggregated RNA expression to subfamilies shared by similar TE copies, sacrificing quantitative accuracy or the genomic context necessary to understand the basis of TE transcription. As a result, the effects of TEs on gene expression and associated phenotypes are not well understood. Here, we present Software for Quantifying Interspersed Repeat Expression (SQuIRE), the first RNA-seq analysis pipeline that provides a quantitative and locus-specific picture of TE expression (https://github.com/wyang17/SQuIRE). SQuIRE is an accurate and user-friendly tool that can be used for a variety of species. We applied SQuIRE to RNA-seq from normal mouse tissues and a Drosophila model of amyotrophic lateral sclerosis. In both model organisms, we recapitulated previously reported TE subfamily expression levels and revealed locus-specific TE expression. We also identified differences in TE transcription patterns relating to transcript type, gene expression and RNA splicing that would be lost with other approaches using subfamily-level analyses. Altogether, our findings illustrate the importance of studying TE transcription with locus-level resolution.
