Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity

Rasmussen, Markus; Sundström, Magnus; Kultima, Hanna Göransson; Botling, Johan; Micke, Patrick; Birgisson, Helgi; Glimelius, Bengt; Isaksson, Anders

doi:10.1186/gb-2011-12-10-r108

Cited by 86 publications

(121 citation statements)

References 20 publications

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“…Aberration calling from Illumina chips was as previously described 33 . The Chromosome Analysis Suite (ChAS, Affymetrix) Software was used to analyse Affymetrix Cytoscan HD data, followed by bioinformatic analysis with TAPS 34 . Copy number aberrations were considered if 10 or more consecutive markers/SNPs qualified as loss or gain.…”

Section: Discussionmentioning

confidence: 99%

“…When nondiploid, calculations were normalized for tumour cell ploidy as obtained by SNP array assessment, or cytogenetic analyses in cases where SNP array interpretation was ambiguous with respect to ploidy. The bioinformatic tool TAPS 34 was used for Affymetrix arrays to estimate absolute allele-specific copy numbers and identify genomic regions with copy number heterogeneity and the most likely composition of copy numbers behind each such observation, as described 34 . The median intensity ratio (2 log ratio ; or BAF in case of copy-neutral heterogeneity) of an identified region was used to calculate relative prevalence of each copy number in the composition, using genomic segments with the involved copy numbers in all tumour cells as reference points.…”

Section: Discussionmentioning

confidence: 99%

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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

et al. 2015

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Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P ¼ 0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

et al. 2015

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“…Absolute ploidy and clonal fractions of selected samples were validated with Tumor Aberration Prediction Suite (TAPS) as previously described (31).…”

Section: Snp Array Analysismentioning

confidence: 99%

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

Crona

Backman

Maharjan

et al. 2015

Clinical Cancer Research

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Purpose: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter-and intratumor genetic heterogeneity has not yet been defined.Experimental Design: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.Results: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.Conclusions: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.

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“…The Tumor Aberration Prediction Suite algorithm (22) (25,26). PAM50 classification was as described for the Guy's (27), METABRIC (23), and TCGA cohorts (6).…”

Section: Dna Copy-number and Gene-expression Analysismentioning

confidence: 99%

IL15RA Drives Antagonistic Mechanisms of Cancer Development and Immune Control in Lymphocyte-Enriched Triple-Negative Breast Cancers

et al. 2014

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Despite its aggressive nature, triple-negative breast cancer (TNBC) often exhibits leucocyte infiltrations that correlate with favorable prognosis. In this study, we offer an explanation for this apparent conundrum by defining TNBC cell subsets that overexpress the IL15 immune receptor IL15RA. This receptor usually forms a heterotrimer with the IL2 receptors IL2RB and IL2RG, which regulates the proliferation and differentiation of cytotoxic T cells and NK cells. However, unlike IL15RA, the IL2RB and IL2RG receptors are not upregulated in basal-like TNBC breast cancer cells that express IL15RA. Mechanistic investigations indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absence of IL2RB and IL2RG, whereas neither STAT5 nor JAK2 were activated. RNAi-mediated attenuation of IL15RA established its role in cell growth, apoptosis, and migration, whereas expression of the IL15 cytokine in IL15RA-expressing cells stimulated an autocrine signaling cascade that promoted cell proliferation and migration and blocked apoptosis. Notably, coexpression of IL15RA and IL15 was also sufficient to activate peripheral blood mononuclear cells upon coculture in a paracrine signaling manner. Overall, our findings offer a mechanistic explanation for the paradoxical association of some high-grade breast tumors with better survival outcomes, due to engagement of the immune stroma. Cancer Res; 74(17); 4908-21. Ó2014 AACR.

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Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity

Cited by 86 publications

References 20 publications

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

IL15RA Drives Antagonistic Mechanisms of Cancer Development and Immune Control in Lymphocyte-Enriched Triple-Negative Breast Cancers

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