Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Abstract

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.

Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma

“…These findings are further supported by data from similar studies in lung cancer, esophageal adenocarcinoma, and pediatric tumors (4,8,32). However, given that this study included a limited number of patients all treated differently, additional larger studies are required to further confirm these data given the significance of prognostic markers in melanoma.…”

Biomarkers to Detect Wilms Tumors in Pediatric Patients: Where are We Now?

“…Due to the small number of relapses that occur in WT, this will also require international collaboration to achieve statistically robust results that can be used to change c linical practice. Biopsy: copy number array Can assess microdiversity which is associated with poor outcome [39] SIX1/SIX2 protein in blood/urine SIX1/SIX2 is overexpressed in Wilms tumors; SIX2 expression is associated with blastemal histology [12] Genomic copy number changes in blood/urine Detection of adverse outcome/relapse associated changes (1q/1p/16q/15q/17p). Overcomes intratumoral heterogeneity, can identify tumors with adverse prognosis [8,52] Detection of tumor-specific methylated DNA in blood/urine Feasibility shown, needs expanding to more patients to assess use in diagnosis or tumor monitoring [43] Analysis of Let-7 in tumor or blood/urine Let-7 is dysregulated in several tumors but a relationship with outcome is unknown [12,23,53] Analysis of seven miRNAs in circulation Associated with high-risk histology independent of chemotherapy [30] Expression of 'oncomir' miRNAs in tumor tissue Correlated with higher stage and metastatic disease [29] SIX1/SIX2 mutation in tumor/circulation Poor response to chemotherapy [13] TP53 mutation in tumor/circulation Anaplasia, poor outcome [19] CTNNB1/WT1 mutation in tumor/circulation Favorable histology (stromal) [54] SIX1/2 mutation + miRNA processing mutation in tumor/circulation…”

“…One study has described the presence of genetic intratumoral microdiversity, whereby future science group www.futuremedicine.com DNA extracted from a 1-mm-sized tumor sample shows multiple clones with different genomic copy number aberrations, with an increase in this microdiversity associating with poor outcome in WT patients [39]. Conversely, patients lacking this microdiversity showed a 100% survival rate.…”

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“…The studies highlighted a heterogeneity issue between matched tissue and blood based mutational profiles. What consequences that will have on decision making, which mutations are clinically actionable, and whether it is a result of tumor clonal heterogeneity or technical variation from usage of different sequencing platforms and bioinformatic workflows (11,45) remains to be seen.…”