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Embryonal precursors of Wilms tumor.

ABSTRACT: Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.

SUBMITTER: Coorens THH

PROVIDER: S-EPMC6914378 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Embryonal precursors of Wilms tumor.

Coorens Tim H H THH Treger Taryn D TD Al-Saadi Reem R Moore Luiza L Tran Maxine G B MGB Mitchell Thomas J TJ Tugnait Suzanne S Thevanesan Christine C Young Matthew D MD Oliver Thomas R W TRW Oostveen Minou M Collord Grace G Tarpey Patrick S PS Cagan Alex A Hooks Yvette Y Brougham Mark M Reynolds Ben C BC Barone Giuseppe G Anderson John J Jorgensen Mette M Burke G A Amos GAA Visser Johannes J Nicholson James C JC Smeulders Naima N Mushtaq Imran I Stewart Grant D GD Campbell Peter J PJ Wedge David C DC Martincorena Iñigo I Rampling Dyanne D Hook Liz L Warren Anne Y AY Coleman Nicholas N Chowdhury Tanzina T Sebire Neil N Drost Jarno J Saeb-Parsy Kourosh K Stratton Michael R MR Straathof Karin K Pritchard-Jones Kathy K Behjati Sam S

Science (New York, N.Y.) 20191201 6470

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal exp ...[more]

PMID: 31806814

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Project description:Background/purposeDespite high long-term survival rates in patients with Wilms tumor, there is a need to develop better prognostic biomarkers in order to maximize cure while avoiding treatment-associated morbidities. Tumor-associated macrophages have been recently associated with poorer prognosis and increased disease progression in a number of adult cancers. We investigated the relationship between macrophages and clinicopathological fators in this pediatric solid tumor.MethodsTissue microarray sections of 124 Wilms tumor cases obtained from the Cooperative Human Tissue Network were stained with CD68, a macrophage marker using standard immunohistochemical techniques and quantified using digital image processing techniques. Macrophage densities were correlated by tumor stage, and survival analyses were conducted with available clinical data. Immunohistochemistry was performed on 25 additional Wilms tumor cases obtained from the tumor bank at Columbia University Medical Center and correlated with presence of tumor microvascular invasion.ResultsMean macrophage count densities in stage IV tumors were significantly greater than densities in stage I and III tumors (p=.021, .036). Although the overall and disease-free survival did not differ between high and low macrophage presence groups across all stages, increased macrophage presence was associated with decreased disease-free survival in patients with stage II tumors (p=0.035). Increased macrophage presence may have also correlated with decreased disease-free survival in stage IV patients, but the sample size was too small to allow detection of this difference with significance (p=0.575). Increased macrophage presence was associated with tumor microvascular invasion (p=0.0004).ConclusionOur results suggest that macrophage recruitment may be associated with disease progression in Wilms tumor. Quantitation of macrophage presence may therefore be a useful adjunct in refining staging algorithms for patients with stage II Wilms tumor. Such data might be useful in the effort to reduce the risk of adverse effects associated with under- or overtreatment of this neoplasm.

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Embryonal precursors of Wilms tumor.

Publications

Embryonal precursors of Wilms tumor.

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