Intratumor Heterogeneity May Contribute to Darwinian Clonal Selection

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(ChemotherapyAdvisor) – Intratumor heterogeneity may present major challenges to personalized medicine and development of biomarkers, in that genomics analyses from single tumor-biopsy samples can underestimate mutational burden, a study in the March 8 issue of the New England Journal of Medicine has found.

Such intratumor heterogeneity may contribute to Darwinian selection of preexisting drug-resistant clones, fostering tumor adaptation and leading to therapeutic failure, the investigators noted. A single tumor-biopsy specimen revealed a minority of genetic aberrations — including mutations, allelic imbalance, and ploidy — present in an entire tumor.

Tumor-biopsy samples were evaluated from four consecutive patients with metastatic renal cell carcinoma enrolled in the Personalized RNA Interference to Enhance the Delivery of Individualized Cytotoxic and Targeted Therapeutics clinical trial of everolimus. Biopsy samples were obtained prior to initiation of six weeks of treatment with everolimus. After a one-week washout period, a nephrectomy was performed. Everolimus treatment was continued after recovery from surgery until tumor progression.

Exon-capture sequencing was performed on tumor DNA from pretreatment biopsy samples of the primary tumor and chest-wall metastasis; primary-tumor regions of the nephrectomy specimen; a perinephric metastasis in the nephrectomy specimen; and two regions of the excised chest-wall metastasis. Chromosome-aberration analysis and ploidy profiling was also conducted. Consequences of intratumor heterogeneity were characterized with immunohistochemical analysis, mutation functional analysis, and messenger RNA expression profiling.

“Multiregion genetic analysis of the four tumors provided evidence of intratumor heterogeneity in every tumor, with spatially separated heterogeneous somatic mutations and chromosomal imbalances leading to phenotypic intratumor diversity (activating mutation in MTOR) and uniformity (loss-of-function mutation in SETD2 and PTEN),” they wrote.

“Reconstructing tumor clonal architectures and the identification of common mutations located in the trunk of the phylogenetic tree may contribute to more robust biomarkers and therapeutic approaches,” they concluded.


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