Dataset Information

Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

ABSTRACT: Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.

SUBMITTER: Lu YW

PROVIDER: S-EPMC4811559 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

Lu You-Wang YW Zhang Hui-Feng HF Liang Rui R Xie Zhen-Rong ZR Luo Hua-You HY Zeng Yu-Jian YJ Xu Yu Y Wang La-Mei LM Kong Xiang-Yang XY Wang Kun-Hua KH

PloS one 20160329 3

Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ...[more]

PMID: 27023146

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Project description:BackgroundNumerous studies have used multi-region sampling approaches to characterize intra-tumor heterogeneity (ITH) in hepatocellular carcinoma (HCC). However, conventional multi-region sampling strategies do not preserve the spatial details of samples, and thus, the potential influences of spatial distribution on patient-wise ITH (represents the overall heterogeneity level of the tumor in a given patient) have long been overlooked. Furthermore, gene-wise transcriptional ITH (represents the expression pattern of genes across different intra-tumor regions) in HCC is also under-explored, highlighting the need for a comprehensive investigation.MethodsTo address the problem of spatial information loss, we propose a simple and easy-to-implement strategy called spatial localization sampling (SLS). We performed multi-region sampling and sequencing on 14 patients with HCC, collecting a total of 75 tumor samples with spatial information and molecular data. Normalized diversity score and integrated heterogeneity score (IHS) were then developed to measure patient-wise and gene-wise ITH, respectively.ResultsA significant correlation between spatial and molecular heterogeneity was uncovered, implying that spatial distribution of sampling sites did influence ITH estimation in HCC. We demonstrated that the normalized diversity score had the ability to overcome sampling location bias and provide a more accurate estimation of patient-wise ITH. According to this metric, HCC tumors could be divided into two classes (low-ITH and high-ITH tumors) with significant differences in multiple biological properties. Through IHS analysis, we revealed a highly heterogenous immune microenvironment in HCC and identified some low-ITH checkpoint genes with immunotherapeutic potential. We also constructed a low-heterogeneity risk stratification (LHRS) signature based on the IHS results which could accurately predict the survival outcome of patients with HCC on a single tumor biopsy sample.ConclusionsThis study provides new insights into the complex phenotypes of HCC and may serve as a guide for future studies in this field.

Dataset Information

Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

Publications

Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

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