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Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.

ABSTRACT: Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

SUBMITTER: Zhang J

PROVIDER: S-EPMC4354858 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.

Zhang Jianjun J Fujimoto Junya J Zhang Jianhua J Wedge David C DC Song Xingzhi X Zhang Jiexin J Seth Sahil S Chow Chi-Wan CW Cao Yu Y Gumbs Curtis C Gold Kathryn A KA Kalhor Neda N Little Latasha L Mahadeshwar Harshad H Moran Cesar C Protopopov Alexei A Sun Huandong H Tang Jiabin J Wu Xifeng X Ye Yuanqing Y William William N WN Lee J Jack JJ Heymach John V JV Hong Waun Ki WK Swisher Stephen S Wistuba Ignacio I II Futreal P Andrew PA

Science (New York, N.Y.) 20141001 6206

Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing ...[more]

PMID: 25301631

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Project description:BACKGROUND:Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS:To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS:Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS:Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

Dataset Information

Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.

Publications

Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.

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