Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma

Xing Hua; Wei Zhao; Angela C. Pesatori; Dario Consonni; Neil E. Caporaso; Tongwu Zhang; Bin Zhu; Mingyi Wang; Kristine Jones; Belynda Hicks; Lei Song; Joshua Sampson; David C. Wedge; Jianxin Shi; Maria Teresa Landi

doi:10.1038/s41467-020-16295-5

Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma

Xing Hua, Wei Zhao, Angela C. Pesatori, Dario Consonni, Neil E. Caporaso, Tongwu Zhang, Bin Zhu, Mingyi Wang, Kristine Jones, Belynda Hicks, Lei Song, Joshua Sampson, David C. Wedge, Jianxin Shi, Maria Teresa Landi

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.

Original language	English
Article number	2459
Journal	Nature Communications
Volume	11
Issue number	1
Early online date	18 May 2020
DOIs	https://doi.org/10.1038/s41467-020-16295-5
Publication status	Published - 18 May 2020

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Manchester Cancer Research Centre

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title = "Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma",

abstract = "Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.",

author = "Xing Hua and Wei Zhao and Pesatori, {Angela C.} and Dario Consonni and Caporaso, {Neil E.} and Tongwu Zhang and Bin Zhu and Mingyi Wang and Kristine Jones and Belynda Hicks and Lei Song and Joshua Sampson and Wedge, {David C.} and Jianxin Shi and Landi, {Maria Teresa}",

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doi = "10.1038/s41467-020-16295-5",

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T1 - Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma

AU - Hua, Xing

AU - Zhao, Wei

AU - Pesatori, Angela C.

AU - Consonni, Dario

AU - Caporaso, Neil E.

AU - Zhang, Tongwu

AU - Zhu, Bin

AU - Wang, Mingyi

AU - Jones, Kristine

AU - Hicks, Belynda

AU - Song, Lei

AU - Sampson, Joshua

AU - Wedge, David C.

AU - Shi, Jianxin

AU - Landi, Maria Teresa

PY - 2020/5/18

Y1 - 2020/5/18

N2 - Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.

AB - Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.

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Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma

Abstract

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UN SDGs

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