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.
Highlights
Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD)
We found that the pairwise somatic copy number aberrations (SCNAs) distances were positively correlated with DNA methylation distances (Fig. 6a, Spearman’s correlation coefficient’s = 0.586, p < 1 × 10−16)
We examined the topology of evolutionary trees inferred from SCNAs and DNA methylation and observed high similarity
Summary
Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). 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. We perform a comprehensive analysis of ITH of somatic mutations in cancer driver genes, copy number aberrations and DNA methylation in 292 tumor samples from 84 patients with LUAD. We order genetic and epigenetic events along the LUAD evolutionary trajectories, and test the hypothesis that co-occurrence of genetic and epigenetic mechanisms characterizes the evolution of LUADs. we assess the clonality of targetable cancer driver genes and evaluate the association of ITH with clinical outcomes (survival and, separately, risk of metastasis) correcting for sample purity and using an unbiased statistical model which takes into account the number of samples examined from each tumor
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