Subclonal evolution of pulmonary adenocarcinomas delineated by spatially distributed somatic mitochondrial mutations
Introduction
Despite great improvements through the implementation of personalized therapeutic strategies for the treatment of lung adenocarcinoma (ADC) [1] targeting e.g. EGFR mutations, ALK and ROS1 rearrangements or PD/PDL-1, prognosis remains limited. The development of resistance mechanisms [2] is a major cause for the still low 5-year overall survival rate of less than 20% [3]. A key factor of therapy resistance is intratumor heterogeneity (ITH) [4,5], mainly due to genomic and epigenomic instability as well as to a branched subclonal evolution caused by differing selective conditions, like microenvironmental stress [6]. To further improve clinical outcome, better understanding of the mechanisms of tumor evolution resulting in multi-level tumor heterogeneity is of great importance. Employing comprehensive sequencing approaches, several studies have meticulously analyzed the temporal and spatial genetic heterogeneity in nuclear DNA and identified the dynamics of subclonal lesions during tumor progression and therapeutic treatment [2,[7], [8], [9], [10]], some of which are already clinically relevant for prediction of therapy resistance [11] and recurrence [12].
Addressing the role of mitochondrial alterations in tumorigenesis [[13], [14], [15]], we comprehensively analyzed the prevalence of somatic mutations of the mitochondrial genome (mtDNA) in non-small cell lung cancer recently [16]. Our findings suggest that mtDNA mutations are passenger mutations rather than directly oncogenic. However, with a 10-fold higher mutation rate compared to genomic mutations, somatic mtDNA mutations might be a sensitive tool to identify different subclonal lineages within a tumor and thus support deciphering spatial tumor evolution [17].
In order to shed more light on the potential role of mitochondria in this scenario, we comprehensively investigated the spatial distribution of somatic mtDNA mutations in ADC. We demonstrate that the identification and differentiation of ubiquitous and regional restricted mutations is a promising tool to identify spatial tumor evolution by detecting subclonal structures and the correlation with disease-free survival (DFS).
Section snippets
Samples
All tumor specimens used in the present study were resected at the Thoraxklinik at University Hospital Heidelberg and diagnosed according to the 2015 World Health Organization Classification criteria for lung cancer [18] at the Institute of Pathology at Heidelberg University.
Formalin-fixed and paraffin embedded tumor samples were processed with the support of the tissue bank of the National Center for Tumor Diseases (NCT; project: # 1746, # 2015, # 2577) and used in accordance with the ethical
Differentiation of ubiquitous and regional restricted somatic mitochondrial mutations
In total, we analyzed 392 samples from 19 ADC (Table 1). Heteroplasmic mutations were identified in four cases (#1, #7, #8, #19) which were present in the corresponding non-neoplastic tissues with an allele frequency of less than 100%, as well as throughout all tumor samples of a respective case.
Somatic mtDNA mutations could be detected in at least one segment in 18 (96%) of the analyzed cases, with a range of 0–7 mutations per segment and 1–17 different mutations per tumor (Fig. 1A). A total
Discussion
In this study, we comprehensively analyzed the spatial distribution of somatic mtDNA mutations throughout a complete 2-dimensional expansion of 19 ADC. We demonstrated that multi-regional analyses identify subclonal structures, which help to build oncogenic models for a better understanding of spatial morpho-molecular ADC evolution. Further, we shed more light on the potential tumorigenic impact of mtDNA mutations as well as their prognostic relevance.
We detected somatic mtDNA mutations in all
Funding
AW was supported by an excellence grant from the Else Kröner-Fresenius Foundation [2014_EKES.05].
Acknowledgements
We thank Veronika Geißler and Christiane Zgorzelski for excellent technical assistance and the Tissue Bank of the National Centre for Tumor Diseases, Heidelberg.
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Present address: Institute of Pathology, Cytopathology, and Molecular Pathology UEGP MVZ Giessen / Wetzlar / Limburg, Germany.