Prevalence of somatic mitochondrial mutations and spatial distribution of mitochondria in non-small cell lung cancer

Kazdal, Daniel; Harms, Alexander; Endris, Volker; Penzel, Roland; Kriegsmann, Mark; Eichhorn, Florian; Muley, Thomas; Pfarr, Nicole; Weichert, Wilko; Warth, Arne

doi:10.1038/bjc.2017.155

Cited by 28 publications

(14 citation statements)

References 40 publications

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“…Following formalin fixation, central tumor sections of 19 ADCs (see Table for clinicopathological data) representing the largest tumor diameters were systematically cut into segments in a 5 mm × 5 mm grid‐like fashion . All segments were labeled with ink marks to facilitate the reconstruction of the full section prior to embedding into paraffin.…”

Section: Methodsmentioning

confidence: 99%

“…Following formalin fixation, central tumor sections of 19 ADCs (see Table 1 for clinicopathological data) representing the largest tumor diameters were systematically cut into segments in a 5 mm 3 5 mm grid-like fashion. 20 All segments were labeled with ink marks to facilitate the reconstruction of the full section prior to embedding into paraffin. The predominant histological growth pattern in each segment (defined as the pattern with the largest percentage) was determined by an experienced pathologist (AW) on consecutive H&E-stained sections.…”

Section: Samplesmentioning

confidence: 99%

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Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas

Dietz

Harms

Endris

et al. 2017

Intl Journal of Cancer

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Multiregional analysis provided first indications for morphological and molecular heterogeneity in lung adenocarcinomas (ADCs), but comprehensive morpho-molecular comparisons are still lacking. The purpose of our study was to investigate the spatial distribution of EGFR and KRAS alterations systematically throughout whole tumor cross-sections in correlation with the tumor cell content and the histopathological patterns. Central sections of 19 ADCs were subdivided into 467 segments of 5 mm × 5 mm. We determined the predominant histological growth pattern and the allele frequencies of driver gene mutations by digital PCR in every segment. We further quantified the absolute cell counts and proportions of tumor and non-neoplastic cells in all segments to normalize the mutant allele frequencies. Driver gene mutations could be detected in >99% of the tumor containing segments, with high levels of inter- and intratumor heterogeneity regarding the mutant allele frequency (range: 0.04-19.36). Different patterns for the distribution of the variant allele frequency within a tumor were recognizable. While some cases showed ubiquitously low or high levels, others revealed regions with focally elevated frequencies. Differences between KRAS and EGFR alterations were not significant. The great majority of the analyzed tumor sections (16/19) exhibited two or more morphological growth patterns. Mutant allele frequencies were significantly higher in segments with a predominant solid pattern compared to all other histologies (p < 0.01). Our data indicate that driver gene mutations are present with high levels of inter- and intratumor heterogeneity throughout the whole tumor, with a correlation between the allele frequencies and histological growth patterns.

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Section: Methodsmentioning

confidence: 99%

Section: Samplesmentioning

confidence: 99%

Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas

Dietz

Harms

Endris

et al. 2017

Intl Journal of Cancer

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“…Six lymph node metastases from four of these patients were evaluated analogously. Tumor sections with the largest diameters were segmented into of 5 x 5 mm areas as described previously . The predominant histological growth pattern in each segment (defined as the pattern with the highest percentage) was determined by an experienced pathologist (AW) on consecutive H&E‐stained sections.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor sections with the largest diameters were segmented into of 5 x 5 mm areas as described previously. 18,23 The predominant histological growth pattern in each segment (defined as the pattern with the highest percentage) was determined by an experienced pathologist (AW) on consecutive H&E-stained sections. Of the seven patients, four carried a mutation in the KRAS gene, three in TP53 (two of these were double mutants).…”

Section: Patients and Samplesmentioning

confidence: 99%

Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas

Dietz

Lifshitz

Kazdal

et al. 2018

Intl Journal of Cancer

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Lung adenocarcinoma (ADC) is the most prevalent subtype of lung cancer and characterized by considerable morphological and mutational heterogeneity. However, little is known about the epigenomic intratumor variability between spatially separated histological growth patterns of ADC. In order to reconstruct the clonal evolution of histomorphological patterns, we performed global DNA methylation profiling of 27 primary tumor regions, seven matched normal tissues and six lymph node metastases from seven ADC cases. Additionally, we investigated the methylation data from 369 samples of the TCGA ADC cohort. All regions showed varying degrees of methylation changes between segments of different, but also of the same growth patterns. Similarly, copy number variations were seen between spatially distinct segments of each patient. Hierarchical clustering of promoter methylation revealed extensive heterogeneity within and between the cases. Intratumor DNA methylation heterogeneity demonstrated a branched clonal evolution of ADC regions driven by genomic instability with subclonal copy number changes. Notably, methylation profiles within tumors were not more similar to each other than to those from other individuals. In two cases, different tumor regions of the same individuals were represented in distant clusters of the TCGA cohort, illustrating the extensive epigenomic intratumor heterogeneity of ADCs. We found no evidence for the lymph node metastases to be derived from a common growth pattern. Instead, they had evolved early and separately from a particular pattern in each primary tumor. Our results suggest that extensive variation of epigenomic features contributes to the molecular and phenotypic heterogeneity of primary ADCs and lymph node metastases.

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“…Decreased ATP production and apoptotic rate, increased cell growth, and increased risk of certain cancers have been associated with mitochondrial mutations [12,17,21,22]. For lung cancer, previous investigations attempting to delineate the role of mitochondrial mutations have been performed with PCR or microarray with small sample sizes, heterogeneity of stage, or patients from different ethnicities, and the associations of mitochondrial mutations and clinical outcomes were not profound [23,24]. Hence, evaluation of the predictive power of mitochondrial variants for clinical outcomes has not been conclusive so far.…”

Section: Introductionmentioning

confidence: 99%

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma

Raghav

Hsu

et al. 2020

Cancers

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Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93–28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

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Prevalence of somatic mitochondrial mutations and spatial distribution of mitochondria in non-small cell lung cancer

Cited by 28 publications

References 40 publications

Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas

Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas

Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma

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