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Exploring the spatiotemporal genetic heterogeneity in metastatic lung adenocarcinoma using a nuclei flow-sorting approach

ABSTRACT: Variable tumor cellularity can limit sensitivity and precision in comparative genomics, because differences in tumor content can result in misclassifying truncal mutations as region-specific private mutations in stroma-rich regions, especially when studying tissue specimens of mediocre tumor cellularity such as LUADs. To address this issue, we refined a nuclei flow-sorting approach by sorting nuclei based on ploidy and the LUAD lineage marker thyroid transcription factor 1 (TTF-1) and applied this method to investigate genome-wide somatic copy number aberrations (SCNA) and mutations of 409 cancer genes in 39 tumor populations obtained from 16 primary tumors and 21 matched metastases. This approach increased the mean tumor purity from 54% (range: 7-89%) of unsorted material to 92% (range: 79-99%) after sorting. Despite this rise in tumor purity, we detected limited genetic heterogeneity between primary tumors and their metastases. In fact, 88% of SCNAs and 80% of mutations were propagated from primary tumors to metastases and low allele frequency mutations accounted for much of the mutational heterogeneity. Even though the presence of SCNAs indicated a history of chromosomal instability (CIN) in all tumors, metastases did not have more SCNAs than primary tumors. Moreover, tumors with biallelic TP53 or ATM mutations had high numbers of SCNAs, yet they were associated with a low interlesional genetic heterogeneity. The results of our study thus provide evidence that most macroevolutionary events occur in primary tumors before metastatic dissemination and advocate for a limited degree of CIN over time and space in this cohort of LUADs. Sampling of primary tumors thus may suffice to detect most mutations and SCNAs. In addition, metastases but not primary tumors had seeded additional metastases in three of four patients; this provides a genomic rational for surgical treatment of such oligometastatic LUADs. Overall design: In total, there are 39 copy number Agilent 180k SurePrint arrays, representing 16 patients with 37 LUAD tumor samples, including 35 fresh frozen tissues and 2 FFPE tissues. There are 11 patients with primary tumor and one matched metastasis (22 arrays, one for each sample), 3 patients with primary tumor and two matched metastasis (9 arrays, one for each sample), one patient with primary tumor and three matched metastasis (4 arrays, one for each sample) and one patient with multiple populations in the primary tumor and one metastasis (4 arrays, 3 for each population in the primary tumor and 1 for the metastasis).

INSTRUMENT(S): Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Probe Name version)

SUBMITTER: Thomas Lorber  

PROVIDER: GSE119763 | GEO | 2018-09-11


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