Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Abstract

There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

“…4A). Genomic analysis of the same cohort of IPNs in our previous study have revealed progressive increase in mutation burden from AAH to ADC, while SCNA only became obvious after stage of AIS and AI events were rare in AAH and AIS 7 .…”

“…29 lung nodules from 15 patients had multiregional specimens for spatial heterogeneity assessment (Supplementary Table 1). Wholeexome sequencing (WES) data was available for all specimens (EGAS00001004960) 7 .…”

“…We have initiated an international collaboration for the collection and characterization of these lung precancers, pre-invasive and early invasive ADC presenting as IPNs. We recently reported the genomic landscape, including the genomic intra-tumor heterogeneity (ITH), of 116 IPNs from 53 patients and revealed evidence of progressive evolution from AAH to AIS, MIA, and ADC at the single-nucleotide level and macroevolution at the transitions from AAH to AIS, and from AIS to MIA associated with somatic copy number aberration (SCNA) and allelic imbalance (AI), respectively 7 . In addition, we found that genomic ITH is more pronounced in AAH than in ADC, which suggests a clonal sweeping model during the neoplastic progression of AAH 7 .…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…Technical advances in lung cancer screening as well as its expanded implementation have allowed the detection of what was termed as indeterminate pulmonary nodules (IPNs), as well as brought forth the potential of investigating these resected nodules in novel and unique cohorts. IPNs of the lung were found to be histologically elusive, classifying as AAH, adenoma in situ (AIS), minimally invasive adenoma (MIA), or even invasive LUAD (265). Using multi-region exome sequencing, researchers investigated the evolutionary trajectory of those IPNs, revealing evidence for a progressive genomic evolution from AAH to AIS, MIA, and LUADs, as well as a selective evolutionary model characterized by the outgrowth of fit subclones and sweep of unfit subclones, during initiation and early progression of lung preneoplasia (265).…”

“…IPNs of the lung were found to be histologically elusive, classifying as AAH, adenoma in situ (AIS), minimally invasive adenoma (MIA), or even invasive LUAD (265). Using multi-region exome sequencing, researchers investigated the evolutionary trajectory of those IPNs, revealing evidence for a progressive genomic evolution from AAH to AIS, MIA, and LUADs, as well as a selective evolutionary model characterized by the outgrowth of fit subclones and sweep of unfit subclones, during initiation and early progression of lung preneoplasia (265). Further analysis of neoantigens in this dataset may provide valuable insights into the concurrent evolution of the immunogneomic landscape mirroring the progression of PMLs into LUADs.…”