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Abstract
Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.
Highlights
Histology plays an essential role in therapeutic decision-making for lung cancer patients
Primary lung cancers are histologically classified into small cell lung cancers (SCLC) and nonsmall cell lung cancers (NSCLC), with the latter including adenocarcinoma (LUAD), squamous cell carcinoma (LUSC), and largecell neuroendocrine carcinoma (LCNEC) as the main histologic subtypes
We leverage three unique datasets to show that the histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics: (1) whole-exome sequencing (WES) and transcriptomic data from 19 microdissected tumor regions of different histology from 9 primary lung cancer patients with mixed histologic patterns including 6 LUAD, 6 LCNEC, 3 SCLC, 3 LUSC, and one poorly differentiated NSCLC-NOS; (2) transcriptomic data from 141 cell lines of different histologic subtypes from the Cancer Cell Line Encyclopedia (CCLE)[15] including 14 LCNEC, 57 LUAD, 48 SCLC, and 22 LUSC; (3) transcriptomic data from a total of 343 patients including 14 LCNEC, 273 LUAD, 9 SCLC, and 47 LUSC with lung cancers of different histologic subtypes[16,17]
Summary
Histology plays an essential role in therapeutic decision-making for lung cancer patients. Previous studies revealed that tumors from different patients or even multiple independent primary lung cancers within the same patients can have identical morphology yet share no mutations[5], while there can be a morphologic difference in different regions within the same tumors that share the majority of mutations[6] These findings suggest that morphology may not be primarily determined by genomic features. The majority of these studies revealed shared driver mutations between different histologic components[8,9,10,11,12,13,14] These findings are overall in line with the prior hypothesis that genomic changes were not the main determinants of histology. We leverage three unique datasets to show that the histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics: (1) whole-exome sequencing (WES) and transcriptomic data from 19 microdissected tumor regions of different histology from 9 primary lung cancer patients with mixed histologic patterns including 6 LUAD, 6 LCNEC, 3 SCLC, 3 LUSC, and one poorly differentiated NSCLC-NOS; (2) transcriptomic data from 141 cell lines of different histologic subtypes from the Cancer Cell Line Encyclopedia (CCLE)[15] including 14 LCNEC, 57 LUAD, 48 SCLC, and 22 LUSC; (3) transcriptomic data from a total of 343 patients including 14 LCNEC, 273 LUAD, 9 SCLC, and 47 LUSC with lung cancers of different histologic subtypes[16,17]
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