Roma, Luca; Ercan, Caner; Conticelli, Floriana; Akyürek, Nalan; Prince, Spasenija Savic; Mertz, Kirsten D; Diebold, Joachim; Lardinois, Didier; Piscuoglio, Salvatore; Ng, K Y Charlotte; Bubendorf, Lukas (2024). Tracing tumor heterogeneity of pleomorphic carcinoma of the lung. Journal of thoracic oncology, 19(9), pp. 1284-1296. Elsevier 10.1016/j.jtho.2024.04.019
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BACKGROUND
Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous non-small-cell lung carcinoma whose underlying biology is still poorly understood.
METHODS
Forty-two tumor areas from 20 PPC patients were microdissected, including 39 primary tumors and 3 metastases and the histologically distinct components were subjected to whole exome sequencing (WES) separately. We further performed in silico analysis of microdissected bulk RNAseq and methylation data of 28 samples from 14 PPC patients. We validated our findings using immunohistochemistry.
RESULTS
The epithelial and the sarcomatoid components of PPCs shared a large number of genomic alterations. Most mutations in cancer driver genes were clonal and truncal between the two components of PPCs suggesting a common ancestor. The high number of alterations in the RTK-RAS pathway suggests that it plays an important role in the evolution of PPC. The metastases morphologically and genetically resembled the epithelial or the sarcomatoid components of the tumor. The transcriptomic and epigenetic profiles of the sarcomatoid components of PPCs with matched squamous-like or adenocarcinoma-like components differed from each other and they shared more similarities to their matched epithelial components. NCAM1/CD56 was preferentially expressed in the sarcomatoid component of squamous-like PPCs, whereas CDH1/E-Cadherin expression was downregulated in the sarcomatoid component of most PPCs.
CONCLUSION
LUAD-like PPCs are mainly driven by RTK-RAS signaling, whereas epithelial-mesenchymal transition programs as highlighted by increased NCAM1 and decreased CDH1 expression govern the epithelial-sarcomatoid transition between the clonally related tumor components. Several alterations in PPCs pinpoint therapeutic opportunities.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Ng, Kiu Yan Charlotte |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1556-1380 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
10 May 2024 14:12 |
Last Modified: |
08 Sep 2024 00:13 |
Publisher DOI: |
10.1016/j.jtho.2024.04.019 |
PubMed ID: |
38723776 |
Uncontrolled Keywords: |
EMT NCAM1/CD56 Pleomorphic carcinoma genomic evolution sarcomatoid lung cancer tumor heterogeneity |
BORIS DOI: |
10.48350/196677 |
URI: |
https://boris.unibe.ch/id/eprint/196677 |
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