Tracing tumor heterogeneity of pleomorphic carcinoma of the lung

Luca Roma; Caner Ercan; Floriana Conticelli; Nalan Akyürek; Spasenija Savic Prince; Kirsten D Mertz; Joachim Diebold; Didier Lardinois; Salvatore Piscuoglio; Charlotte Ky Ng; Lukas Bubendorf

doi:10.1016/j.jtho.2024.04.019

Tracing tumor heterogeneity of pleomorphic carcinoma of the lung

J Thorac Oncol. 2024 May 7:S1556-0864(24)00205-3. doi: 10.1016/j.jtho.2024.04.019. Online ahead of print.

Authors

Affiliations

¹ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
² Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Public Health, University of Naples Federico II, Naples, Italy.
³ Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey.
⁴ Institute for Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
⁵ Institute of Pathology, Cantonal Hospital Lucerne, Switzerland.
⁶ Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.
⁷ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
⁸ Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
⁹ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: Lukas.Bubendorf@usb.ch.

PMID: 38723776
DOI: 10.1016/j.jtho.2024.04.019

Abstract

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.

Keywords: EMT; NCAM1/CD56; Pleomorphic carcinoma; genomic evolution; sarcomatoid lung cancer; tumor heterogeneity.