Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer
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Anna Karlsson1, Hans Brunnström2,3, Kajsa Ericson Lindquist3, Karin Jirström2,3, Mats Jönsson1, Frida Rosengren1, Christel Reuterswärd1, Helena Cirenajwis1, Åke Borg1,6, Per Jönsson4, Maria Planck1,5, Göran Jönsson1,6, Johan Staaf1,6
1Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE 22381 Lund, Sweden
2Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, SE 22185 Lund, Sweden
3Department of Pathology, Regional Laboratories Region Skåne, SE 22185 Lund, Sweden
4Department of Thoracic Surgery, Lund University, Skåne University Hospital, SE 22185 Lund, Sweden
5Department of Oncology, Skåne University Hospital, SE 22185 Lund, Sweden
6Create Health Strategic Center for Translational Cancer Research, Lund University, Medicon Village, SE 22381 Lund, Sweden
Johan Staaf, e-mail: firstname.lastname@example.org
Keywords: large cell lung cancer, LCNEC, mutation, gene fusion, ALK
Received: March 01, 2015 Accepted: June 05, 2015 Published: June 17, 2015
Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3–9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.
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