Abstract IA09: Squamous cell carcinoma pathology, etiology, and molecular drivers.
Authors: Elisabeth Brambilla
Journal: Clinical Cancer Research (2014)

Abstract Squamous cell carcinoma (SCC) accounts for approximately 20% of all lung cancers in the United States and 30% in Europe [1-3]. It is a model of smokers related tumors with SCLC. The frequency of peripheral lung involvement has increased as compared to central squamous cell carcinoma. Morphologically, squamous differentiation is identified by inter-cellular bridging, squamous pearl formation and individual cell keratinisation. The intensity of these features characterizes well differentiated squamous cell carcinoma, versus poorly differentiated tumors that lack clear squamous morphology, are more difficult to differentiate from large cell carcinoma or from non cell lung carcinoma on small biopsies. In this cases the molecular marker P63 and/or P40 (the delta-N deleted P63 isoform) and negativity of TTF1 allows for a tumor to be classified as SCC. With high concordance q with the genomic prediction from exome sequencing (D.Seidel et al,Science Translational Medicine 2013 in press ) In addition to keratinized (well differentiated) and non keratinized (poorly differentiated) squamous cell carcinoma, basaloid carcinoma represent a third class recently identified as a specific molecular entity among SCC on gene expression profiling (WHO 2004 Travis , E. Brambilla, submitted 2013), with a significantly dismal prognosis among SCC. Basaloid carcinoma carries 95 % P53 mutation (G-T transversion). Supervised analyses reveal that basaloïd SCC significantly display a specific mRNA profile. Genes related to cell cycle, transcription factors, germ cells specific signatures, mRNA spliceosome, chromatin modification, and stemness are shown to be overexpressed in pure basaloid tumors, while genes related to squamous differentiation are shown to be underexpressed. This is highly coherent with the poorly differentiated status fast growth and aggressiveness of these tumors. Moreover, unsupervised analyses identify a molecular subgroup corresponding to pure basaloïd tumors. The transcription factor SOX4 showed 100% specificity and 50% sensitivity to discriminate basaloïd tumors in our cohort confirmed by immunohistochemical analysis. Using a centroid-based predictor, this molecular subtype was found in 8 independent public datasets (n=58/533), and was shown associated to a very poor survival as compared to other SCC (adjusted HR =2.45, p =0.00001 SCC. In addition to gene copy number alterations common to all SCC at the single gene level, gains of MYB, JUN, FGFR1, PIK3C3, DSC/DSG genes were found more frequent in pure basaloïd tumors. First identification of genomic druggable oncogene target were FGFR1 amplification [4] sensitive to a specific FGFR inhibitor [5] and DDR2 (Discoidin domain receptor) mutation [6] sensitive to dasatinib. Recently significant knowledge of genomics of SCC has been provided by comprehensive analysis of genetic alteration as part of the cancer gene genome atlas (TGA) [7] which transformed the landscape of genomic and epigenomic alterations. Among specific genetic alterations discovered as driver oncogenes targetable by specific therapies, FGFR1 amplification to 25 % of SCC even smokers restricted to those cases exposed to tobacco carcinogens (upper and lower airways) exclusively, DDR2 mutation accounting for 3 % of SCCand PIK3 amplication (PIK3CA inhibitors). The PIK3CA is amplified in 20-30 % of SCC. In addition, frequent mutation has been discovered on CDKN2/P16 gene, PTEN, PIK3CA, KEAP1 and other NRF2 complex (NRF2, Cul3) and MLL2, as well as significant copy number alterations including amplifications on SOX2, confirming previous description of a 3q 26 amplicon in all subtypes triggering high expression of SOX2 ,TP63 and PIK3CA [8, 9] and deletion of CDKN2/P16. Many of the somatic alterations identified in SCC were drivers of pathway important for initiation and tumor progression even those not yet but potentially targetable like SOX2. Therapeutic targets are ready for DDR2 mutation (dasatinib) and FRGR1 amplification (FGFR TKI) with anticipated approval for a target for PIK3CA. All together about 60 % of squamous cell carcinoma are potentially targetable with specific therapies [7,10]. Citation Format: Elisabeth Brambilla. Squamous cell carcinoma pathology, etiology, and molecular drivers. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA09.