title: Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types.
abstract: In order to gain a better understanding of the underlying biology of squamous cell carcinoma (SCC), we tested the hypothesis that SCC originating from different organs may possess common molecular alterations. SCC samples (N = 361) were examined using clinical-grade targeted next-generation sequencing (NGS). The most frequent SCC tumor types were head and neck, lung, cutaneous, gastrointestinal and gynecologic cancers. The most common gene alterations were TP53 (64.5% of patients), PIK3CA (28.5%), CDKN2A (24.4%), SOX2 (17.7%), and CCND1 (15.8%). By comparing NGS results of our SCC cohort to a non-SCC cohort (N = 277), we found that CDKN2A, SOX2, NOTCH1, TP53, PIK3CA, CCND1, and FBXW7 were significantly more frequently altered, unlike KRAS, which was less frequently altered in SCC specimens (all P < 0.05; multivariable analysis). Therefore, we identified "squamousness" gene signatures (TP53, PIK3CA, CCND1, CDKN2A, SOX2, NOTCH 1, and FBXW7 aberrations, and absence of KRAS alterations) that were significantly more frequent in SCC versus non-SCC histologies. A multivariable co-alteration analysis established 2 SCC subgroups: (i) patients in whom TP53 and cyclin pathway (CDKN2A and CCND1) alterations strongly correlated but in whom PIK3CA aberrations were less frequent; and (ii) patients with PIK3CA alterations in whom TP53 mutations were less frequent (all P ≤ 0 .001, multivariable analysis). In conclusion, we identified a set of 8 genes altered with significantly different frequencies when SCC and non-SCC were compared, suggesting the existence of patterns for "squamousness." Targeting the PI3K-AKT-mTOR and/or cyclin pathway components in SCC may be warranted.
authors.affiliation: a Center for Personalized Cancer Therapy; University of California San Diego Moores Cancer Center ; La Jolla , CA USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Schwaederle
authors.forename: Sheryl K
authors.initials: SK
authors.lastname: Elkin
authors.forename: Brett N
authors.initials: BN
authors.lastname: Tomson
authors.forename: Jennifer Levin
authors.initials: JL
authors.lastname: Carter
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005833:Genital Neoplasms, Female / Q000378:metabolism / Q000473:pathology*; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016213:Cyclins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human
keywords: SCC; cancer; gene signature; next-generation sequencing; squamous