Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types

<p>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 <i>TP53</i> (64.5% of patients), <i>PIK3CA</i> (28.5%), <i>CDKN2A</i> (24.4%), <i>SOX2</i> (17.7%), and <i>CCND1</i> (15.8%). By comparing NGS results of our SCC cohort to a non-SCC cohort (N = 277), we found that <i>CDKN2A, SOX2, NOTCH1, TP53, PIK3CA, CCND1</i>, and <i>FBXW7</i> were significantly more frequently altered, unlike <i>KRAS</i>, which was less frequently altered in SCC specimens (all P < 0.05; multivariable analysis). Therefore, we identified “squamousness” gene signatures (<i>TP53, PIK3CA, CCND1, CDKN2A, SOX2, NOTCH 1</i>, and <i>FBXW7</i> aberrations, and absence of <i>KRAS</i> 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 <i>TP53</i> and cyclin pathway (<i>CDKN2A</i> and <i>CCND1)</i> alterations strongly correlated but in whom <i>PIK3CA</i> aberrations were less frequent; and (ii) patients with <i>PIK3CA</i> alterations in whom <i>TP53</i> 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.</p