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Abstract：
The mechanism and predictive biomarkers of sinonasal inverted papilloma (IP) transformation into squamous cell carcinoma (SCC) are still unclear. We investigated the genetic mutations involved and the predictive biomarkers. Fourteen patients with SCC arising from IP and six patients with IPs without malignant transformation (sIP) were included. DNA was extracted separately from areas of normal tissue, IP, dysplasia, and SCC. Whole exome sequencing and immunohistochemistry was performed. Major oncogenic mutations were observed in the progression from IP to SCC. The most frequently mutated genes were TP53 (39%) and CDKN2A (27%). Mutations in TP53 and/or CDKN2A were observed in three of six IPs with malignant transformation (cIP); none were observed in sIPs. Tumor mutational burden (TMB) increased from IP to SCC (0.64/Mb, 1.11/Mb, and 1.25 for IP, dysplasia, and SCC, respectively). TMB was higher in the cIPs than in the sIPs (0.64/Mb vs 0.3/Mb). Three cIPs showed a diffuse strong or null pattern in p53, and one showed a total loss of p16, a distinct pattern from sIPs. Our result suggests that TP53 and CDKN2A status can be predictive markers of malignant transformation of IP. Furthermore, immunohistochemistry of p53 and p16 expression can be surrogate markers for TP53 and CDKN2A status.
摘要：
鼻腔鼻窦内翻性乳头状瘤（IP）转化为鳞状细胞癌（SCC）的机制和预测生物标志物尚不清楚。我们调查了所涉及的基因突变和预测性生物标志物。包括14例因IP引起的SCC患者和6例无恶变（sIP）的IP患者。DNA分别从正常组织区域提取,IP,发育不良,SCC。进行全外显子组测序和免疫组织化学。在从IP到SCC的进展中观察到主要的致癌突变。最常见的突变基因是TP53（39％）和CDKN2A（27％）。在具有恶性转化（cIP）的六个IP中的三个中观察到TP53和/或CDKN2A的突变；在sIP中没有观察到。肿瘤突变负荷（TMB）从IP增加到SCC（0.64/Mb，1.11/Mb,和1.25的IP，发育不良,SCC,分别)。cIP中的TMB高于sIP中的TMB（0.64/Mbvs0.3/Mb）。三个cIP在p53中显示出弥漫性强或无效模式，一个显示出p16的完全丢失，与sIP不同。我们的结果表明，TP53和CDKN2A状态可能是IP恶性转化的预测标志物。此外，p53和p16表达的免疫组织化学可以作为TP53和CDKN2A状态的替代标记。
