Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation.
Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation.
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为了更好地了解膀胱原发性印戒细胞癌（SRCC）的遗传基础，这是一种非常罕见且尚未探索的疾病。首先，通过免疫组织化学方法寻找组织病理学特征。其次，对一名58岁的男性患者进行了大规模平行全外显子组测序（WES），该患者患有无痛性肉眼血尿，病理诊断为膀胱原发性SRCC，然后与TCGA的普通尿路上皮癌（UC）基因进行比较。此外，使用SEER数据库进行了基于人群的分析，以研究预后（SRCC与UC）。我们确定了63个拷贝数变异（CNVs）与增益计数和181个CNVs与损失计数。C > T共发现4515个突变，成功率大于89%。最常见的突变途径是RTK-RAS，它有85个基因参与致癌信号传导。在基于ACMG的过滤之后，对易感基因进行最终筛选。此外，还检测到NBN、KCTD 18、SPATA 13、ANKRD 36、OR 2L 5、MALRD 1和LSMEM 1等驱动基因。生殖系DNA的桑格测序揭示了序列中OR 2L 5的突变碱基A/G的存在，这是首次在膀胱原发性SRCC中发现的。此外，免疫组织化学谱显示膀胱原发性SRCC对CK 7、CK 20、加塔-3呈阳性，CK（AE 1/AE 2）、EMA和Ki 67表达阳性。在基于SEER的研究中，与UC患者相比，膀胱原发性SRCC患者的预后更差，中位总生存期（OS）分别为14个月和41个月，P = 0.001，即使在调整考克斯回归模型中的变量后，膀胱SRCC的生存率也更差HR = 1.119，95% CI = 1.119。（1.081-1.328），P = 0.0001。这些结果表明，抑制潜在的驱动突变可能是膀胱原发性SRCC替代标准化疗的可行辅助治疗方法，这种可能性需要进一步的临床研究。膀胱印戒细胞癌的详细方法图。
To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole‐exome sequencing (WES) was performed on a 58‐year‐old male patient who had painless macroscopic hematuria and was pathologically diagnosed with primary SRCC of the bladder, followed by comparing with genes of ordinary urothelial cancer (UC) from TCGA. Furthermore, a population‐based analysis using the SEER database was performed to investigate the prognosis (SRCC vs. UC). We identified 63 copy number variations (CNVs) with gain counts and 181 CNVs with loss counts. Totally 4515 mutations were discovered in C > T with a success rate of greater than 89%. The most frequently mutated pathway was RTK‐RAS which has 85 genes involved in carcinogenic signaling. Final screening on predisposing genes is performed after filtering based on ACMG. Moreover, several driver genes, including NBN, KCTD18, SPATA13, ANKRD36, OR2L5, MALRD1, and LSMEM1, were detected. Sanger sequencing of germline DNA revealed the presence of a mutant base A/G of OR2L5 in the sequence, which was discovered for the first time in primary SRCC of the bladder. Furthermore, the immunohistochemical profile showed that primary SRCC of the bladder were positive for CK7, CK20, GATA‐3, and expression of CK(AE1/AE2), EMA, and Ki67. In the SEER‐based study, the patients with primary SRCC of the bladder got a worse prognosis compared to those with UC with median months overall survival (OS) 14 vs. 41, respectively, P = 0001, even after adjusting the variables in the Cox regression model, the SRCC of the bladder showed worse survival HR = 1.119, 95% CI = (1.081–1.328), P = 0.0001. These results imply that suppression of potential driver mutations may be a viable adjuvant treatment approach for primary SRCC in the bladder in place of standard chemotherapy, a possibility that warrants further clinical investigation. Detailed methodology diagram of signet ring cell carcinoma of bladder.
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