CDK12 改变和 ARID1A 突变是高级唾液腺癌不良预后和治疗靶点的预测因子：国家基因组分析数据库分析。

CDK12 alterations and ARID1A mutations are predictors of poor prognosis and therapeutic targets in high-grade salivary gland carcinoma: analysis of the National Genomic Profiling Database.

机构信息

Department of Otolaryngology, Head and Neck Surgery, The University of Tokyo, Tokyo, Japan.

Department of Next-Generation Precision Medicine Development Laboratory, The University of Tokyo, Tokyo, Japan.

出版信息

Jpn J Clin Oncol. 2023 Aug 30;53(9):798-807. doi: 10.1093/jjco/hyad066.

DOI:10.1093/jjco/hyad066

PMID:37357968

Abstract

BACKGROUND

Due to the diversity of histopathologic types in salivary gland carcinoma, genomic analysis of large cohorts with next-generation sequencing by histologic type has not been adequately performed.

METHODS

We analysed data from 93 patients with salivary duct carcinoma and 243 patients with adenoid cystic carcinoma who underwent comprehensive genomic profiling testing in the Center for Cancer Genomics and Advanced Therapeutics database, a Japanese national genome profiling database. We visualised gene mutation profiles using the OncoPrinter platform. Fisher's exact test, Kaplan-Meier analysis, log-rank test and Cox regression models were used for statistical analysis.

RESULTS

In salivary duct carcinoma, a population with CDK12 and ERBB2 co-amplification was detected in 20 of 37 (54.1%) patients with ERBB2 amplification. We identified five loss-of-function variants in genes related to homologous recombination deficiency, such as BRCA2 and CDK12. Cox survival analysis showed that CDK12 and ERBB2 co-amplification is associated with overall survival (hazard ratio, 3.597; P = 0.045). In salivary duct carcinoma, NOTCH1 mutations were the most common, followed by mutations in chromatin modification genes such as KMT2D, BCOR, KDM6A, ARID1A, EP300 and CREBBP. In the multivariate Cox analysis, activating NOTCH1 mutations (hazard ratio, 3.569; P = 0.009) and ARID1A mutations (hazard ratio, 4.029; P = 0.034) were significantly associated with overall survival.

CONCLUSION

CDK12 and ERBB2 co-amplification is associated with a poor prognosis in salivary duct carcinoma. Chromatin remodelling genes are deeply involved in tumour progression in adenoid cystic carcinoma. One such gene, ARID1A, was an independent prognostic factor. In salivary duct carcinoma and adenoid cystic carcinoma, there might be minor populations with mutations that could be targeted for treatment with the synthetic lethality approach.

摘要

背景

由于唾液腺癌的组织病理学类型多样，因此尚未通过组织学类型对大型队列进行下一代测序的基因组分析。

方法

我们分析了在癌症基因组和先进治疗中心数据库（日本国家基因组分析数据库）中接受全面基因组分析测试的 93 例涎管癌患者和 243 例腺样囊性癌患者的数据。我们使用 OncoPrinter 平台可视化基因突变谱。Fisher 精确检验、Kaplan-Meier 分析、对数秩检验和 Cox 回归模型用于统计分析。

结果

在涎管癌中，在 37 例 ERBB2 扩增患者中有 20 例（54.1%）检测到 CDK12 和 ERBB2 共扩增。我们在同源重组缺陷相关基因（如 BRCA2 和 CDK12）中鉴定了五个失活功能变体。Cox 生存分析表明，CDK12 和 ERBB2 共扩增与总生存相关（风险比，3.597；P=0.045）。在涎管癌中，NOTCH1 突变最为常见，其次是染色质修饰基因的突变，如 KMT2D、BCOR、KDM6A、ARID1A、EP300 和 CREBBP。在多变量 Cox 分析中，激活的 NOTCH1 突变（风险比，3.569；P=0.009）和 ARID1A 突变（风险比，4.029；P=0.034）与总生存显著相关。