Department of Surgery and.
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
J Clin Invest. 2019 Oct 1;129(10):4276-4289. doi: 10.1172/JCI128227.
BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).
腺样囊性癌（ACC）是一种罕见的恶性肿瘤，发生于唾液腺和其他部位，其特点是复发率和远处转移率高。复发性/转移性（R/M）ACC 通常无法治愈，这是由于缺乏有效的全身治疗方法。为了改善预后，需要更深入地了解 R/M 肿瘤中的遗传改变和脆弱性。
对 1045 例 ACC （177 例原发，868 例 R/M）进行了综合基因组分析，以确定与晚期和转移性肿瘤相关的改变。评估了肿瘤内遗传异质性、种系突变和治疗的可操作性。
与原发肿瘤相比，R/M 肿瘤中关键的 Notch（NOTCH1，26.3% vs. 8.5%；NOTCH2，4.6% vs. 2.3%；NOTCH3，5.7% vs. 2.3%；NOTCH4，3.6% vs. 0.6%）和染色质重塑（KDM6A，15.2% vs. 3.4%；KMT2C/MLL3，14.3% vs. 4.0%；ARID1B，14.1% vs. 4.0%）基因的改变更为丰富。TERT 启动子突变（R/M 病例的 13.1%）与 NOTCH1 突变（q=3.3×10-4）和 MYB/MYBL1 融合（q=5.6×10-3）均相互排斥，提示存在不同的、替代的肿瘤发生机制。这一改变网络定义了 4 个不同的 ACC 亚组：MYB+NOTCH1+、MYB+/其他、MYBWTNOTCH1+和 MYBWTTERT+。尽管突变负荷较低，但我们在许多样本中发现了明显的肿瘤内遗传异质性，包括多区域测序中的分支进化。
这些观察结果共同重新定义了 ACC 进展的分子基础，并确定了进一步用于精准治疗的靶点。
腺样囊性癌研究基金会、潘兴广场索恩癌症研究赠款、佩恩·韦伯主席、癌症研究站、NIH R01 CA205426、STARR 癌症联盟、NCI R35 CA232097、弗雷德里克·阿德勒主席、生存周期、生存循环、NIH K08 DE027738 和 R01 DE027738，以及 MSKCC 通过 NIH/NCI 癌症中心支持赠款（P30 CA008748）。
