Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma
Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma
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DOI：
10.1172/jci128227
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发表时间：
2019-10-01
影响因子：
15.9
通讯作者：
Morris, Luc G. T.
中科院分区：
文献类型：
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作者：
Ho, Allen S.;Ochoa, Angelica;Morris, Luc G. T.
背景。腺样囊性癌（ACC）是一种罕见的恶性肿瘤，起源于唾液腺和其他部位，其特点是复发率高，远处扩散。由于缺乏积极的全身治疗，复发/转移（R/M） acc通常是无法治愈的。为了改善预后，需要更深入地了解R/M肿瘤的遗传改变和脆弱性。对1,045例ACCs（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。评估肿瘤内遗传异质性、种系突变和治疗可操作性。与原发肿瘤相比，R/M肿瘤富含关键Notch基因（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%）的改变。TERT启动子突变（占R/M病例的13.1%）与NOTCH1突变（q = 3.3 x 10(-4)）和MYB/MYBL1融合（q = 5.6 x 10(-3)）相互排斥，提示肿瘤发生的离散、可选机制。这种改变网络定义了4种不同的ACC亚群：MYB(+)NOTCH1(+), MYB+/other, MYBWTNOTCH1（+）和(MYBTERT+)-T-WT。尽管突变负荷较低，但我们发现许多样本具有明显的肿瘤内遗传异质性，包括跨多区域测序的分支进化。这些观察结果共同重新定义了ACC进展的分子基础，并确定了精确治疗的进一步靶点。
BACKGROUND. Adenoid 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.METHODS. An 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.RESULTS. Compared 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 x 10(-4)) and MYB/MYBL1 fusions (q = 5.6 x 10(-3)), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB(+)NOTCH1(+), MYB+/other, MYBWTNOTCH1(+), and (MYBTERT+)-T-WT. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSION. These observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.