Background Adenoid cystic carcinoma (ACC), an uncommon and indolent salivary gland malignancy, is characterized by varied morphologic and clinical manifestations. Molecular genetic studies of ACC identified certain structural and mutational alterations that may play a driver role in tumor development. The evolution and regional consistency of these events in ACC development progression are uncertain. Methods To investigate the spatial and temporal clonal landscape of ACC, whole-genome sequencing and variant analyses were performed on 34 regionally sampled primary tumors and their concurrent and metachronous metastatic deposits from eight patients. Results The average mutation rate per case (primary and metastasis) was 0.32 per million base pairs, and the average incidence of shared mutations in primary and metastatic specimens in each case was 21.9% (range = 0%-44.4%). The analyses revealed considerable spatial clonal differences within and between primary tumors and metastatic disease. Phylogeny formation displayed branching evolution with a main trunk and two distinct mono-splits in all cases. One of the main branches represented intratumor subclonal diversity, and the other delineated metastatic departure and progression. All metastatic tumors shared clonal linkage to their matching primary in concordance with parallel dissemination of metastasis. Synchronous metastases were genomically more similar to their primary than metachronous metastatic disease. Truncal genetic alterations included somatic mutations in the NOTCH pathway genes (NOTCH1 and SPEN) and t(6;9) associated gene fusions. Conclusions Our study delineated clonal and subclonal phylogeny for primary and metastatic ACC, defined early genetic drivers, and provides a conceptual framework for a rational strategy to integrate heterogeneity in clinical assessment.

中文翻译：

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唾液腺样囊性癌的时空基因组异质性，系统发育和转移演变。

背景腺样囊性癌（ACC）是一种罕见的唾液腺恶性肿瘤，其特征在于形态学和临床表现各异。ACC的分子遗传学研究确定了某些结构和突变改变，这些改变可能在肿瘤发展中起驱动作用。这些事件在ACC发展进程中的演变和区域一致性尚不确定。方法为了调查ACC的时空克隆格局，对8例患者的34例区域性原发性肿瘤及其并发和异时转移性沉积物进行了全基因组测序和变异分析。结果每例（原发和转移）的平均突变率为每百万碱基对0.32，在每种情况下，原发性和转移性标本共有突变的平均发生率为21.9％（范围= 0％-44.4％）。分析显示原发肿瘤和转移性疾病之间以及之间存在相当大的空间克隆差异。系统发育的形成在所有情况下都显示出具有主干和两个不同单分裂的分支进化。主要分支之一代表肿瘤内亚克隆多样性，另一个代表转移转移和进展。所有转移性肿瘤与转移的平行扩散一致，与它们的配对原发肿瘤之间具有克隆联系。从基因上讲，同步转移与同步转移相比在基因上更类似于原发转移。躯干遗传改变包括NOTCH通路基因（NOTCH1和SPEN）中的体细胞突变和与t（6; 9）相关的基因融合。