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Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma.

ABSTRACT: 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.

SUBMITTER: Liu B

PROVIDER: S-EPMC6059240 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma.

Liu Bin B Mitani Yoshitsugu Y Rao Xiayu X Zafereo Mark M Zhang Jianjun J Zhang Jianhua J Futreal P Andrew PA Lozano Guillermina G El-Naggar Adel K AK

Journal of the National Cancer Institute 20171001 10

<h4>Background</h4>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.<h4>Methods</h4>To investigate the spatial and temporal clonal landscape of ACC, whole-ge ...[more]

PMID: 29117356

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Project description:BACKGROUND: Salivary adenoid cystic carcinoma (SACC) is one of the most common malignancies of salivary gland. Recurrence or/and early metastasis is its biological properties. In SACC, neoplastic myoepithelial cells secrete proteoglycans unconventionally full of the cribriform or tubular and glandular structures of SACC. Literatures have demonstrated that extracellular matrix provided an essential microenvironment for the biological behavior of SACC. However, there is rare study of the effect of proteoglycans on the potential metastasis of SACC.In this study, human xylosyltransferase-I (XTLY-I) gene, which catalyzes the rate-limited step of proteoglycans biosynthesis, was knocked down by RNA interference (RNAi) to inhibit the proteoglycans biosynthesis in SACC cell line with high tendency of lung metastasis (SACC-M). The impact of down-regulated proteoglycans on the metastasis characters of SACC-M cells was analyzed and discussed. This research could provide a new idea for the clinical treatment of SACC. METHODS: The eukaryotic expression vector of short hairpin RNA (shRNA) targeting XTLY-I gene was constructed and transfected into SACC-M cells. A stably transfectant cell line named SACC-M-WJ4 was isolated. The XTLY-I expression was measured by real-time PCR and Western blot; the reduction of proteoglycans was measured. The invasion and metastasis of SACC-M-WJ4 cells were detected; the effect of down-regulated proteoglycans on the potential lung metastasis of nude mice was observed, respectively. RESULTS: The shRNA plasmid targeting XTLY-I gene showed powerful efficiency of RNAi. The mRNA level of target gene decreased by 86.81%, the protein level was decreased by 80.10%, respectively. The silence of XTLY-I gene resulted in the reduction of proteoglycans significantly in SACC-M-WJ4 cells. The inhibitory rate of proteoglycans was 58.17% (24 h), 66.06% (48 h), 57.91% (72 h), 59.36% (96 h), and 55.65% (120 h), respectively. The reduction of proteoglycans suppressed the adhesion, invasion and metastasis properties of SACC-M cells, and decreased the lung metastasis of SACC-M cells markedly either. CONCLUSION: The data suggested that the silence of XTLY-I gene in SACC-M cells could suppress proteoglycans biosynthesis and secretion significantly. The reduction of proteoglycans inhibited cell adhesion, invasion and metastasis of SACC-M cells. There is a close relationship between proteoglycans and the biological behavior of SACC.

Dataset Information

Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma.

Publications

Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma.

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