Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma Journal Article
| Authors: | Ho, A. S.; Ochoa, A.; Jayakumaran, G.; Zehir, A.; Valero Mayor, C.; Tepe, J.; Makarov, V.; Dalin, M. G.; He, J.; Bailey, M.; Montesion, M.; Ross, J. S.; Miller, V. A.; Chan, L.; Ganly, I.; Dogan, S.; Katabi, N.; Tsipouras, P.; Ha, P.; Agrawal, N.; Solit, D. B.; Futreal, P. A.; El Naggar, A. K.; Reis-Filho, J. S.; Weigelt, B.; Ho, A. L.; Schultz, N.; Chan, T. A.; Morris, L. G. T. |
| Article Title: | Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma |
| Abstract: | 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 × 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. CONCLUSION. These observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies. © 2019, American Society for Clinical Investigation. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 129 |
| Issue: | 10 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2019-10-01 |
| Start Page: | 4276 |
| End Page: | 4289 |
| Language: | English |
| DOI: | 10.1172/jci128227 |
| PUBMED: | 31483290 |
| PROVIDER: | scopus |
| PMCID: | PMC6763222 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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