TY - JOUR AU - Ho, Allen S. AU - Ochoa, Angelica AU - Jayakumaran, Gowtham AU - Zehir, Ahmet AU - Valero Mayor, Cristina AU - Tepe, Justin AU - Makarov, Vladimir AU - Dalin, Martin G. AU - He, Jie AU - Bailey, Mark AU - Montesion, Meagan AU - Ross, Jeffrey S. AU - Miller, Vincent A. AU - Chan, Lindsay AU - Ganly, Ian AU - Dogan, Snjezana AU - Katabi, Nora AU - Tsipouras, Petros AU - Ha, Patrick AU - Agrawal, Nishant AU - Solit, David B. AU - Futreal, P. Andrew AU - El Naggar, Adel K. AU - Reis-Filho, Jorge S. AU - Weigelt, Britta AU - Ho, Alan L. AU - Schultz, Nikolaus AU - Chan, Timothy A. AU - Morris, Luc G.T. T1 - Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma PY - 2019/10/01/ AB - 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.FUNDING Adenoid 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). JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI128227 VL - 129 IS - 10 UR - https://doi.org/10.1172/JCI128227 SP - 4276 EP - 4289 PB - The American Society for Clinical Investigation ER -