Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 10, Pages 4276-4289Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI128227
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Funding
- Adenoid Cystic Carcinoma Research Foundation
- Pershing Square Sohn Cancer Research grant
- PaineWebber Chair
- Stand Up 2 Cancer
- NIH [R01 CA205426, K08 DE024774, R01 DE027738]
- STARR Cancer Consortium
- NCI [R35 CA232097]
- Frederick Adler Chair
- Cycle for Survival
- Jayme Flowers Fund
- Sebastian Nativo Fund
- Cedars-Sinai Precision Health
- Donna and Jesse Garber Award for Cancer Research
- MSKCC through NIH/NCI Cancer Center Support Grant [P30 CA008748]
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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.
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