TY - JOUR
T1 - Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma
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.
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
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.
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U2 - 10.1172/JCI128227
DO - 10.1172/JCI128227
M3 - Article
C2 - 31483290
AN - SCOPUS:85072791585
SN - 0021-9738
VL - 129
SP - 4276
EP - 4289
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -