KDM6A, ARID1A and SETD2 loss-of-function mutations as prognostic biomarkers and their association with sites of metastatic progression in locally-advanced, recurrent or metastatic adenoid cystic carcinoma
Rack, S. Patel, K. Heathcote, E. Mistry, H. Betts, G. Harrington, K. Metcalf, R.
Rack, S.
Patel, K.
Heathcote, E.
Mistry, H.
Betts, G.
Harrington, K.
Metcalf, R.
Abstract
OBJECTIVES: Recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) is typically slow growing however, some patients have more rapid progression. We sought to classify mutations in chromatin regulating genes in ACC to determine the impact of chromatin regulatory disfunction on clinical outcomes. MATERIALS AND METHODS: Matched clinical-genomic data from 271 pts with non-resectable or R/M ACC were included in this study. 132 pts were recruited locally. 139 ACC pts were included from cBioPortal for analysis. Mutations were classified as pathogenic using standardised bioinformatic pipelines. Analyses was performed to determine the impact of one or more mutations on overall survival from recurrence (OSr) and site of metastases. RESULTS: KDM6A mutations were seen in 12 % of patients, followed by ARID1A 9 %, EP300 6 %, CREBBP 5 %, KMT2D 5 %, SETD2 2.6 %, an KMT2C 1.8 %. While 15 % of patients harboured activating NOTCH1/2 mutations, which co-occurred with mutations in KDM6A, ARID1A, and CREBBP. NOTCH activation (8.4 v 2.3 years, p= <0.005), KDM6A (6.6 v 4.6 years, p = 0.008) and SETD2 (5.9 v 3.8 years, p = 0.04) mutations were associated with worse OSr. In NOTCH wild-type patients, median OSr for KDM6A 9.2 v 4.8 years (p = 0.07) and SETD2 was 9.8 v 3.2 years (p = 0.04). KDM6A (OR 4.5, 95 % CI 1.7-13.2, p = 0.002) mutations were significantly associated with bone metastasises and ARID1A mutations were associated with bone (OR 3.5, 95 % CI 1.2-11.8, p = 0.025) and liver (OR 3.0, 95 % CI 1.0-9.1, p = 0.053) in NOTCH wild-type patients. CONCLUSIONS: ARID1A, KDM6A and SETD2 loss of function mutations negatively impact clinical outcomes in R/M-ACC irrespective of NOTCH status.
Description
Date
2025
Publisher
Collections
Keywords
Type
Article
Citation
Rack S, Patel K, Heathcote E, Mistry H, Betts G, Harrington K, et al. KDM6A, ARID1A and SETD2 loss-of-function mutations as prognostic biomarkers and their association with sites of metastatic progression in locally-advanced, recurrent or metastatic adenoid cystic carcinoma. Oral oncology. 2025 Jul;166:107229. PubMed PMID: 40381467. Epub 2025/05/18. eng.