Loss of CDKN2A/B is a molecular marker of high-grade histology and is associated with aggressive behavior in acinic cell carcinoma Journal Article
| Authors: | Dogan, S.; Xu, B.; Rana, S.; Chen, H.; Ghossein, R. A.; Berger, M. F.; Ho, A. L.; Katabi, N. |
| Article Title: | Loss of CDKN2A/B is a molecular marker of high-grade histology and is associated with aggressive behavior in acinic cell carcinoma |
| Abstract: | Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a 2-tiered grading scheme in AciCC was proposed to recognize patients at risk of poor outcome. We performed genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined programmed death ligand 1 (PD-L1) expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade (HG) and 21 low-grade AciCCs. Forty-three cases were subjected to targeted exome sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. PD-L1 immunohistochemistry was performed in 33 cases. Tumor mutation burden was low with a median of 1 and 2 mutations in low-grade and HG AciCCs, respectively. CDKN2A/B was the most frequently altered gene, and loss-of -function mutations were found only in HG but not in low-grade AciCCs (18/31 [58.1%] vs 0/12 [0%], P < .001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 16/18 (88.9%) CDKN2A/B mutants versus 11/25 (44%) wild-type cases (P =.004, Fisher exact test). Sequential profiling of multiple temporally distant samples from the same patient demonstrated intratumor heterogeneity, including the detection of CDKN2A/B deletion in the second, in HG metastasis only. ATM and PTEN mutations were detected in 6/31 (19.4%) and 5/31 (16.1%); ARID2, BIRC3, and FBXW7 mutations each in 4/31 (12.9%); and TP53, MTAP, and FAT1 each in 3/31 (9.7%) HG AciCC. PD-L1epositive labeling was more common in HG AciCC (9/17, 52.9% vs 3/16, 18.9%, P = .071). CDKN2A/B mutations in AciCC represent a molecular marker of HG histology and disease progres-sion, providing a rationale for further studies to determine their prognostic and therapeutic sig-nificance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered to be a treatment option for a subset of patients with AciCC.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved. |
| Keywords: | survival; pten; cdkn2a; atm; expression; b; cancer; prognosis; high-grade acinic cell carcinoma |
| Journal Title: | Modern Pathology |
| Volume: | 36 |
| Issue: | 7 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2023-07-01 |
| Start Page: | 100150 |
| Language: | English |
| ACCESSION: | WOS:000966148700001 |
| DOI: | 10.1016/j.modpat.2023.100150 |
| PROVIDER: | wos |
| PUBMED: | 36841437 |
| PMCID: | PMC10447625 |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Snjezana Dogan -- Source: Wos |
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