Loss of CDKN2A/B is a Molecular Marker of High-grade Histology and is Associated with Aggressive Behavior in Acinic Cell Carcinoma.

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 two-tiered grading scheme in AciCC was proposed to recognize patients at risk for poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined PD-L1 expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade and 21 low-grade AciCCs. Forty-three cases were subjected to a targeted exome sequencing by MSK-IMPACT. PD-L1 immunohistochemistry was performed on 33 cases. Tumor mutation burden was low with a median 1 and 2 mutations in low-grade and high-grade AciCCs, respectively. CDKN2A/B was the most frequently altered gene and loss-of-function mutations were found only in high-grade but not in low-grade AciCCs (58.1%, 18/31 vs. 0/12, p<0.001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 88.9% (16/18) CDKN2A/B mutants vs. 44% (11/25) wild-type cases (p=0.004, Fisher's exact test). Sequential profiling of multiple, temporally distant samples from the same patient demonstrated intratumor heterogeneity including detection of CDKN2A/B deletion in the second, high-grade metastasis only. ATM and PTEN mutations were detected in 19.4% (6/31) and 16.1% (5/31), ARID2, BIRC3 and FBXW7 mutations each in 12.9% (4/31), and TP53, MTAP and FAT1 each in 9.7% (3/31) HG AciCC. PD-L1 positive labeling was more common in high-grade AciCC (9/17, 52.9% vs 3/16, 18.9%, p=0.071). CDKN2A/B mutations in AciCC represent a molecular marker of high-grade histology and disease progression providing a rationale for further studies to determine their prognostic and therapeutic significance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered as a treatment option for a subset of AciCC patients.