Deletion of 1p32-p36 Is the Most Frequent Genetic Change and Poor Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

Abstract

Purpose: Adenoid cystic carcinoma (ACC) is a relatively uncommon salivary gland malignancy known for its protean phenotypic features and pernicious clinical behavior. Currently, no effective therapy is available for patients with advanced nonresectable, recurrent, and/or metastatic disease. The purpose of this study is to identify prognostic factors other than tumor stage that can be used to predict the outcome of the patients with ACC. Experimental Design: We used comparative genomic hybridization (CGH) to identify copy number aberrations in 53 primaryACCs. Array CGH and fluorescence in situ hybridization analysis was used to validate CGH results on selected cases.We correlated these copy number aberrations with clinicopathologic factors using Pearson's m 2 or by the two-tailed Fisher exact test. The disease-specific survival and disease-free intervals were generated by the Kaplan-Meier product limit method. Results: Chromosomal losses (n = 134) were more frequent than gains (n = 74). The most frequent genetic change was the loss of 1p32-p36 in 44% of the cases followed by 6q23-q27, and 12q12-q14. The most frequently gained chromosomal regions were 8 and 18. Of the chromosomal aberrations, loss of 1p32-p36 was the only abnormality significantly associated with patient's outcome. Conclusions: This study, for the first time, identifies loss of 1p32-p36 as a significant aberration in ACC. Molecular characterization of 1p32-36 region using the available genomic technologies may lead to the identification of new genes critical to the development of novel therapeutic targets for this disease copy number aberration.Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by heterogeneous phenotypic features and persistently progressive biological behavior (1 -6). Histopathologically, ACC manifests three histologic patterns, including the solid, cribriform, and tubular forms, in variable combination and dominance (7). The solid pattern is typically associated with aggressive clinical course. ACCs are known for their proclivity to perineural invasion, which significantly contribute to the intractable nature of this disease (1,8,9). Surgical resection with and without postoperative radiotherapy remains the primary treatment modality for the management of this disease. However, patients with advanced local presentation, recurrence, and/or distant metastasis have limited therapeutic options (8, 9). Therefore, elucidation of molecular events that predict the malignant risk is critical in understanding the biology, clinical behavior, and management of ACC.Previous conventional cytogenetic studies of ACC, although limited in numbers and scope, have revealed translocations involving chromosome 6q with multiple chromosomal partners (10, 11). Subsequent analysis, using comparative genomic hybridization (CGH) of these tumors have reported recurrent chromosomal gains of 16p, 17q, 19, and 22q13 and losses at 6q23-qter, 12q12-q13, 13q21-q22, and 19 (12, 13). Recently, an array CGH study of 18 p...

Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

“…ACC tumors exhibit nonrandom gains or losses of specific chromosome regions, including what may be an ACC‐specific deletion of chromosome 1p35–36. Other frequent deletions are located at 6q24, 12q, and 14q 23, 24, 25. However, the most intriguing alteration is a translocation between chromosomes 6q and 9p [(6;9)(q22–23;p23–24)].…”

Adenoid Cystic Carcinoma: Clinical and Molecular Features

“…Secondary genetic mechanisms are not well-understood, however. In attempts to identify genomic alterations that occur in ACC, there have been at least 6 studies of ACC cohorts employing the techniques of comparative genomic hybridization (CGH) and array comparative genomic hybridization (aCGH) which globally sample the copy number status of tumor genomes [38][39][40][41][42][43]. The results of these studies have been quite variable but areas of deletion that have been identified in two or more tumors in each of two or more of these studies include 1p (8-44 %), 5q (8-18 %), 6q (14-30 %), 9p (12-33 %), 9q (8-9 %), 12q (9-33 %), 13q (11-35 %), 14q (4-22 %), 17p (11-13 %), and Xp (8-9 %).…”

“…Analyses of chromosomal ploidy have shown that most classic non-solid ACC show a low degree of aneuploidy, much less than other types of carcinomas, but, ACC with solid histology show increased aneuploidy [51,52]. Studies using CGH and aCGH show a correlation of the degree of genetic alterations (change in DNA copy number, chromosome number, genetic deletion) with the degree of solid growth pattern [39,41,42], consistent with the notion that ACCs with solid histology represent a later stage in tumor progression. One study of four ACC with high-grade transformation suggests that genomic amplification events are more common in transformed tumors than in conventional tumors, with identification of the MYC gene as perhaps a common mechanism for transformation [53].…”

Integration of Biomarkers Including Molecular Targeted Therapies in Head and Neck Cancer

“…Further characterization of this molecular alteration in a broad range of head and neck adenoid cystic carcinomas is needed to further define it's role as a potential biomarker. Frequent loss of 1p32-p36 has also been identified in adenoid cystic carcinoma and correlated with solid/basaloid morphology and poorer prognosis [17]. These observations favor potential tumor suppressor genes in this region which are lost and may allow for directed targeted therapy in the future.…”