|Year : 2019 | Volume
| Issue : 2 | Page : 73-78
Genomic Alterations Landscape in Adenoid Cystic Carcinoma of Head and Neck
Immanuel Joseph MDS , Thavarajah Rooban, Joshua Elizabeth, Umadevi Krishnamohan Rao, Kannan Ranganathan
Department of Oral and Maxillofacial Pathology, Ragas Dental College and Hospital, Chennai, Tamil Nadu, India
|Date of Submission||09-Mar-2019|
|Date of Decision||13-Apr-2019|
|Date of Acceptance||10-Jul-2019|
|Date of Web Publication||29-Jan-2020|
Dr. Immanuel Joseph
2/102, East Coast Road, Uthandi, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Adenoid cystic carcinoma (ACC) accounts for 1% of all head and neck cancers and 10% to 22% of all malignant tumors of the salivary glands. ACC is associated with MYB- nuclear factor I/B-type (NFIB) gene fusion in about 50% of the cases. The genetic alteration (GA) landscape of ACC of head and neck region in this aspect has not been much studied, mainly due to small cohorts. We aim to describe the GA landscape of MYB-NFIB gene fusions, copy number alterations, and mutations of the related gene MYBL1 in human ACC by studying its association with regard to demographics and histopathological parameters. Materials and Methods: Using the GA data of ACC from a peer-reviewed web portal, we studied the presence of MYB-NFIB gene fusion with respect to age and gender distribution, site involved (major/minor salivary gland, lacrimal gland, cancer metastasis, others), histopathological diagnosis, perineural invasion (PNI), and the overall number of mutations. Descriptive statistics and Chi square test were performed. Data were entered and analyzed using SPSS version 23. The mutation counts between the type of gene fusions involved and the gender of patients was studied using analysis of variance tests. Results: Of the 214 reported ACC cases, 65 (30%) cases had MYB-NFIB fusion alone, 15 (7%) other had rare fusions, and 12 (6%) other had GAs. Perineural invasion was found to be associated with MYB gene fusion cases with or without copy number alterations (P = 0.022). The number of mutations were significantly associated with the gender of patient (P = 0.003) and NFIB gene fusions (P = 0.001). The other factors had no statistical significance. Conclusion: MYB-NFIB gene fusion and associated GA correlates with perineural involvement in ACC.
Keywords: Adenoid cystic carcinoma, genetic alterations, myb gene, myb-nfib gene fusion, salivary gland
|How to cite this article:|
Joseph I, Rooban T, Elizabeth J, Rao UK, Ranganathan K. Genomic Alterations Landscape in Adenoid Cystic Carcinoma of Head and Neck. J Orofac Sci 2019;11:73-8
|How to cite this URL:|
Joseph I, Rooban T, Elizabeth J, Rao UK, Ranganathan K. Genomic Alterations Landscape in Adenoid Cystic Carcinoma of Head and Neck. J Orofac Sci [serial online] 2019 [cited 2020 Jun 4];11:73-8. Available from: http://www.jofs.in/text.asp?2019/11/2/73/272646
| Introduction|| |
Adenoid cystic carcinoma (ACC) is the most commonly reported malignant tumor of human minor salivary glands., Apart from its occurrence in the major and minor salivary glands, ACC also occurs in the sinonasal tract, tracheobronchial tree, breast, vulva, and skin. It is characterized by perineural invasion (PNI), a high recurrence rate, distant metastases, and an unfavorable response toward therapeutic measures.,,, These factors contribute to the current high mortality rate.
About 50% of salivary ACC is characterized by MYB-nuclear factor I/B-type (NFIB) gene fusion. This MYB activating gene fusion was first discovered in ACCs of breast and head and neck (HN) by Persson et al. The gene fusion involves the exons of MYB gene and the transcription factor NFIB reciprocal t(6;9) translocations., The fusion breakpoint is reported to occur at the target sites of micro-RNAs leading to overexpression of highly active MYB-NFIB fusion protein.
Involvement of MYB-NFIB is reported to influence the histopathological type and perineural events. Although t(6:9)(q22-23;p23-24) is a specific molecular event in ACC, its reliability as an exclusive diagnostic tool is still debatable as this fusion product is seen in only 28% to 49% of ACC patients. Further, the presence of fusion partners of MYB other than NFIB (e.g., MYBL1, also known as AMYB, a closely related member of MYB), other genetic alterations (GAs), and high MYB oncogene expression independent of the fusion mechanism affects tumor behavior. The presence of t(6;9) does not seem to be necessary for higher expression of MYB protein, which could be due to other GAs.
In this article, we aim to present the association of human salivary ACC MYB-NFIB fusion with the histopathological types and PNI characteristics and study the prevalence of non-MYB-NFIB fusion expressions, copy number alterations (CNAs), and number of mutations accumulated.
| Materials and Methods|| |
The data of GA of HN-ACC along with the clinicopathological profile of the patients were retrieved from the existing, peer-reviewed cBio Cancer Genomics Web portal., It is an open-access resource for multidimensional cancer genomics data from more than 5000 tumor samples from 20 cancer studies. The cBioPortal has guided the authors to cite the references, when publishing the results based on its genomic database. As this is a secondary database analysis, this study was exempted from ethical approval by the Ethical Committee of Ragas Dental College and Hospital, Chennai, Tamil Nadu on January 28, 2019. The database had details of 214 patients diagnosed with HN-ACC from the year 2013 to 2015. The demographic variables of age at diagnosis (in years) and gender (male/female), other variables like the site of tumor (major and minor salivary glands, lacrimal gland, metastatic site, other sites), predominant histopathological types (cribriform/solid/tubular) of HN-ACC, PNI (yes/no), MYB and associated gene alterations, details of CNA, mutation count, and details of mutations were collected. These data retrieved from the Cancer Genomics Web portal were entered and analyzed using statistical software Social Package for Social Service (ver. 23, IBM, IL, USA). Descriptive statistics and Chi square test were performed for all categorical variables. Multiple comparisons were done for significant continuous variables and studied using one-way analysis of variance test. P ≤ 0.05 was taken as significant.
| Results|| |
In all, 111 (52%) were males compared to 103 (48%) females forming the study group. The mean age at diagnosis in males were 55.3 ± 12.6 years and in females were 55 ± 14.8 years. The difference was not statistically significant (P = 0.79). Of the 214 cases, there were 65 cases from oral cavity, 64 from salivary gland, and 13 from orbital cavity, and one case each of laryngeal and sinonasal cavity along with 70 unidentified sites. The MYB-NFIB translocation of t(6:9) was noted in 54 cases and t(8:9) in 14 cases, negative in 34 cases, and not available in 112 cases.
The association between the mutational counts in ACC patients along with their gender was also analyzed [Table 1]. The average mutation counts were found to be higher in male patients (16.3 ± 11.3) compared to females (10.5 ± 9.9) (P = 0.003).
|Table 1 Association of mutation counts with gender of patients (N = 214)|
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Association Between Sites of Tumor Involved With MYB-NFIB Gene Alterations
Of the 214 cases, 76 cases had details of site along with MYB-NFIB details. The most common site was the minor salivary glands [Figure 1]. Fifty cases from the minor salivary glands had MYB-NFIB gene fusion and three cases had MYB-NFIB gene fusion with alterations. Tumor site involving the parotid gland had eight cases with MYB-NFIB gene fusion and one case with MYB-NFIB gene fusion with alterations followed by nine cases of submandibular salivary gland, two cases of sublingual salivary gland, and two cases from other nonsalivary gland sites such as the orbital cavity that had MYB-NFIB gene fusions. There was only one reported case from a metastatic site (thyroid) which had CNAs alone. These findings were statistically significant (P = 0.00).
MYB Gene Fusions and Alterations (N = 214)
Of the 214 cases studied, 71 (33%) cases had MYB-NFIB gene fusions [Figure 2], one (1%) case had other fusion involved with MYB gene [MYB-PDCD1LG2 (programmed cell death 1 ligand 2) fusion], five (2%) cases had other gene alterations which are CNA and home deletions associated with MYB-NFIB fusion, and 137 (64%) cases had no genetic involvement or had details missing.
|Figure 2 ACC–MYB gene fusions and alterations (N = 214). ACC, adenoid cystic carcinoma.|
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Histopathological Variant of ACC and MYB Gene Alterations
Of the 214 cases, the histopathological type of ACC was available for 76 cases [Figure 3]. MYB-NFIB fusion gene product was the most commonly seen GA associated with all the types of ACC (46 cases of cribriform, 20 cases of solid type, and four cases of tubular type). Four cases of cribriform variety had MYB-NFIB fusion with alterations and one case of cribriform type had CNAs. One case of solid pattern had MYB-PDCD1LG2 gene fusion without NFIB involvement (P = 0.526).
|Figure 3 ACC histopathological type and associated MYB gene alterations (N = 76). ACC, adenoid cystic carcinoma.|
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Perineural Involvement and MYB Gene Alterations
PNI was seen in 70 cases of ACC and its associated MYB gene alterations was also studied [Figure 4]. MYB-NFIB gene fusion was most commonly associated with PNI showing statistical significance of P = 0.02. Fifty-eight (83%) cases who had MYB-NFIB fusion had associated PNI; four (6%) cases had MYB-NFIB gene fusion with alterations (CNA, homozygous deletions) and one (1%) case who had other gene fusions apart from MYB had PNI. One case with CNAs and six (9%) cases with MYB-NFIB fusion did not have PNI.
Other Gene Fusions Not Involving MYB
Fusion partners involved with NFIB gene were XRCC4, NKAIN2, PTPRD, and AIG2 genes. Fusion partners with MYBL1 gene (AMYB) were NFIB and YTHDF3 and few cases (n = 3) involved truncation of MYBL1.
| Discussion|| |
The genetic mutational landscape of ACC has been the subject of study in the recent past. As a result of the oncogenic signature event, the chromosomal translocation occurring in t(6;9)(q22-23; p23-24) specific for ACC, the MYB-NFIB fusion product leads to the altered expression of MYB-associated genes, such as those responsible for apoptosis, cell cycle regulation, and cell growth and angiogenesis. The MYB gene overexpression and associated GAs have been reported to influence ACC prognosis irrespective of its origin and predict the risk of local recurrence and distant metastases.,
The main characteristic features of ACC are PNI occurring in 22% to 46% of cases, multiple local recurrences, and distant metastases that are reported in 40% of cases leading to a worse prognosis. Regional lymph-node involvement is reported to be rare, as in present study.
In the present study, data was retrieved from cBioportal genomic database. There were 214 cases of ACC of HN, of which, the major portion of the affected population were males. The mean age at the time of diagnosis for both genders was almost alike, similar to Spiro et al. and Stallmach et al. Moreover, the incidence of ACC in minor salivary glands was found to be common at the 4th and 5th decades of life, the mean age being 54 years which was concurrent with present study.,
The most commonly reported site of ACC, in the present study was the minor salivary glands. Most cases arise from the palate and are diagnosed at the advanced stages. The fusion status of the majority of cases in the minor salivary glands were found to be MYB-NFIB positive (P = 0.00) and it has been highlighted that these cases have high chances of recurrence and a decrease in disease-free survival rate.
We identified MYB fusion partners apart from NFIB (7%), other GAs (6%) like mutations, truncations, CNAs, and gene amplifications. These could also play a role in driving ACC tumors by mechanisms which activate MYB other than NFIB, as high MYB overexpression were also seen in fusion-negative tumors. In the present study, the fusion partner with MYB other than NFIB was PDCD1LG2. Other non-MYB gene fusions were NFIB-XRCC4, NFIB-NKAIN2, NFIB-PTPRD, NFIB-AIG1, and MYBL1-NFIB gene fusions. The gene fusion between NFIB and MYBL1, a gene closely related to MYB, has also been recently described in a subset of ACC. Few rare gene fusions associated with the MYBL1 gene (MYBL1-YTHDF3 and MYBL1-RAD51B) have also been reported., Although the oncogenic role of MYB in ACC is a major event, there is a need for detailed analysis of non-MYB-driven ACCs to unravel the underlying molecular pathogenesis.
Among the histopathological variants of ACC (N = 76), the cribriform pattern (67%) was the most common variant found in our study followed by the solid and tubular patterns. The association between the histopathological variants and MYB gene alterations was studied. We found that MYB-NFIB gene fusion was seen in all the types, namely, cribriform (n = 46), solid (n = 20), and tubular (n = 4) growth patterns (P = 0.423). In their study by Xu et al., 34 cases of ACC were tested for MYB-NFIB Fluorescent in-situ hybridisation (FISH) study and they concluded that the fusion status did not appear to be related to the growth pattern of the tumor. MYB-NFIB gene fusion associated with other GAs was found in four cases of the cribriform variant.
One of the hallmark features of ACC is its propensity for perineural spread. PNI, commonly reported in 29% to 63% of ACC cases,,,,, including a recent cohort study, where 80% of cases have been reported. In another study, 83% of cases with balanced translocation had PNI as compared to 54% of patients without any translocation, indicating an increase in the trend for PNI associated with MYB translocation tumors. In the current review, majority of cases (n = 58; 83%) which were fusion positive had associated PNI compared with six cases without PNI.
In conclusion, MYB-NFIB fusion and associated gene alterations help in predicting perineural invasion in ACC tumors of HN. The participation of other genes and gene fusions without the involvement of MYB in ACC can also be a related cause for the other subset of non-MYB ACCs that need to be explored in future. As the prognostic implication of ACC is based on the expression level of MYB and its downstream effectors regardless of MYB-NFIB status of the tumor, future treatment can be directed toward both MYB and non-MYB-driven tumors.
Presentation at a meeting
This concept with its results was presented at the XXVII National IAOMP Conference, Amritsar, Punjab, on November 17, 2018.
The authors would acknowledge the cBioportal cancer genomics for providing their large-scale data sets to analyse and download cancer genome and the Tamil Nadu Dr. MGR Medical University for their constant encouragement toward research work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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