Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland

Simon Andreasen*, Tina Klitmøller Agander, Kristine Bjørndal, Daiva Erentaite, Steffen Heegaard, Stine R. Larsen, Linea Cecilie Melchior, Qihua Tan, Benedicte Parm Ulhøi, Irene Wessel, Preben Homøe

*Corresponding author for this work

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Abstract

Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted nextgeneration sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3%). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread.

Original languageEnglish
JournalOncotarget
Volume9
Issue number28
Pages (from-to)19675-19687
ISSN1949-2553
DOIs
Publication statusPublished - 13. Apr 2018

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Adenoid Cystic Carcinoma
MicroRNAs
Mutation
Neoplasms

Keywords

  • Adenoid cystic carcinoma
  • Metastases
  • MicroRNA
  • MYB
  • Salivary gland

Cite this

Andreasen, Simon ; Agander, Tina Klitmøller ; Bjørndal, Kristine ; Erentaite, Daiva ; Heegaard, Steffen ; Larsen, Stine R. ; Melchior, Linea Cecilie ; Tan, Qihua ; Ulhøi, Benedicte Parm ; Wessel, Irene ; Homøe, Preben. / Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland. In: Oncotarget. 2018 ; Vol. 9, No. 28. pp. 19675-19687.
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title = "Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland",
abstract = "Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted nextgeneration sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3{\%}). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread.",
keywords = "Adenoid cystic carcinoma, Metastases, MicroRNA, MYB, Salivary gland",
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Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland. / Andreasen, Simon; Agander, Tina Klitmøller; Bjørndal, Kristine; Erentaite, Daiva; Heegaard, Steffen; Larsen, Stine R.; Melchior, Linea Cecilie; Tan, Qihua; Ulhøi, Benedicte Parm; Wessel, Irene; Homøe, Preben.

In: Oncotarget, Vol. 9, No. 28, 13.04.2018, p. 19675-19687.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland

AU - Andreasen, Simon

AU - Agander, Tina Klitmøller

AU - Bjørndal, Kristine

AU - Erentaite, Daiva

AU - Heegaard, Steffen

AU - Larsen, Stine R.

AU - Melchior, Linea Cecilie

AU - Tan, Qihua

AU - Ulhøi, Benedicte Parm

AU - Wessel, Irene

AU - Homøe, Preben

PY - 2018/4/13

Y1 - 2018/4/13

N2 - Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted nextgeneration sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3%). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread.

AB - Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted nextgeneration sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3%). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread.

KW - Adenoid cystic carcinoma

KW - Metastases

KW - MicroRNA

KW - MYB

KW - Salivary gland

U2 - 10.18632/oncotarget.24800

DO - 10.18632/oncotarget.24800

M3 - Journal article

VL - 9

SP - 19675

EP - 19687

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 28

ER -