MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status

a cohort study

Simon Andreasen , Qihua Tan, Tina Klitmøller Agander, Hansen Thomas V. O., Petr Steiner, Kristine Bjørndal, Estrid Høgdall, Stine Rosenkilde Larsen, Daiva Erentaite, Caroline Holkmann Olsen, Benedicte Parm Ulhøi, Steffen Heegaard, Irene Wessel, Preben Homøe

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.
Original languageEnglish
JournalVirchows Archiv
Volume473
Issue number3
Pages (from-to)329-340
ISSN0945-6317
DOIs
Publication statusPublished - Sep 2018

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Adenoid Cystic Carcinoma
MicroRNAs
Cohort Studies
Neoplasms
Survival Analysis
Multivariate Analysis

Keywords

  • Adenoid cystic carcinoma
  • microRNA
  • MYB
  • MYBL1
  • Prognosis
  • Salivary gland
  • MicroRNAs/analysis
  • Humans
  • Middle Aged
  • Gene Fusion
  • Male
  • Young Adult
  • Carcinoma, Adenoid Cystic/genetics
  • Salivary Gland Neoplasms/genetics
  • Adolescent
  • Aged, 80 and over
  • Adult
  • Female
  • Aged
  • Cohort Studies

Cite this

Andreasen , Simon ; Tan, Qihua ; Agander, Tina Klitmøller ; Thomas V. O., Hansen ; Steiner, Petr ; Bjørndal, Kristine ; Høgdall, Estrid ; Larsen, Stine Rosenkilde ; Erentaite, Daiva ; Olsen, Caroline Holkmann ; Ulhøi, Benedicte Parm ; Heegaard, Steffen ; Wessel, Irene ; Homøe, Preben . / MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status : a cohort study. In: Virchows Archiv. 2018 ; Vol. 473, No. 3. pp. 329-340.
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title = "MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status: a cohort study",
abstract = "Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.",
keywords = "Adenoid cystic carcinoma, microRNA, MYB, MYBL1, Prognosis, Salivary gland, MicroRNAs/analysis, Humans, Middle Aged, Gene Fusion, Male, Young Adult, Carcinoma, Adenoid Cystic/genetics, Salivary Gland Neoplasms/genetics, Adolescent, Aged, 80 and over, Adult, Female, Aged, Cohort Studies",
author = "Simon Andreasen and Qihua Tan and Agander, {Tina Klitm{\o}ller} and {Thomas V. O.}, Hansen and Petr Steiner and Kristine Bj{\o}rndal and Estrid H{\o}gdall and Larsen, {Stine Rosenkilde} and Daiva Erentaite and Olsen, {Caroline Holkmann} and Ulh{\o}i, {Benedicte Parm} and Steffen Heegaard and Irene Wessel and Preben Hom{\o}e",
year = "2018",
month = "9",
doi = "10.1007/s00428-018-2423-0",
language = "English",
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pages = "329--340",
journal = "Virchows Archiv",
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Andreasen , S, Tan, Q, Agander, TK, Thomas V. O., H, Steiner, P, Bjørndal, K, Høgdall, E, Larsen, SR, Erentaite, D, Olsen, CH, Ulhøi, BP, Heegaard, S, Wessel, I & Homøe, P 2018, 'MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status: a cohort study', Virchows Archiv, vol. 473, no. 3, pp. 329-340. https://doi.org/10.1007/s00428-018-2423-0

MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status : a cohort study. / Andreasen , Simon; Tan, Qihua; Agander, Tina Klitmøller; Thomas V. O., Hansen ; Steiner, Petr; Bjørndal, Kristine; Høgdall, Estrid ; Larsen, Stine Rosenkilde; Erentaite, Daiva ; Olsen, Caroline Holkmann ; Ulhøi, Benedicte Parm ; Heegaard, Steffen ; Wessel, Irene ; Homøe, Preben .

In: Virchows Archiv, Vol. 473, No. 3, 09.2018, p. 329-340.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status

T2 - a cohort study

AU - Andreasen , Simon

AU - Tan, Qihua

AU - Agander, Tina Klitmøller

AU - Thomas V. O., Hansen

AU - Steiner, Petr

AU - Bjørndal, Kristine

AU - Høgdall, Estrid

AU - Larsen, Stine Rosenkilde

AU - Erentaite, Daiva

AU - Olsen, Caroline Holkmann

AU - Ulhøi, Benedicte Parm

AU - Heegaard, Steffen

AU - Wessel, Irene

AU - Homøe, Preben

PY - 2018/9

Y1 - 2018/9

N2 - Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.

AB - Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.

KW - Adenoid cystic carcinoma

KW - microRNA

KW - MYB

KW - MYBL1

KW - Prognosis

KW - Salivary gland

KW - MicroRNAs/analysis

KW - Humans

KW - Middle Aged

KW - Gene Fusion

KW - Male

KW - Young Adult

KW - Carcinoma, Adenoid Cystic/genetics

KW - Salivary Gland Neoplasms/genetics

KW - Adolescent

KW - Aged, 80 and over

KW - Adult

KW - Female

KW - Aged

KW - Cohort Studies

U2 - 10.1007/s00428-018-2423-0

DO - 10.1007/s00428-018-2423-0

M3 - Journal article

VL - 473

SP - 329

EP - 340

JO - Virchows Archiv

JF - Virchows Archiv

SN - 0945-6317

IS - 3

ER -