The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma

Kaori Ueda; Takayuki Murase; Daisuke Kawakita; Toshitaka Nagao; Kimihide Kusafuka; Masato Nakaguro; Makoto Urano; Hidetaka Yamamoto; Ken-Ichi Taguchi; Satoshi Kano; Yuichiro Tada; Kiyoaki Tsukahara; Kenji Okami; Tetsuro Onitsuka; Yasushi Fujimoto; Kazuo Sakurai; Nobuhiro Hanai; Toru Nagao; Ryo Kawata; Naohito Hato; Ken-Ichi Nibu; Hiroshi Inagaki

doi:10.1016/j.modpat.2023.100274

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma

Mod Pathol. 2023 Oct;36(10):100274. doi: 10.1016/j.modpat.2023.100274. Epub 2023 Jul 7.

Authors

Kaori Ueda¹, Takayuki Murase², Daisuke Kawakita³, Toshitaka Nagao⁴, Kimihide Kusafuka⁵, Masato Nakaguro⁶, Makoto Urano⁷, Hidetaka Yamamoto⁸, Ken-Ichi Taguchi⁹, Satoshi Kano¹⁰, Yuichiro Tada¹¹, Kiyoaki Tsukahara¹², Kenji Okami¹³, Tetsuro Onitsuka¹⁴, Yasushi Fujimoto¹⁵, Kazuo Sakurai¹⁶, Nobuhiro Hanai¹⁷, Toru Nagao¹⁸, Ryo Kawata¹⁹, Naohito Hato²⁰, Ken-Ichi Nibu²¹, Hiroshi Inagaki²²

Affiliations

¹ Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Maxillofacial Surgery, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.
² Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
³ Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁴ Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan.
⁵ Department of Pathology, Shizuoka General Hospital, Shizuoka, Japan.
⁶ Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.
⁷ Department of Diagnostic Pathology, Bantane Hospital, Fujita Health University School of Medicine, Nagoya, Japan.
⁸ Department of Anatomic Pathology, Graduate of School of Medical Science, Kyushu University, Fukuoka, Japan.
⁹ Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
¹⁰ Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹¹ Department of Head and Neck Oncology and Surgery, International University of Health and Welfare, Mita Hospital, Tokyo, Japan.
¹² Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan.
¹³ Department of Otolaryngology-Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan.
¹⁴ Division of Head and Neck Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
¹⁵ Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Otolaryngology-Head and Neck Surgery, Aichi Medical University, Nagakute, Japan.
¹⁶ Department of Otorhinolaryngology, Fujita Health University, Okazaki Medical Center, Okazaki, Japan.
¹⁷ Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁸ Department of Maxillofacial Surgery, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.
¹⁹ Department of Otorhinolaryngology-Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
²⁰ Department of Otolaryngology, Ehime University School of Medicine, Toon, Japan.
²¹ Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
²² Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address: hinagaki@med.nagoya-cu.ac.jp.

PMID: 37423587
DOI: 10.1016/j.modpat.2023.100274

Abstract

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

Keywords: FISH; MYB::NFIB; MYBL1::NFIB; adenoid cystic carcinoma; superenhancers.