PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid

Anno:

2019

PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid

Marchiò C1,2, Da Cruz Paula A3, Gularte-Merida R4, Basili T4, Brandes A4, da Silva EM4, Silveira C4, Ferrando L4,5, Metovic J6, Maletta F6, Annaratone L1,2, Pareja F4, Rubin BP7, Hoschar AP7, De Rosa G8, La Rosa S9, Bongiovanni M9, Purgina B10, Piana S11, Volante M12, Weigelt B4, Reis-Filho JS13,14, Papotti M15.

Mod Pathol. 2019 Dec;32(12):1734-1743. doi: 10.1038/s41379-019-0313-x. Epub 2019 Jul 4.

Author information

1: Pathology Division, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
2: Department of Medical Sciences, University of Turin, Torino, Italy.
3: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5: Department of Internal Medicine, University of Genova, Genova, Italy.
6: Department of Oncology, University of Turin, at Città della Salute Hospital, Torino, Italy.
7: Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
8: Pathology Division, Mauriziano Hospital, Torino, Italy.
9: Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland.
10: Department of Pathology and Laboratory Medicine, Ottawa Hospital, ON, Canada.
11: Pathology Unit, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS, Reggio Emilia, Italy.
12: San Luigi Gonzaga Hospital and Department of Oncology, University of Turin, Orbassano, Italy.
13: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reisfilj@mskcc.org.
14: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reisfilj@mskcc.org.
15: Department of Oncology, University of Turin, at Città della Salute Hospital, Torino, Italy. mauro.papotti@unito.it.

Abstract

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.