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Published on: March 29, 2019
Molecular Characterization of Muellerian Tumors of the Urinary Tract
Nadina Ortiz-Brüchle1,2, Sophie Wucherpfennig1,2, Michael Rose1,2
1Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
Abstract:
In the 2016 WHO classification of genitourinary tumors Muellerian tumors of the urinary tract (MTUT) comprise clear cell adenocarcinomas and endometrioid carcinomas. Since these rare tumors remained understudied, we aimed to characterize their molecular background by performing DNA- and RNA-based targeted panel sequencing. All tumors (n = 11) presented single nucleotide alterations (SNVs), with ARID1A mutations being the most prevalent (5/11, 45%). Besides frequent ARID1A mutations, loss of ARID1A protein is not a suitable marker since protein expression is (partly) preserved also in mutated cases. Copy number alterations (CNVs) were found in 64% of cases (7/11), exclusively gene amplifications. Interestingly, a functionally relevant RSPO2 gene fusion/microdeletion was discovered in the endometrioid adenocarcinoma case. Comparing our findings with mutational profiles of other tumor entities, absence of TERT promoter mutations argues for a non-urothelial origin. No similarities were also found between MTUT and kidney cancers while parallels were observed for specific SNVs with endometrial carcinomas. In conclusion, immunohistochemical PAX8-positivity and lack of TERT promoter mutations could serve as key diagnostic features in difficult cases. Thus, understanding the molecular background of these tumors helps to refine treatment options and offers the possibility of targeted therapies in cases where needed.
Insights
Muellerian tumors of the urinary tract (MTUT) are rare. Molecular profiling revealed frequent ARID1A mutations and absence of TERT promoter mutations, suggesting non-urothelial origins and aiding diagnosis.
Area of Science:
- Genitourinary oncology
- Molecular pathology
- Cancer genomics
Background:
- Muellerian tumors of the urinary tract (MTUT), including clear cell and endometrioid carcinomas, are rare and understudied entities.
- The 2016 WHO classification recognized MTUT, highlighting the need for further characterization.
- Understanding the molecular landscape of MTUT is crucial for accurate diagnosis and therapeutic development.
Purpose of the Study:
- To characterize the molecular background of Muellerian tumors of the urinary tract (MTUT).
- To identify key genetic alterations and potential diagnostic markers.
- To compare the mutational profile of MTUT with other tumor types to infer lineage.
Main Methods:
- Targeted panel sequencing (DNA- and RNA-based) was performed on 11 MTUT cases.
- Analysis included single nucleotide alterations (SNVs) and copy number alterations (CNVs).
- Immunohistochemistry for PAX8 and assessment of TERT promoter mutations were utilized for diagnostic comparison.
Main Results:
- All 11 MTUTs exhibited single nucleotide alterations (SNVs), with ARID1A mutations being the most frequent (45%).
- Copy number alterations (CNVs) were present in 64% of cases, exclusively as gene amplifications.
- A functionally relevant RSPO2 gene fusion/microdeletion was identified in an endometrioid adenocarcinoma case. Absence of TERT promoter mutations suggests a non-urothelial origin, with parallels to endometrial carcinomas.
Conclusions:
- ARID1A mutations are a common feature of MTUT, but ARID1A protein loss is not a reliable diagnostic marker.
- Immunohistochemical PAX8-positivity and the absence of TERT promoter mutations are valuable diagnostic features for challenging MTUT cases.
- Elucidating the molecular profile of MTUT facilitates refined treatment strategies and the potential for targeted therapies.
