Abstract 1047: Expression of TYMS in cancer: A tissue microarray study involving 6,613 cancers from 127 tumor entities
Authors: Florian Lutz, Nicolai Leege, Katharina Möller, Florian Viehweger, Ria Schlichter, Andreas M. Luebke, Martina Kluth, Claudia Hube-Magg, Andrea Hinsch, Christian Bernreuther, Guido Sauter, David Dum, Andreas H. Marx, Ronald Simon, Till Krech, Till S. Clauditz, Frank Jacobsen, Eike Burandt, Stefan Steurer, Patrick Lebok, Christoph Fraune, Sarah Minner, Natalia Gorbokon, Maximilian Lennartz
Journal: Cancer Research (2024)

Abstract Thymidylate synthase (TS, TYMS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) which is one of the nucleotides forming the DNA. TYMS is thus essential for DNA synthesis and represents an important target for several chemotherapeutic drugs including 5-fluorouracil (5-FU) and methotrexate. It has been suggested that tumors with low-levels of TYMS may show a better response to 5-FU than those with high-level expression. Literature data on TYMS expression in different cancer types is controversial, however. To better comprehend the role of TYMS expression in cancer, TYMS was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMAs) containing 9,015 samples from 127 different tumor types as well as 8 samples each of 6 different normal tissue types. TYMS immunostaining was always cytoplasmic and/or nuclear. It was only detectable in a minority of normal cell types and was strongest in a subset of lymphoid cells, especially in germinal centers and in the thymus as well as in hematopoetic cells of the bone marrow. Detectable TYMS staining occurred in 3,749 (46.7%) of the 8,030 analyzable tumors, including 2,958 (36.8%) with weak, 609 (7.6%) with moderate, and 182 (2.3%) with strong positivity. A total of 114 of 127 tumor categories showed TYMS expression in at least one case, 64 tumor categories showed TYMS staining ≥50% of cases, and 47 tumor categories included at least one case with strong TYMS positivity. The frequency of TYMS positivity was highest in various subtypes of B- and T-cell lymphoma (80-100%), sarcomas, carcinosarcomas and sarcomatoid carcinomas (33.3-100%), primary and metastatic malignant melanoma (70.5-90.7%), adenocarcinoma of the uterine cervix (78.3%), squamous cell carcinomas of various sites of origin (57.1-77.9%), and testicular germ cell tumors (19.4-67.4%). In all four tumor entities for which clinico-pathological data could be assessed, high TYMS expression was associated with features of aggressive disease. High TYMS expression was linked to high histologic grade (p&amp;lt;0.0001) in endometrioid endometrium carcinoma, advanced pT stage (p=0.0061) in high-grade serous ovarian carcinoma, poor histologic grade (p&amp;lt;0.0001) in squamous cell carcinomas of 11 different organs of origin, and to advanced stage (p&amp;lt;0.0001), tumor invasion in blood and lymph vessels (p≤0.0064) as well as microsatellite instability (p&amp;lt;0.0001) in colon cancers. TYMS is often overexpressed as compared to normal tissues in a broad range of different cancer entities. Our data suggest that high-level of TYMS expression is a feature of cancer aggressiveness in many different cancer types. Citation Format: Florian Lutz, Nicolai Leege, Katharina Möller, Florian Viehweger, Ria Schlichter, Andreas M. Luebke, Martina Kluth, Claudia Hube-Magg, Andrea Hinsch, Christian Bernreuther, Guido Sauter, David Dum, Andreas H. Marx, Ronald Simon, Till Krech, Till S. Clauditz, Frank Jacobsen, Eike Burandt, Stefan Steurer, Patrick Lebok, Christoph Fraune, Sarah Minner, Natalia Gorbokon, Maximilian Lennartz. Expression of TYMS in cancer: A tissue microarray study involving 6,613 cancers from 127 tumor entities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1047.