PhD Scientific Days 2025

Poster Session I. - D: Pathological and Oncological Sciences

TMSB4X 5’UTR alterations are possible driver events harbouring phased variants with a potential for disease monitoring across DLBCL genetic subgroups.

Name of the presenter

Varga Luca

Institute/workplace of the presenter

SE Department of Pathology and Experimental Cancer Research

Authors

Luca Varga¹, Gabriella Szepesi¹, Tamás László¹, Róbert Horváth¹, Nóra Szoboszlai¹, Richárd Hanza¹, Király Péter Attila², Márk Plander³, Árpád Bátai⁴, Tímea Gurbity-Pálfi⁵, Zsolt Nagy⁶, Tamás Masszi⁶, Réka Mózes¹, András Matolcsy¹, Donát Alpár¹, Botond Timár¹, András Masszi¹, Bence Bátai^1,6, Csaba Bödör¹

1: SE Department of Pathology and Experimental Cancer Research
2: National Institute of Oncology, Budapest, HU
3: Markusovszky University Teaching Hospital, Szombathely, HU
4: Fejér County Szent György University Teaching Hospital, Székesfehérvár, HU
5: University of Szeged, Szeged, Hungary
6: Semmelweis University, Department of Internal Medicine and Haematology, Budapest, Hungary

Text of the abstract

Introduction
Diffuse large B-cell lymphoma is an aggressive disease. It is characterised by both molecular and clinical heterogeneity, however, currently there is no reliable marker to predict disease progression. Phased variants are somatic mutations in close proximity (<150 bp) in cis orientation. Their identification has been used to increase sensitivity in minimal residual disease detection from cell-free DNA. As these variants appear in hypermutated regions, their characterisation might offer additional information on gene involvement in DLBCL.
Aims
Our aim was to characterise the genetic landscape of DLBCL in a Hungarian prospective observational study to further elucidate driving mechanisms of the disease beyond genetic subgroup classification.
Method
We collected FFPE samples from 117 newly diagnosed DLBCL patients from nine Hungarian centres between 2021-2023 (69 female/48 male; median age at diagnosis: 64; Hans algorithm: 56 non-GC/42 GC/19 NA). We performed targeted next-generation DNA sequencing using a custom Agilent XT HS2 panel. Variant calling and analysis were performed using a custom pipeline, the subgroup classification was performed using the LymphGen webtool. Likely driver genes were investigated using the dNdScv R package.
Results
LymphGen classification was successful in 50.4% of cases. Copy number gains were observed most commonly in regions spanning the BCL6 (56.4%), REL (52.1%), and BCL11A (52.1%) genes, while copy number losses the FAT1 (25.6%), NOL9 (23.1%), and TP73 (20.5%) genes. There were no significant differences in the numbers of observed phased variants between LymphGen subgroups (Kruskal-Wallis test, p=0.35). When comparing the dNdScv and phased results, the TMSB4X gene harboured phased variants in the 5’UTR region in over 10% of samples, paired with a significant q-value obtained from dNdScv (14 patients; q<0.001). The overwhelming majority of phased variants were located in the 5’UTR region (93.7%), in all cases at least one variant per pair. Considering single variants, at least one 5’UTR variant was present in 62/117 samples spanning the chrX:12993244-12994364 region. TMSB4X 5’UTR mutations were present in all LymphGen subtypes.
Conclusion
Our results highlight the role of TMSB4X 5’UTR variants as potential driver alterations with MRD monitoring potential.
Funding
EKÖP-2024-73
OTKA K21_137948
SE250+ 2024/25 II.