Clinical and Molecular Characterization of Clear Cell Adenocarcinoma of the Urinary Tract: A Multi-Institutional Study
Recommended Citation
Aron M, Chandrashekar D, Abdulfatah E, Zein-Sabatto B, Lobo J, Canete-Portillo6 S, Kunju L, Cox R, Przybycin C, Al-Obaidy K, Idrees M, Falzarano S, Harada S, Wu A, Netto G. Clinical and Molecular Characterization of Clear Cell Adenocarcinoma of the Urinary Tract: A Multi-Institutional Study. Lab Invest 2024; 104(3):S903-S904.
Document Type
Conference Proceeding
Publication Date
3-1-2024
Publication Title
Lab Invest
Abstract
Background: Clear cell adenocarcinoma of the urinary tract (CCA-UT) are aggressive tumors that present at an advanced stage and are typically associated with poor prognosis. There is very limited data on the molecular alterations in CCA-UT. This study expands on the previously reported clinicopathologic features of CCA-UT {#522, Mod Path 2022;35:(suppl 2):562}, and explores the molecular landscape of the largest cohort to date, of these rare tumors. Design: Our cohort consisted of 35 cases from 6 participating institutions. Whole exome sequencing (WES) and RNA sequencing of all the tumors and controls were performed on the Illumina NovaSeq6000 sequencer. The data generated was analyzed using the genome analysis toolkit pipeline. Somatic mutations were annotated using Funcotator and OncoKB annotator. Variants with ClinVar annotation ”pathogenic” or “likely pathogenic” or OncoKB annotation “oncogenic“ or “likely oncogenic” were selected for visualization using maftools. Tumor mutational burden (TMB) and MSI analysis was performed using PyTMB and MSIsensor tools, respectively. Results: Clinical data and follow up information were available in 34 patients (Table 1). 79% of the cases occurred in women, with a median age of 61 years. The tumors were predominantly located in the urethra (17, 50%), followed by proximal urethra/bladder neck (11, 31.4%) and bladder (6;17.6%). Most cases were high stage (pT2:15, pT3:11, pT4:8) and on clinical follow-up 26.5% died of disease. All cases were microsatellite stable and TMB was >10 mut/Mb in only 3 cases. Pathogenic/oncogenic variants were identified in 32 cases, and these alterations most frequently involved chromatin modifiers (ATRX, KMT2C, ARID1A and ARID1B), NF1, ATM, and ERBB2 genes (Figures 1, 2A and 2B ). ERBB2 showed gain of function mutations, while the other genes showed loss of function mutations. RNA sequencing identified 2635 up-regulated and 927 down-regulated genes in CCA-UT. Some of the differentially expressed genes in CCA-UT included those involved in extracellular matrix (ECM) organization, structure, ECMreceptor interaction, and cell adhesion. Conclusions: CCA-UT are aggressive tumors with over 50% of cases presenting as high stage disease, and over 25% dying of the disease on clinical follow-up. The identification of previously unreported pathogenic alterations in targetable genes including chromatin modifiers, ATM, and ERBB2 in CCA-UT generates novel therapeutic options, with the potential of impacting prognosis in this pernicious tumor.
Volume
104
Issue
3
First Page
S903
Last Page
S904
