The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis

Kentaro Ohara, André Figueiredo Rendeiro, Bhavneet Bhinder, Kenneth Wha Eng, Hiranmayi Ravichandran, Duy Nguyen, David Pisapia, Aram Vosoughi, Evan Fernandez, Kyrillus S. Shohdy, Jyothi Manohar, Shaham Beg, David Wilkes, Brian D. Robinson, Francesca Khani, Rohan Bareja, Scott T. Tagawa, Madhu M. Ouseph, Andrea Sboner, Olivier Elemento, Bishoy M. Faltas () and Juan Miguel Mosquera ()
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Kentaro Ohara: Weill Cornell Medicine
André Figueiredo Rendeiro: Weill Cornell Medicine
Bhavneet Bhinder: Weill Cornell Medicine
Kenneth Wha Eng: Weill Cornell Medicine
Hiranmayi Ravichandran: Weill Cornell Medicine
Duy Nguyen: Division of Hematology and Medical Oncology, Weill Cornell Medicine
David Pisapia: Weill Cornell Medicine
Aram Vosoughi: Weill Cornell Medicine
Evan Fernandez: Weill Cornell Medicine
Kyrillus S. Shohdy: Division of Hematology and Medical Oncology, Weill Cornell Medicine
Jyothi Manohar: Weill Cornell Medicine
Shaham Beg: Weill Cornell Medicine
David Wilkes: Weill Cornell Medicine
Brian D. Robinson: Weill Cornell Medicine
Francesca Khani: Weill Cornell Medicine
Rohan Bareja: Weill Cornell Medicine
Scott T. Tagawa: Weill Cornell Medicine
Madhu M. Ouseph: Weill Cornell Medicine
Andrea Sboner: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Bishoy M. Faltas: Weill Cornell Medicine
Juan Miguel Mosquera: Weill Cornell Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient.

Date: 2024
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DOI: 10.1038/s41467-024-46320-w

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