Upcoming event

Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling

  • Brian D. Robinson,
  • Panagiotis J. Vlachostergios,
  • Bhavneet Bhinder,
  • Weisi Liu,
  • Kailyn Li,
  • Tyler J. Moss,
  • Rohan Bareja,
  • Kyung Park,
  • Peyman Tavassoli,
  • Joanna Cyrta,
  • Scott T. Tagawa,
  • David M. Nanus,
  • Himisha Beltran,
  • Ana M. Molina,
  • Francesca Khani,
  • Juan Miguel Mosquera,
  • Evanguelos Xylinas,
  • Shahrokh F. Shariat,
  • Douglas S. Scherr,
  • Mark A. Rubin,
  • Seth P. Lerner,
  • Surena F. Matin,
  • Olivier Elemento,
  • Bishoy M. Faltas

Publication: Nature Communications , July 2019

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.

Commented by Dr. Benjamin Pradere

In this study, Robinson et al. performed a comprehensive genomic and transcriptomic analysis of UTUC to identify the key biological features that differentiate UTUC from UCB. The Center Genome Atlas (TCGA) has recently classified urothelial carcinoma of the bladder (UCB) into five molecular subtypes (luminal-papillary, luminal-infiltrated, luminal, basal/squamous, neuronal). Nevertheless, the analyses did not include UTUC and molecular subtypes and immune milieu remain unclear.

The authors analyzed whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from high-grade UTUC tumors from patients at 3 different institutions and compared to WES and RNAseq data from UCB tumors from the TCGA cohort.

The evaluation of the mutational profiles revealed a higher frequency of FGFR3 mutations in UTUC compared to UCB. They highlight three mutational processes responsible of the majority of mutation in UTUC (APOBEC, MMR, NER).

To define whether somatic dysregulation of DDR genes could induce a hypermutated phenotype in non-Lynch UTUC patients, they assessed the mRNA expression level of DDR pathway genes in UTUC and UCB. They observed significantly lower somatic mRNA expression of three canonical MMR genes: MLH1, MSH2, and MSH6 in UTUC tumors compared to UCB. We found that the levels of MLH1, PMS2, MSH2, and MSH6 proteins were significantly lower in UTUC tumors). This confirmed that lower expression of these proteins is a characteristic feature of UTUC even in the absence of germline or somatic mutations in the respective genes in the UTUC cohort. This suggests that the somatic downregulation of MMR proteins is insufficient to produce MSI and is not a major driver of mutagenesis in non-Lynch UTUC. Collectively, these findings indicate that the decrease in the mRNA and protein levels of MMR genes in sporadic UTUC does not translate into MSI or a higher TMB.

In the study, more than 80% of the UTUC tumors clustered with the luminal subtypes compared to only 46% in the UCB. This demonstrated that the luminal-papillary component is a defining feature of UTUC. Their results suggest that the majority of UTUCs represent a distinct subset within the continuum of UC differentiation that shares similar characteristics with the luminal-papillary subtype of UCB. Moreover, they found that UTUC has a T-cell depleted immune contexture and that FGFR3 is a putative driver of UTUC’s immune-depleted contexture.

In conclusion, the findings of this study suggest that sporadic UTUC is not hypermutated, and consistently luminal-papillary and T-cell depleted. These results in the mutational landscape and immune contexture in non-Lynch syndrome UTUCs could explain the lack of higher response rates of UTUC compared to UCB in clinical trials of immune checkpoint inhibitors in the metastatic setting. Moreover, the putative role of FGFR3 suggest that clinical trials with FGFR3 inhibitors as single agent or in combination with immune checkpoint blockade are warranted.