Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

Fujii, Yoichi; Sato, Yusuke; Suzuki, Hiromichi; Kakiuchi, Nobuyuki; Yoshizato, Tetsuichi; Lenis, Andrew T.; Maekawa, Shigekatsu; Yokoyama, Akira; Takeuchi, Yasuhide; Inoue, Yoshikage; Ochi, Yotaro; Shiozawa, Yusuke; Aoki, Kosuke; Yoshida, Kenichi; Kataoka, Keisuke; Nakagawa, Masahiro; Nannya, Yasuhito; Makishima, Hideki; Miyakawa, Jimpei; Kawai, Taketo; Morikawa, Teppei; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Nagae, Genta; Sanada, Masashi; Sugihara, Eiji; Sato, Taka Aki; Nakagawa, Tohru; Fukayama, Masashi; Ushiku, Tetsuo; Aburatani, Hiroyuki; Miyano, Satoru; Coleman, Jonathan; Homma, Yukio; Solit, David B.; Kume, Haruki; Ogawa, Seishi

doi:10.1016/j.ccell.2021.05.008

Cited by 99 publications

(118 citation statements)

References 79 publications

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“…Moreover, similar to previous studies, they found a majority of luminal-like tumors (71.5%) [37]. They also confirmed a different mutational profile between tumors arising in ureters versus renal pelvis, suggesting a distinct carcinogenesis mechanism depending on location in the urothelium [37]. They also sequenced urinary sediment-derived DNA and found 82.2% (95% CI, 71.5−90.2%) of sensitivity and 100% (95% CI, 81.5−100%) of specificity of this approach for UTUC diagnosis [37].…”

Section: The Molecular Landscape Of Utucsupporting

confidence: 90%

“…Indeed, patients classified in TP53/MDM2 and triple-negative subgroups had the worse disease-specific survival. Moreover, similar to previous studies, they found a majority of luminal-like tumors (71.5%) [37]. They also confirmed a different mutational profile between tumors arising in ureters versus renal pelvis, suggesting a distinct carcinogenesis mechanism depending on location in the urothelium [37].…”

Section: The Molecular Landscape Of Utucsupporting

confidence: 89%

“…They also confirmed a different mutational profile between tumors arising in ureters versus renal pelvis, suggesting a distinct carcinogenesis mechanism depending on location in the urothelium [37]. They also sequenced urinary sediment-derived DNA and found 82.2% (95% CI, 71.5−90.2%) of sensitivity and 100% (95% CI, 81.5−100%) of specificity of this approach for UTUC diagnosis [37]. Broadly, upper-tract urothelial carcinomas can be divided into two subtypes, namely EpiC-high and EpiC-low.…”

Section: The Molecular Landscape Of Utucmentioning

confidence: 57%

“…Further mechanistic studies showed that ZFP36L1 loss of function experiments in urothelial cell lines led to increased cell migration and epithelial-mesenchymal transition [12]. More recently, Fujii et al conducted a comprehensive molecular study of 198 UTUC patients through whole-exome sequencing (WES), single nucleotide polymorphism (SNP) array, RNA sequencing, and methylation analysis [37]. They reported 5 molecular subtypes (hypermutated (5.5%), TP53/MDM2 (37.7%), RAS (15.1%), FGFR3 (35.2%) and triple-negative (6.5%)) that correlates with clinicopathological features [37].…”

Section: The Molecular Landscape Of Utucmentioning

confidence: 99%

“…More recently, Fujii et al conducted a comprehensive molecular study of 198 UTUC patients through whole-exome sequencing (WES), single nucleotide polymorphism (SNP) array, RNA sequencing, and methylation analysis [37]. They reported 5 molecular subtypes (hypermutated (5.5%), TP53/MDM2 (37.7%), RAS (15.1%), FGFR3 (35.2%) and triple-negative (6.5%)) that correlates with clinicopathological features [37]. Indeed, patients classified in TP53/MDM2 and triple-negative subgroups had the worse disease-specific survival.…”

Section: The Molecular Landscape Of Utucmentioning

confidence: 99%

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Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Thouvenin

Chanzá

Alhalabi

et al. 2021

Cancers

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Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC.

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Section: The Molecular Landscape Of Utucsupporting

confidence: 90%

Section: The Molecular Landscape Of Utucsupporting

confidence: 89%

Section: The Molecular Landscape Of Utucmentioning

confidence: 57%

Section: The Molecular Landscape Of Utucmentioning

confidence: 99%

Section: The Molecular Landscape Of Utucmentioning

confidence: 99%

See 3 more Smart Citations

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Thouvenin

Chanzá

Alhalabi

et al. 2021

Cancers

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A deep‐learning workflow to predict upper tract urothelial carcinoma protein‐based subtypes from H&E slides supporting the prioritization of patients for molecular testing

Angeloni,

van Doeveren,

Lindner

et al. 2024

The Journal of Pathology CR

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Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein‐based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence‐based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein‐based subtypes were identified, and a deep‐learning (DL) workflow was developed to predict them directly from routine histopathological H&E slides. Protein‐based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non‐papillary tumors. DL model building relied on a transfer‐learning approach by fine‐tuning a pre‐trained ResNet50. Classification performance was measured via three‐fold repeated cross‐validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67–0.99), 0.8 (95% CI: 0.62–0.99), and 0.81 (95% CI: 0.65–0.96) was reached in the three repetitions. High‐confidence DL‐based predicted subtypes showed significant associations (p < 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD‐L1) combined positive score (p < 0.001) and FGFR3 mutational status (p = 0.002), with high‐confidence basal predictions containing a higher proportion of PD‐L1 positive samples and high‐confidence luminal predictions a higher proportion of FGFR3‐mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein‐based UTUC subtypes, associated with the presence of targetable alterations, directly from H&E slides.

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Cumulative incidence and risk factors for recurrence of upper tract urothelial carcinoma in patients undergoing radical cystectomy

Yamashita,

Nakamura,

Notsu

et al. 2024

BJUI Compass

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ObjectivesThis study aimed to evaluate the cumulative incidence of upper tract urothelial carcinoma (UTUC) recurrence and identify its risk factors in patients who underwent radical cystectomy (RC).Patients and methodsWe performed RC on 385 patients between September 2002 and February 2020. After excluding 20 patients—13 with simultaneous nephroureterectomy, 6 with distal ureteral stump positivity and 1 with urachal cancer—365 patients were included in the analysis. To predict UTUC recurrence, we examined the cancer extension pattern in cystectomy specimens and categorized them into three types: cancer located only in the bladder (bladder‐only type), cancer extending to the urethra or distal ureter (one‐extension type) and cancer extending to both the urethra and distal ureter (both‐extension type). We determined hazard ratios for UTUC recurrence for each covariate, including this cancer extension pattern.ResultsOf the 365 patients, 60% had the bladder‐only type, 30% had the one‐extension type and 10% had the both‐extension type. During a median follow‐up period of 72 months for survivors, UTUC recurred in 25 of the 365 patients, with cumulative incidences of 3.7% at 5 years and 8.3% at 10 years. The median interval from cystectomy to recurrence was 65 months (interquartile range: 36–92 months). In the multivariate analysis, the extension pattern was a significant predictor of UTUC recurrence. The hazard ratios for UTUC recurrence were 3.12 (95% confidence interval [CI] = 1.15–8.43, p = 0.025) for the one‐extension type and 5.96 (95% CI = 1.98–17.91, p = 0.001) for the both‐extension type compared with the bladder‐only type.ConclusionsThe cancer extension pattern in cystectomy specimens is predictive of UTUC recurrence. A more extensive cancer extension in cystectomy specimens elevates the risk of subsequent UTUC recurrence. Intensive long‐term monitoring is essential, particularly for patients with the both‐extension type.

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Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

Cited by 99 publications

References 79 publications

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

A deep‐learning workflow to predict upper tract urothelial carcinoma protein‐based subtypes from H&E slides supporting the prioritization of patients for molecular testing

Cumulative incidence and risk factors for recurrence of upper tract urothelial carcinoma in patients undergoing radical cystectomy

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