Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma

Gargiuli, Chiara; Sepe, Pierangela; Tessari, Anna; Sheetz, Tyler; Colecchia, Maurizio; Braud, F.G.M. De; Procopio, Giuseppe; Sensi, Marialuisa; Verzoni, Elena; Dugo, Matteo

doi:10.3390/cancers13122903

Cited by 7 publications

(8 citation statements)

References 79 publications

(123 reference statements)

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“…The identification of these distinct subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches. These insights could lead to rationalize the use of targeted therapies or immunotherapy for rare tumors according to the individual genomic alterations harbored [36]. Genetic and cytogenetic alterations in ncRCC aressumarized in Table 1.…”

Section: Collecting Duct Carcinomamentioning

confidence: 99%

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Sepe¹,

Ottini²,

Pircher³

et al. 2021

Cancers

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Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

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Section: Collecting Duct Carcinomamentioning

confidence: 99%

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Sepe¹,

Ottini²,

Pircher³

et al. 2021

Cancers

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“…Recently Gargiuli et al. ( 27 ), through integration of multiple datasets, compared cdRCC to UTUC, others RCC and normal tissue. The authors showed that cdRCC was characterized by a distinctive transcriptional program linked to the principal cells of the collecting ducts providing evidence that supports this origin and suggested at least two molecular subtypes of cdRCC distinguished by cell signaling, metabolic and immune-related alterations.…”

Section: Molecular Landscape Of Cdrccmentioning

confidence: 99%

“…On the other hand, the downregulated genes were linked to biological oxidations, amino acid metabolism, cell-cell communication, cellular response to external stimuli and G-protein coupled receptors (GPCR). Through the analysis of cancer cell line pharmacogenomics datasets, the authors showed that the gene-signature was predictive of higher sensitivity to some therapeutics options as tyrosine kinase inhibitors, SRC and MAPK signaling inhibitors ( 27 ).…”

Section: Molecular Landscape Of Cdrccmentioning

confidence: 99%

“…cdRCC-S2 instead was associated with enrichment of gene related to multiple metabolic pathways, cell cycle, DNA repair, gene expression, programmed cell death, extracellular matrix organization, vesicle mediated transport, adaptive immune-related pathways (T-cell receptor, B-cell receptor, cytokine-signaling, MHC-class I and MHC-class II). No differences for overall immune infiltration and interferon-gene sets were observed ( 27 ). Unveiling these processes uniquely enriched or depleted in cdRCC might provide therapeutic options for these patients.…”

Section: Molecular Landscape Of Cdrccmentioning

confidence: 99%

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Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease

et al. 2022

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Collecting duct renal cell carcinoma (cdRCC), which until recently was thought to arise from the collecting ducts of Bellini in the renal medulla, is a rare and aggressive type of non-clear renal cell carcinoma (ncRCC), accounting for 1% of all renal tumors and with nearly 50% of patients being diagnosed with Stage IV disease. The median overall survival in this setting is less than 12 months. Several regimens of chemotherapies had been used based on morphologic and cytogenetic similarities with urothelial cell carcinoma described previously, although the prognosis still remains poor. The use of targeted therapies also did not result in favorable outcomes. Recent works using NGS have highlighted genomic alterations in SETD2, CDKN2A, SMARCB1, and NF2. Moreover, transcriptomic studies have confirmed the differences between urothelial carcinoma and cdRCC, the possible true origin of this disease in the distal convoluted tubule (DCT), differentiating from other RCC (e.g., clear cell and papillary) that derive from the proximal convoluted tubule (PCT), and enrichment in immune cells that may harbor insights in novel treatment strategies with immunotherapy and target agents. In this review, we update the current aspects of the clinical, molecular characterization, and new targeted therapeutic options for Collecting duct carcinoma and highlight the future perspectives of treatment in this setting.

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“…In addition, an integrative transcriptomic study of 17 CDC patients identified that CDC may originate from the distal convoluted tubules of the nephron. Moreover, CDC is considered not only a metabolic disease but also an oxidoreductase activity and pyruvate metabolism [ 16 ]. These studies have mainly focused on Western populations, whereas the genomic profile of CDC patients in the Chinese population remains unclear.…”

Section: Introductionmentioning

confidence: 99%

A genomic mutation spectrum of collecting duct carcinoma in the Chinese population

Zhang

Huang

et al. 2022

BMC Med Genomics

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Background Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population. Methods Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts. Results Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway. Conclusions Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.

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Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma

Cited by 7 publications

References 79 publications

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease

A genomic mutation spectrum of collecting duct carcinoma in the Chinese population

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