The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Zhu, Bin; Poeta, Maria Luana; Costantini, Manuela; Zhang, Tongwu; Shi, Jianxin; Sentinelli, Steno; Zhao, Wei; Pompeo, Vincenzo; Cardelli, Maurizio; Alexandrov, Boian S.; Otlu, Burçak; Hua, Xing; Jones, Kristine; Brodie, Seth A.; Toro, Jorge R.; Yeager, Meredith; Wang, Mingyi; Hicks, Belynda; Alexandrov, Ludmil B.; Brown, Kevin M.; Wedge, David C.; Chanock, Stephen J.; Fazio, Vito Michele; Gallucci, Michele; Landi, Maria Teresa

doi:10.1101/478156

Cited by 2 publications

(3 citation statements)

References 81 publications

(48 reference statements)

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“…Both pRCC patients had an average of 73% globally clonal mutations, higher than all but two non-metastatic ccRCC cases (73% in PT6 and 81% in PT13). Lower intratumoral heterogeneity and higher global clonality have been previously reported for pRCC, when compared with ccRCC (40).…”

Section: Resultsmentioning

confidence: 66%

Origins and timing of emerging lesions in advanced renal cell carcinoma

Wallace¹,

Porten

Lo³

et al. 2021

Preprint

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Purpose: Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in 4-10% of cases and is associated with advanced disease. RCC with VTT and distant metastasis represents a unique clinical entity, and provides opportunities to examine the origins and relative timing of tumor lesion emergence and to identify molecular correlates with disease state. Experimental Design: We performed genomic and evolutionary analyses on 16 RCC patients with VTT, with eight also having metastases, using multi-region exome and RNA sequencing. Results: No genomic alterations were specifically associated with the VTT or metastasis lesions; each tumor had multiple hallmark driver alterations, consistent with advanced disease state. We found that 21% (3/14) of clear-cell RCC cases could be assigned a previously defined "evolutionary subtype". Somatic mutation signatures were largely consistent with previously established RCC signatures, and showed low heterogeneity across regions of each tumor. Mismatch repair and homologous recombination ("BRCA-ness") deficiency signatures consistently co-occurred across most tumors, suggesting a pervasive role for intracellular DNA damage in RCC and the potential for related treatment strategies. Phylogenetic timing analysis of metastatic cases suggested that in most tumors, metastases branched from the primary tumor prior to formation of VTT and in some cases before diversification of the primary tumor. Both VTT and the earliest metastases were predicted to emerge many years prior to diagnosis. Transcriptional landscape analysis identified key differences distinguishing each lesion type from primary tumor: VTT upregulated TNF𝛼 signaling and associated inflammatory pathways, whereas metastases upregulated MTOR signaling. Conclusions: Our results provide a map of how RCC tumors can evolve, with metastatic clones typically emerging early in RCC development and taking hold via MTOR signaling, and later formation of VTT via local inflammatory processes.

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Section: Resultsmentioning

confidence: 66%

Origins and timing of emerging lesions in advanced renal cell carcinoma

Wallace¹,

Porten

Lo³

et al. 2021

Preprint

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“…Early symptoms of KIRC are not easy to detect, typically manifested as an abdominal mass, gross hematuria, and waist pain, but this typical triad has been rarely seen. Once KIRC patients are found to have typical symptoms, it is often accompanied by distant metastasis [3,7,14] . Since patients with KIRC are resistant to radiotherapy and chemotherapy, surgery remains the primary treatment for patients with KIRC [15] .…”

Section: Discussionmentioning

confidence: 99%

“…RCC is the sixteenth commonest cancer worldwide, accounting for about 431000 new cases and 179000 cancer-related deaths a year [2] . Kindy renal clear cell carcinoma (KIRC) is the most common type of renal malignancy from the renal tubule, being responsible for approximately 75-80% of all patients of RCC [3,4] . KIRC is a serious hazard to human health [5] .…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Cuproptosis-Related Predictive Risk Signatures based on renal clear cell carcinoma

Liang

Cui

et al. 2023

Preprint

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Background: Renal clear cell carcinoma is the main type of kidney cancer and its prognosis is poor. The role of cuproptosis as an emerging tumor treatment modality in renal clear cell carcinoma is still unclear. Therefore, it is urgent to discover new prognostic markers and the role of Cuproptosis in renal cancer. Method: The source of cuproptosis-related genes was collected from the reported study from PubMed. RNA expression data and the clinical information of the corresponding patient were obtained from The Cancer Genome Atlas (TCGA) database. We randomly split the whole case into training and testing cohorts. We used three different regression analyses to confirm that lncRNAs with prognostic relevance of KIRC in the training cohort. The test cohort and the whole cohort were also included in the regression analysis to prove the accuracy of the model. eventually, a nomogram on account of clinical characteristics as well as risk scores was constructed to predict survival KIRC. Result: 119 lncRNAs linked to overall survival were gained by univariate cox regression analysis. Furthermore, to further screen for prognosis-related lncRNAs and to optimize the signature, 119 genes were included in LASSO regression as well as multifactorial Cox regression analysis. A new prognostic predictive risk profile containing four lncRNA was produced. Kaplan-Meier (KM) curve showed that patients in the high-risk group showed poor survival in all three components. The area under the curves (AUCs) for 1 year calculated from the roc curve for the three components is 0.754, 0.698, and 0.743. 0.721 and 0. 753. Moreover, the nomogram allows the calculation of 1-, 3-, and 5-year survival rates for patients with renal clear cell carcinoma. Conclusion: A new prognostic signature with four CRLs (MYG1-AS1, MELTF-AS1, AL161782.1, AC112220.2) have significant prognostic value for KIRC was conducted. It may provide a new therapeutic treatment for KIRC patients in the clinical.

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The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Cited by 2 publications

References 81 publications

Origins and timing of emerging lesions in advanced renal cell carcinoma

Origins and timing of emerging lesions in advanced renal cell carcinoma

Identification and Validation of Cuproptosis-Related Predictive Risk Signatures based on renal clear cell carcinoma

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