Intratumoural heterogeneity may hinder precision medicine strategies in patients with clear cell renal cell carcinoma

2018 ◽  
Vol 71 (5) ◽  
pp. 467-471 ◽  
Author(s):  
Maria Rosaria Raspollini ◽  
Ilaria Montagnani ◽  
Rodolfo Montironi ◽  
Francesca Castiglione ◽  
Guido Martignoni ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Precision Medicine ◽  
Renal Cell ◽  
Clear Cell ◽  
Molecular Heterogeneity ◽  
Precision Oncology ◽  
Cell Renal Cell Carcinoma ◽  
Renal Sinus ◽  
The Moment

Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status. This study analyses the presence of any mutation of KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR genes in 20 tissue blocks from a case of ccRCC and its metastasis. We observed the presence of the mutation at pH1047R of PIK3CA gene in five samples of the tumour, while the remaining 15 samples did not show any mutation at PIK3CA or any other investigated gene. There is a great need to develop novel RCC sampling strategies to overcome tumour heterogeneity prior to define precision oncology strategies.

Dynamic contrast-enhanced MRI to predict intratumoral molecular heterogeneity in clear cell renal cell carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4580-4580
Author(s):  
Durga Udayakumar ◽  
Ze Zhang ◽  
Durgesh Dwivedi ◽  
Yin Xi ◽  
Tao Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Molecular Heterogeneity ◽  
Cell Renal Cell Carcinoma ◽  
Post Contrast ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced

4580 Background: Mutation/inactivation of VHL in clear cell renal cell carcinoma (ccRCC) leads to upregulation of hypoxia inducible factors ( HIFs) and angiogenesis. However, ccRCC is characterized by high intra-tumor heterogeneity (ITH). Random small samples such as those in percutaneous biopsies are likely limited for characterization of molecular alterations in heterogeneous ccRCCs. We hypothesize that whole-tumor dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is useful to noninvasively identify ITH in ccRCC. Methods: This IRB-approved, prospective, HIPAA-compliant study, included 62 ccRCCs. 3T DCE MRI was obtained prior to nephrectomy. Surgical specimens were sectioned to match MRI acquisition plane. 182 snap frozen samples (49 tumors) and adjacent uninvolved renal parenchyma (URP) were collected. RNA isolations, cDNA library preparation and mRNA sequencing were performed using standard protocols. RNA expression in 81 tumor samples were correlated (Spearman ranked) with % enhancement in a region of interest (ROI) drawn in the same location of the tumor on pre- and 3 different post-contrast DCE MRI phases. Gene function overrepresentation (OR) analyses were done on top positively and negatively correlated genes. False discovery rate (FDR) < 0.1 was considered statistically significant. Results: Principal component analysis of > 20,000 genes indicated distinct gene expression in tumors from URP. Unsupervised clustering showed enrichment of ccA samples (better prognosis) compared to ccB samples (worse prognosis). Importantly, ccA and ccB samples coexisted in 25% of tumors. DCE-MRI % enhancement correlated with expression of > 300 genes (p < 0.003, FDR < 0.1). OR analyses placed angiogenic pathway gene processes and the immune/inflammatory response processes within the top 5 positively- and negatively-correlated gene functions, respectively. HIF2 target genes correlated positively with % enhancement. Conclusions: DCE MRI detects specific molecular signatures and may help overcome the challenges of ITH in ccRCC. Further research is needed to explore the potential role of DCE MRI to assess response to antiangiogenic and immune-based therapies.

scholarly journals Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ninadh M. D’Costa ◽  
Davide Cina ◽  
Raunak Shrestha ◽  
Robert H. Bell ◽  
Yen-Yi Lin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Treatment Response ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Signature ◽  
Precision Oncology ◽  
Cell Renal Cell Carcinoma

scholarly journals Contact with renal sinus is associated with poor prognosis in surgically treated pT1 clear cell renal cell carcinoma

2020 ◽  
Vol 27 (8) ◽  
pp. 657-662 ◽  
Author(s):  
Keita Izumi ◽  
Kazutaka Saito ◽  
Takayuki Nakayama ◽  
Shohei Fukuda ◽  
Hiroshi Fukushima ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Poor Prognosis ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Renal Sinus

Collision Tumor of the Kidney with Clear Cell Renal Cell Carcinoma and Papillary Renal Cell Carcinoma Components: Report of a Rare Case

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S64-S64
Author(s):  
S R Avalos Hernandez ◽  
S Liu ◽  
F Sameeta ◽  
W Mneimneh
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Collision Tumor ◽  
Renal Tumors ◽  
Vimentin Expression ◽  
Cell Renal Cell Carcinoma ◽  
Renal Sinus ◽  
Collision Tumors

Abstract Introduction/Objective Collision tumors refer to the phenomenon where distinct, well-defined tumor subtypes are present within a single lesion. While this phenomenon has been described in different organs, it has been rarely encountered in renal tumors outside the context of rare tumor susceptibility syndromes. Collision tumors of the kidney may encompass any known benign or malignant renal tumor types. However, a collision tumor of two different renal cell carcinoma (RCC) subtypes is remarkably rare. Methods A 43-year-old male was referred to our institution for the management of a right lower pole renal mass. The right radical nephrectomy specimen revealed a 6.5 x 5.0 x 4.0 cm well circumscribed, yellow-orange and hemorrhagic cortical mass abutting the renal capsule and extending into the renal sinus fat. A grossly distinct 1.5 x 1.4 x 1.2 cm pale, nodular area was demonstrated at the periphery of the tumor. Results Microscopically, the tumor displayed two distinct, neoplastic components within the same mass, without transitional morphology. The majority of the tumor consisted of a nuclear-grade-2 conventional clear cell RCC, while the peripheral nodule represented a type-2 papillary RCC component. Immunostains further supported these findings: The papillary component was strongly and diffusely positive for CK7 and P504S/AMACR with variable EMA and vimentin expression, and negative for CAIX, while the clear cell component was positive for CAIX, EMA and vimentin with only focal and weak staining for CK7 and faint nonspecific P5O4S/AMACR staining. TFE3 Mart1 and HMB45 immunostains were negative in the tumor. Conclusion Collision tumor of the kidney with two distinct RCC subtypes is an exceedingly rare finding. Careful gross examination may be the first clue to identify such lesions, and sampling of all grossly distinct tumor areas is crucial. The identification of collision tumors may have important therapeutic implications, given the difference in pathophysiology and outcome between RCC subtypes.

scholarly journals Comprehensive Genomic Analysis of Metastatic Non–Clear-Cell Renal Cell Carcinoma to Identify Therapeutic Targets

2019 ◽  
pp. 1-18 ◽  
Author(s):  
Maria I. Carlo ◽  
Nabeela Khan ◽  
Ahmet Zehir ◽  
Sujata Patil ◽  
Yasser Ged ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Clear Cell ◽  
De Novo ◽  
Genomic Analysis ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Cell Renal Cell Carcinoma

PURPOSENon–clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor– and mammalian target of rapamycin–directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies.PATIENTS AND METHODSWe retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture–based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated.RESULTSOf 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in MET, TSC1/2, and an ALK translocation. Of 45 patients who had germline testing, 11 (24%) harbored mutations, seven of which could potentially guide therapy. Of 115 available tumors for analysis, two (1.7%) had high and six (5%) had intermediate MSI status.CONCLUSIONThe mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation.

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