Publications by authors named "Virginie Verkarre"

98 Publications

Complement C1s and C4d as prognostic biomarkers in renal cancer: emergence of non-canonical functions of C1s.

Cancer Immunol Res 2021 May 26. Epub 2021 May 26.

Inflammation, Complement and Cancer, Cordeliers Research Center, INSERM UMRS 1138

The complement system plays a complex role in cancer. In clear cell renal cell carcinoma (ccRCC), local production of complement proteins drives tumor progression, but the mechanisms by which they do this are poorly understood. We found that complement activation, as reflected by high plasma C4d or as C4d deposits at the tumor site, was associated with poor prognosis in 2 cohorts of patients with ccRCC. High expression of the C4-activating enzyme C1s by tumor cells was associated with poor prognosis in 3 cohorts. Multivariate Cox analysis revealed that the prognostic value of C1s was independent from complement deposits, suggesting the possibility of complement cascade-unrelated, pro-tumoral functions for C1s. Silencing of C1s in cancer cell lines resulted in decreased proliferation and viability of the cells and in increased activation of T cells in in vitro co-cultures. Tumors expressing high levels of C1s showed high infiltration of macrophages and T cells. Modification of the tumor cell phenotype and T-cell activation were independent of extracellular C1s levels, suggesting that C1s was acting in an intracellular, non-canonical manner. In conclusion, our data point to C1s playing a dual role in promoting ccRCC progression by triggering complement activation and by modulating the tumor cell phenotype and tumor microenvironment in a complement cascade-independent, non-canonical manner. Overexpression of C1s by tumor cells could be a new escape mechanism to promote tumor progression.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0532DOI Listing
May 2021

Intracellular Factor H drives tumor progression independently of the complement cascade.

Cancer Immunol Res 2021 May 26. Epub 2021 May 26.

Inflammation, Complement and Cancer, Cordeliers Research Center, INSERM UMRS 1138

The complement system is a powerful and druggable innate immune component of the tumor microenvironment. Nevertheless, it is challenging to elucidate the exact mechanisms by which complement affects tumor growth. In this study, we examined the processes by which the master complement regulator Factor H (FH) affects clear cell renal cell carcinoma (ccRCC) and lung cancer, two cancers in which complement overactivation predicts poor prognosis. FH was present in two distinct cellular compartments: the membranous (mb-FH) and intracellular (int-FH) compartments. Int-FH resided in lysosomes and colocalized with C3. In ccRCC and lung adenocarcinoma FH exerted protumoral action through an intracellular, noncanonical mechanism. FH silencing in ccRCC cell lines resulted in decreased proliferation, due to cell cycle arrest and increased mortality, and this was associated with increased p53 phosphorylation and NF-κB translocation to the nucleus. Moreover, the migration of the FH-silenced cells was reduced, likely due to altered morphology. These effects were cell type-specific since no modifications occurred upon CFH silencing in other FH-expressing cells tested: tubular cells (from which ccRCC originates), endothelial cells (HUVECs) and squamous cell lung cancer cells. Consistent with this, in ccRCC and lung adenocarcinoma, but not in lung squamous cell carcinoma, int-FH conferred poor prognosis in patient cohorts. Mb-FH performed its canonical function of complement regulation but had no impact on tumor cell phenotype or patient survival. The discovery of intracellular functions for FH redefines the role of the protein in tumor progression and its use as a prognostic biomarker or potential therapeutic target.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0787DOI Listing
May 2021

[A rare tumor of the penis occurring in context of Peyronie's disease].

Ann Pathol 2021 Apr 22. Epub 2021 Apr 22.

Service de pathologie, centre, université de Paris, hôpital européen Georges-Pompidou, AP-HP, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2021.03.019DOI Listing
April 2021

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Mar 4. Epub 2021 Mar 4.

Department of Pathology MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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http://dx.doi.org/10.1038/s41379-021-00779-wDOI Listing
March 2021

Delayed retroperitoneal liposarcoma diagnosis and management in a patient with massive obesity.

Eur J Clin Nutr 2021 Mar 1. Epub 2021 Mar 1.

AP-HP-centre, Service de Nutrition, Centre Spécialisé Obésité, Hôpital européen Georges-Pompidou, Paris, France.

People suffering from extreme obesity may be exposed to delayed diagnosis and treatment of cancer. A 37-year-old woman (weight = 245 kg, body mass index (BMI) = 79 kg/m), presented a sepsis associated with nonspecific abdominal pain for 4 months. After several unsuccessful attempts due to her weight and a large waist circumference, abdominal CT scan was finally successfully performed and showed a large retroperitoneal mass. An ultrasound-guided core needle biopsy was performed and was in favor of a liposarcoma. Surgery was performed to remove the entire tumor of an estimated weight of 98 kg, a giant retroperitoneal dedifferentiated liposarcoma. This case highlights the difficulties to screen, diagnose, and manage cancers encountered in patients suffering from massive obesity.
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http://dx.doi.org/10.1038/s41430-020-00855-5DOI Listing
March 2021

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Jun 1;34(6):1167-1184. Epub 2021 Feb 1.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
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http://dx.doi.org/10.1038/s41379-021-00737-6DOI Listing
June 2021

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival.

Cancers (Basel) 2021 Jan 28;13(3). Epub 2021 Jan 28.

Centre de Recherche des Cordeliers, Laboratory of Integrative Cancer Immunology, INSERM, Université de Paris, 75015 Paris, France.

(1) Background-The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. (2) Methods-This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS. (3) Results-Low (IS-0), intermediate (IS-1-2), and high (IS-3-4) ISs were observed in 36.5, 43.7, and 19.8% of the cohort, respectively. IS was positively associated with a pathologic complete response (pCR; -value = 0.0096). A high IS was found in 35.7% of patients with a pCR, whereas it was found in 11.3% of patients without a pCR. A low IS was observed in 48.4% of patients with no pCR and in 21.4% of patients with a pCR. Low-, intermediate-, and high-IS patients had five-year recurrence-free rates of 37.2%, 36.5%, and 72.6%, respectively. In the multivariable analysis, a high IS was associated with a prolonged TTR (high vs. low: = 0.0134) and OS (high vs. low: = 0.011). (4) Conclusions-This study showed the significant prognostic and predictive roles of IS regarding localized MIBC.
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http://dx.doi.org/10.3390/cancers13030494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865364PMC
January 2021

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

J Clin Pathol 2021 May 29;74(5):291-299. Epub 2021 Jan 29.

Pathology, University Hospital Center of Martinique, Fort-de-France, Martinique.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.
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http://dx.doi.org/10.1136/jclinpath-2020-207372DOI Listing
May 2021

MET alterations in biphasic squamoid alveolar papillary renal cell carcinomas and clinicopathological features.

Mod Pathol 2021 03 7;34(3):647-659. Epub 2020 Aug 7.

Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Service de Pathologie, F-75015, Paris, France.

Biphasic squamoid alveolar papillary renal cell carcinoma (BSA-PRCC) is a recently studied lesion considered a morphologic variant of papillary renal cell carcinoma (RCC), more closely related to type 1. Considering the role of proto-oncogene MET in both sporadic type 1 papillary RCC and hereditary papillary RCC, we aimed to explore the role of MET activation in the oncogenesis of BSA-PRCC. We identified 17 patients with either unique (n = 14) or multiple (n = 3) BSA-PRCC, all localized, and performed an integrative analysis of MET status in 18 formalin-fixed paraffin-embedded tumors combining next-generation sequencing analysis, fluorescent in situ hybridization and immunohistochemistry. Trisomy 7 was found in 86% of tumors (14/16) without MET amplification at 7q31 (15/15). A pathogenic MET genetic variant was identified in 60% (9/15) of cases, at the germline level in 57% (4/7) of tested patients or at the somatic level (5/11). MET expression was observed in all tumors with a higher value of combined score in large cells (mean 97%, range 80-100%) than in small cells (mean 74%, range 10-100%) and was lower in two cases without MET copy number gain. In conclusion, our study provides additional evidence to consider biphasic squamoid alveolar papillary RCC as a morphological variant of type 1 papillary renal RCC. Our data strongly suggest that MET represents a major oncogenic driver gene in BSA-PRCC, harboring a higher frequency of MET mutation that encourages to further explore the benefice of anti-MET targeted therapies for aggressive BSA-PRCC.
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http://dx.doi.org/10.1038/s41379-020-0645-6DOI Listing
March 2021

mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division.

Nat Commun 2020 06 24;11(1):3200. Epub 2020 Jun 24.

Institut Necker-Enfants Malades, 14 rue Maria Helena Vieira Da Silva, CS, 61431, Paris, France.

mTOR activation is essential and sufficient to cause polycystic kidneys in Tuberous Sclerosis Complex (TSC) and other genetic disorders. In disease models, a sharp increase of proliferation and cyst formation correlates with a dramatic loss of oriented cell division (OCD). We find that OCD distortion is intrinsically due to S6 kinase 1 (S6K1) activation. The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hyperproliferation, leading to non-cystic harmonious hyper growth of kidneys. Mass spectrometry-based phosphoproteomics for S6K1 substrates revealed Afadin, a known component of cell-cell junctions required to couple intercellular adhesions and cortical cues to spindle orientation. Afadin is directly phosphorylated by S6K1 and abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and α-catenin. Our data reveal that S6K1 hyperactivity alters centrosome positioning in mitotic cells, affecting oriented cell division and promoting kidney cysts in conditions of mTOR hyperactivity.
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http://dx.doi.org/10.1038/s41467-020-16978-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314806PMC
June 2020

[Hereditary kidney cancers: The pathologist's view in 2020].

Ann Pathol 2020 Apr 18;40(2):148-167. Epub 2020 Mar 18.

Réseau national de référence pour cancers rares de l'adulte PREDIR (« Maladie de von Hippel-Lindau et prédispositions héréditaires au cancer rénal ») labellisée par l'Institut national du cancer, université Paris Saclay, Assistance publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; Génétique oncologique EPHE, PSL Université, UMR 9019 CNRS, université Paris-Saclay, institut Gustave-Roussy, Villejuif, France.

Hereditary predispositions to adult kidney tumors involve around 5% of tumors and include a dozen of autosomal dominant syndromes. The most frequent tumors encountered in these setting are clear cell renal cell carcinomas, papillary renal cell carcinomas, chromophobe renal cell carcinomas and angiomyolipomas. Their detection is essential in order to adapt individual care and perform genetic screening of at-risk relatives, especially in the national french network PREDIR, labeled by the National Cancer Institute and dedicated to hereditary predispositions to kidney tumors. Targeted genetic analysis, which was guided in particular by the renal tumor subtype, has recently evolved into genetic analysis using panels of genes. Pathologist contribution's remains however central in the diagnosis of hereditary forms since we currently have immunohistochemical biomarkers that allow us to diagnose two specifically hereditary entities: hereditary leiomyomatosis and renal cell carcinoma associated-renal cell carcinoma, associated with a loss of fumarate hydratase and succinate dehydrogenase-deficient renal cell carcinoma associated with a loss of succinate deshydrogenase B expression. These diagnoses must however be confirmed by the identification of pathogenic germline variation in the corresponding genes. Improvement of kidney tumors characterization has also lead to identify new subtypes, expanding the algorithm of renal tumors associated with hereditary setting. Here we aim to review all subtypes of adult renal tumors encountered in predisposition syndromes.
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http://dx.doi.org/10.1016/j.annpat.2020.02.022DOI Listing
April 2020

[A special uterine leiomyoma].

Ann Pathol 2020 Apr 16;40(2):180-184. Epub 2020 Mar 16.

Hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France.

Fumarate hydratase (FH)-deficient uterine leiomyomas represent 1% of all uterine leiomyomas. They show distinctive morphology, and are often associated with a loss of expression of FH protein, secondary to the inactivation of the FH gene. They can occur sporadically or in the hereditary setting of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome associated with germline mutations of FH gene. So, it is relevant to consider this diagnosis in case of young women with numerous or bulky leiomyomas and evocative microscopic features, in particular at nuclear level. Genetic screening is essential to identify hereditary forms, which require appropriate surveillance and genetic screening of relatives. Here, we report the case of a 20cm uterine leiomyoma in a young 32-year-old woman, whose morphologic and immunohistochemical characteristics were suggestive of FH-deficient leiomyoma.
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http://dx.doi.org/10.1016/j.annpat.2020.02.021DOI Listing
April 2020

[The inherited cancers, the pathologist].

Ann Pathol 2020 Apr 13;40(2):61-62. Epub 2020 Mar 13.

Service d'anatomie et de cytologie pathologiques, université de Caen, Normandie Université, CHU de Caen, avenue Côte-de-Nacre, 14053 Caen cedex, France.

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http://dx.doi.org/10.1016/j.annpat.2020.02.016DOI Listing
April 2020

[Pathologist contribution in the diagnosis of hereditary predisposition to paranganglioma and pheochromocytoma].

Ann Pathol 2020 Apr 4;40(2):134-141. Epub 2020 Mar 4.

Service d'anatomopathologie, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris (AP-HP Centre), 75015 Paris, France.

Hereditary predispositions are responsible for more than 30% of or paraganglioma. Their identification is essential to optimize medical care and to offer an appropriate screening to relatives. To date, there are more than 15 known paraganglioma/pheochromocytoma predisposing genes. The most frequently involved are those encoding the succinate dehydrogenase (SDHx), accounting for half of cases and the VHL gene, causing the Von Hippel Lindau syndrome and representing approximately 20% of genetically determined cases. Patients with SDHB genes mutations have a higher risk of metastatic disease. An oncogenetic counseling is recommended to all patients developing one or several paragangliomas, isolated or associated with other tumors. Apart from the clinical presentation and in particular the syndromic forms characterized by specific tumor spectra, there is no validated morphological criterion allowing to suspect a hereditary form. On the other hand, pathologists have now access to several immunohistochemical tools allowing the identification of some hereditary forms, in particular those linked to the SDHx, VHL and FH genes. Thus, the loss of expression in immunohistochemistry of the SDHB or FH proteins orientates respectively, towards SDHx and FH genes, while the membrane expression of carbonic anhydrase IX (CA-IX) is a sensitive and specific tool pointing towards a VHL anomaly. Other immunohistochemical markers are under evaluation. A systematic SDHB immunohistochemical staining is recommended on all paragangliomas/pheochromocytomas in order to allow an early detection of the most common hereditary forms and to contribute to the interpretation of the genetic results in these patients seen in oncogenetics consultation.
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http://dx.doi.org/10.1016/j.annpat.2020.01.010DOI Listing
April 2020

Clear Cell Papillary Renal Cell Carcinoma: A Recent Entity With Distinct Imaging Patterns.

AJR Am J Roentgenol 2020 03 26;214(3):579-587. Epub 2019 Nov 26.

Department of Adult Radiology, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris, 149 rue de Sèvres, 75015 Paris, France.

Clear cell papillary renal cell carcinoma (RCC), an entity with strikingly indolent behavior, recently was added to the World Health Organization classification of renal tumors and represents the fourth most common histologic type of renal cell carcinoma. This article aims to describe the imaging features of clear cell papillary RCC along with its clinical and pathologic characteristics. This retrospective study consisted of 27 patients with 44 clear cell papillary RCC tumors. The inclusion criteria were a pathologically proven clear cell papillary RCC and the availability of preoperative imaging including at least CT or MRI. Two experienced radiologists performed the imaging analysis independently. Patients (mean age, 62 years old) presented with renal failure in 26% of cases, and four had a tumor-predisposing disease. Multiple clear cell papillary RCC tumors occurred in 5 of the 27 patients. Two imaging patterns were recognizable. Solid clear cell papillary RCC ( = 23, 52%) presented as heterogeneous tumors with minor cystic changes (74%) and rarely exhibited calcifications (10%). All solid tumors showed hyperintensity on T2-weighted images compared with renal cortex and maximal enhancement on corticomedullary phase with a delayed washout. Cystic clear cell papillary RCC ( = 21, 48%) were classified as Bosniak IV (57%), III (33%), or IIF (10%), with a predominant unilocular pattern (76%). Pathologic stage according to TNM classification was mostly pT1a and low grade on nucleolar grade. All patients were alive at the date of last follow-up after treatment with no metastasis or recurrence. Clear cell papillary RCC exhibits two imaging patterns including cystic and solid in almost equal proportion. Imaging characteristics of solid clear cell papillary RCC including high signal T2 intensity and early arterial enhancement are unexpectedly distinct from papillary RCC and very similar to clear cell RCC.
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http://dx.doi.org/10.2214/AJR.19.21681DOI Listing
March 2020

iPSC-Derived Embryoid Bodies as Models of c--Mutated Hereditary Papillary Renal Cell Carcinoma.

Int J Mol Sci 2019 Sep 30;20(19). Epub 2019 Sep 30.

INSERM UMR-S 935 and ESTeam Paris Sud, Université Paris Sud, 94800 Villejuif, France.

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c- mutation, showed overexpression of the BHLHE40 and KDM4C only in the c--mutated PRCC tumors, as predicted by c--mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of "hereditary renal cancer in a dish" model using c--mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.
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http://dx.doi.org/10.3390/ijms20194867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801716PMC
September 2019

Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors.

Clin Genitourin Cancer 2019 10 25;17(5):e981-e994. Epub 2019 May 25.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France. Electronic address:

Introduction: Recent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.

Patients And Methods: Patients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.

Results: In total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.

Conclusion: In accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.
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http://dx.doi.org/10.1016/j.clgc.2019.05.009DOI Listing
October 2019

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth.

Cancer Immunol Res 2019 07 4;7(7):1091-1105. Epub 2019 Jun 4.

Sorbonne Paris Cite, Cordeliers Research Center, University Paris Descartes Paris 5, Paris, France.

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts ( = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0891DOI Listing
July 2019

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

Gut 2019 08 17;68(8):1396-1405. Epub 2018 Nov 17.

Clinical Haematology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.

Objectives: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).

Design: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested in human primary tumour cells isolated from fresh duodenal biopsies.

Results: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL .

Conclusion: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
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http://dx.doi.org/10.1136/gutjnl-2018-317371DOI Listing
August 2019

Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma.

Clin Cancer Res 2019 01 9;25(2):760-770. Epub 2018 Oct 9.

INSERM, UMR970, Paris-Cardiovascular Research Center, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Purpose: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with - and -mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression. Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.

Results: Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in -mutated paragangliomas ( = 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group ( = 0.169), yet mutations were found preferentially in -mutated metastatic tumors ( = 0.0014). Telomerase activation and mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; = 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1; = 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (log-rank tests < 0.0001).

Conclusions: Assessment of telomerase activation and mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0139DOI Listing
January 2019

A Single-Tube, EuroClonality-Inspired, TRG Clonality Multiplex PCR Aids Management of Patients with Enteropathic Diseases, including from Formaldehyde-Fixed, Paraffin-Embedded Tissues.

J Mol Diagn 2019 01 28;21(1):111-122. Epub 2018 Sep 28.

Hematology Laboratory, Necker-Enfants Malades Hosptial and Paris Descartes, Sorbonne Paris Cité University, Paris, France; Hematology Laboratory, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; INSERM UMR1151 and Institut Necker-Enfants Malades, Paris, France; Centre national Expert des Lymphomes Associés à la maladie Coeliaque, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France. Electronic address:

Celiac disease is a chronic inflammation of the small intestine with villous atrophy that can become refractory to a gluten-free diet. Two categories of refractory celiac disease can be distinguished by the phenotype of intraepithelial lymphocytes and the status of TRG genes. Their distinction is important because 30% to 50% of type II but only 0% to 14% of type I evolve to an aggressive enteropathy-associated T-cell lymphoma and therefore require intensive treatment. Currently, differential diagnosis integrates immunohistochemistry, immunophenotyping, and TRG clonality analyses, but each has limitations. A single-tube multiplex TRG PCR (ECN) was prospectively compared to an in-house two-tube TRG PCR (N2T) in 73 samples, including 67 cryopreserved intestine tissues. Thirteen formalin-fixed, paraffin-embedded (FFPE) samples were also analyzed retrospectively. The ECN PCR had comparable efficiency to detect major clonal rearrangements in highly infiltrated tissues from T-cell lymphoproliferative disorders and type II refractory celiac disease and to detect the persistence of minor clones in type II refractory celiac disease follow-up samples. The ECN PCR abolished the risk of amplification of false-positive weak clonal rearrangements in cryopreserved specimens and allowed improved detection of clonal rearrangements in DNA from FFPE samples. The ECN PCR allows robust assessment of cryopreserved and FFPE digestive tissues at diagnosis and follow-up of enteropathies with villous atrophy, thus guiding therapeutic management.
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http://dx.doi.org/10.1016/j.jmoldx.2018.08.006DOI Listing
January 2019

Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease.

Int J Oncol 2018 Oct 19;53(4):1455-1468. Epub 2018 Jul 19.

Oncogenetics Laboratory, EPHE, PSL Research University, 75014 Paris, France.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.
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http://dx.doi.org/10.3892/ijo.2018.4490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086628PMC
October 2018

Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial.

Clin Cancer Res 2018 11 30;24(22):5534-5542. Epub 2018 Jul 30.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France.

The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC). This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS). Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome. Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1045DOI Listing
November 2018

Contemporary assessment of the correlation between Bosniak classification and histological characteristics of surgically removed atypical renal cysts (UroCCR-12 study).

World J Urol 2018 Oct 5;36(10):1643-1649. Epub 2018 May 5.

Department of Urology, Rennes University Hospital, Rennes, France.

Purpose: To evaluate and compare pathological characteristics of renal cysts Bosniak IIF, III and IV in light of recent histological classification.

Patients And Methods: The French research network for kidney cancer UroCCR conducted a multicentre study on patients treated surgically for a renal cyst between 2007 and 2016. Independent radiological and centralized pathological reviews were performed for every patient. Pathological characteristics were compared to the Bosniak classification.

Results: Of a total 216 patients included, 175 (81.0%) tumours (90.9% of Bosniak IV, 69.8% of Bosniak III) were malignant or had a low malignant potential, with 60% of clear cell renal cell carcinoma (CCRCC), 24% of papillary RCC (PRCC) and 6.9% of multilocular cystic renal tumour of low malignant potential (MCRTLMP). Malignancies were mostly of low pT stage (86.4% of pT1-2), and low ISUP grade (68.0% of 1-2). Bosniak III cysts had a lower rate of CCRCC (46.7 vs. 67.3%), higher rate of PRCC (30 vs. 20.9%) and MCRTLMP (18.3 vs. 0.9%) compared to Bosniak IV (p < 0.001). Low-malignant potential lesions were less likely Bosniak IV and pT3-4 stage was more frequent in Bosniak IV vs. III (15.7 vs. 3.5%; p = 0.04). There were two recurrences (1.1%) and no cancer-related death occurred during follow-up.

Conclusion: These results confirmed that cystic renal malignancies have excellent prognosis. Bosniak III cysts had a low malignant potential, which suggests surveillance could be an option for these lesions.
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http://dx.doi.org/10.1007/s00345-018-2307-6DOI Listing
October 2018

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells.

J Vis Exp 2018 02 8(132). Epub 2018 Feb 8.

INSERM U970, Université Paris Descartes; Department of Immunology, Hopital Européen Georges Pompidou;

Immune cells are important components of the tumor microenvironment and influence tumor growth and evolution at all stages of carcinogenesis. Notably, it is now well established that the immune infiltrate in human tumors can correlate with prognosis and response to therapy. The analysis of the immune infiltrate in the tumor microenvironment has become a major challenge for the classification of patients and the response to treatment. The co-expression of inhibitory receptors such as Program Cell Death Protein 1 (PD1; also known as CD279), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA-4), T-Cell Immunoglobulin and Mucin Containing Protein-3 (Tim-3; also known as CD366), and Lymphocyte Activation Gene 3 (Lag-3; also known as CD223), is a hallmark of T cell exhaustion. We developed a multiparametric in situ immunofluorescence staining to identify and quantify at the cellular level the co-expression of these inhibitory receptors. On a retrospective series of frozen tissue of renal cell carcinomas (RCC), using a fluorescence multispectral imaging technology coupled with an image analysis software, it was found that co-expression of PD-1 and Tim-3 on tumor infiltrating CD8 T cells is correlated with a poor prognosis in RCC. To our knowledge, this represents the first study demonstrating that this automated multiplex in situ technology may have some clinical relevance.
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http://dx.doi.org/10.3791/56606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912389PMC
February 2018

[Tim-3: a novel biomarker and therapeutic target in oncology].

Med Sci (Paris) 2018 Mar 16;34(3):231-237. Epub 2018 Mar 16.

Inserm U970, université Paris Descartes Sorbonne Paris-Cité, Paris, France - Équipe labellisée Ligue contre le cancer, Paris, France - Hôpital européen Georges Pompidou, service d'immunologie biologique, 20, rue Leblanc, 75015 Paris, France.

T cells harboring multiple co-inhibitory molecules lose their anti-tumoral functionality. PD-1 is a clinically approved target in cancer therapy, but its expression alone does not mean dysfunctionality. The expression of Tim-3 on numerous cell types (T cell, Treg, dendritic cell, myeloid cells) favors tumor escape to immune cells. Within many tumors, PD-1/Tim-3 coexpressing CD8-T cells lose their ability to secrete cytokines (IFNγ, IL-2, TNFα) and their intratumoral infiltration correlates with a bad prognosis. Tim-3 recently appeared as a potential biomarker of anti-PD-1 resistance. Combined blockade of PD-1 and Tim-3 axis demonstrated potent clinical efficacy in preclinical models and reinforced the rationale of using an anti-Tim-3 to override tumor resistance.
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http://dx.doi.org/10.1051/medsci/20183403011DOI Listing
March 2018

Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors.

Clin Genitourin Cancer 2018 08 5;16(4):266-273. Epub 2018 Feb 5.

Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. Electronic address:

Background: Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel-Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

Patients And Methods: We genotyped 3 VHL SNPs in 199 m-ccRCC patients: rs1642742 T > C, rs1642743 A > G, and rs1678607 C > A. Primary end points were response rate (RR), progression-free survival (PFS), and overall survival (OS) after start of first-line TKI. RR was compared with Fisher's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promotor hypermethylation, VHL mutation status, VHL loss of heterozygosity, ≥ 25% sarcomatoid dedifferentiation, and expression of genes implicated in angiogenesis and immunoresponse (Fisher's exact test and unpaired t tests).

Results: The minor alleles of rs1642742 and rs1642743, known to be in close linkage disequilibrium, were associated with poor outcome, following a recessive pattern. For the rs1642742 CC versus TT/TC genotype, OS was 11 versus 26 months (hazard ratio = 2.3; 95% confidence interval, 1.2-6.6; P = .015). For the rs1642743 GG versus AA/AG genotype, OS was 15 versus 28 months (hazard ratio = 2.6; 95% confidence interval, 1.4-5.0; P = .004). After multivariable analysis, both remained linked with poor OS (P = .018 and P = .009, respectively). There was a trend toward shorter PFS and poorer RR. Both SNPs were associated with ≥ 25% sarcomatoid dedifferentiation (P = .037 and .006, respectively). No significant results were found for rs1678607.

Conclusion: rs1642742 and rs1642743 are candidate biomarkers for poor OS in m-ccRCC patients receiving first-line VEGFR-TKI. They are associated with higher levels of sarcomatoid dedifferentiation.
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http://dx.doi.org/10.1016/j.clgc.2018.01.013DOI Listing
August 2018

Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma.

Acta Oncol 2018 Apr 2;57(4):498-508. Epub 2017 Nov 2.

a Inserm, UMR-1162 , Génomique fonctionnelle des tumeurs solides, IUH , Paris , France.

Objectives: Clear-cell renal cell carcinomas (ccRCC) are characterized by hyper-vascularization and can respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. We aimed to study the predictive value of the expression of genes in the hypoxia induced factor (HIF) - vascular endothelial growth factor (VEGF) - VEGFR-pro-angiogenic pathway in metastatic ccRCC (m-ccRCC) patients treated with sunitinib and the correlation between the expression of these genes and the molecular ccrcc-classification, the expression of genes involved in the immune-suppressive microenvironment and Von Hippel-Lindau (VHL) - and Polybromo-1 (PBRM1) - mutational status.

Material And Methods: m-ccRCC patients treated with sunitinib as first-line targeted therapy were included. Gene expression was studied in the primary nephrectomy sample by qRT-PCR, VHL- and PBRM1-mutational status by sequencing. Response rate by RECIST, progression-free survival (PFS) and overall survival (OS) were study endpoints.

Results: One hundred and four patients were included. On multivariate-analysis, HIF2A-, platelet derived growth factor receptor beta (PDGFRB)-, VEGFC-, VEGFR1- and VEGFR2-expression were correlated with PFS and HIF1A-, HIF2A-, VEGFR1- and VEGFR2-expression with OS. VEGFR2-expression showed the strongest association with outcome, being significantly correlated with all outcome parameters. HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3 were highly expressed in the transcriptomic ccrcc2-subtype of tumors, known to be highly sensitive to sunitinib. In the total tumor series, there was no correlation nor inverse correlation between the expression of genes involved in angiogenesis and in the immune-suppressive microenvironment. In tumors with a bi-allelic PBRM1-inactivation, HIF2A-, VEGFA-, VEGFR1- and VEGFR2-expression were higher, compared to tumors with one or two functional PBRM1-alleles.

Conclusions: Intratumoral expression of genes involved in the HIF-VEGF-VEGFR-pro-angiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in m-ccRCCs. Several genes involved in this pathway are upregulated in the molecular ccrcc2-subgroup, which usually responds well to sunitinib.
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http://dx.doi.org/10.1080/0284186X.2017.1388927DOI Listing
April 2018