Understanding the molecular genetics of renal cell neoplasia: Implications for diagnosis, prognosis and therapy

Indiana University School of Medicine, Clarian Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA.
Expert Review of Anti-infective Therapy (Impact Factor: 2.25). 06/2010; 10(6):843-64. DOI: 10.1586/era.10.72
Source: PubMed


Renal neoplasms exhibit a wide spectrum of molecular characteristics that are closely associated with their diverse morphologic manifestations and clinical behaviors. A wealth of information has been garnered via methodology ranging from classical cytogenetics to FISH and gene expression profiling; however, the exact mechanisms by which each type of renal tumor develops remain incompletely understood. Oddly, tumors with distinctly different morphology and prognosis sometimes show some overlap in the observed genetic abnormalities; by contrast, morphologically well characterized benign and malignant tumors that seem intuitively related cannot necessarily be shown to exhibit a step-wise progression from benign to malignant biologic behavior. Nevertheless, modern methodologies have been highly successful, not only in subclassifying renal tumors, but also in defining previously unrecognized entities. Further avenues of utility for these methods probably include the resolution of challenging differential diagnoses, as well as application in targeted therapy and prediction of outcome. We review the molecular and genetic characteristics of renal neoplasms, with emphasis on markers that demonstrate utility in differentiating morphologically similar neoplasms and in predicting clinical outcome.

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Available from: Shaobo Zhang, Feb 11, 2015
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    • "Hereditary forms are associated with mutations in the c-met oncogene, which occurs in only 5–13% of sporadic cases [4]; 75% of sporadic cases of PRCC demonstrate trisomy 7 [5]. However, the molecular and genetic features of PRCC are complex and usually involve several different chromosomes and abnormalities, the most common of which are gains of chromosome 7 and/or 17 or loss of chromosome Y [5]. PRCC may also be classified based on histological features and gene expression profiles into type 1 or type 2 tumors [3]. "
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    ABSTRACT: Patient: Female, 20Final Diagnosis: Papillary renal cell carcinomaSymptoms: HemopthysisMedication: SutentClinical Procedure: CT guided biopsySpecialty: OncologyObjective:Rare diseaseBackground:Papillary renal cell carcinoma (PRCC) is a rare disease and is a carcinoma of the renal tubular epithelium, comprising only 10–15% of all renal cell carcinoma cases. The majority of cases occur in the sixth decade of life. PRCC rarely occurs before the fourth decade in the absence of family history. This paper describes an aggressive, sporadic case of PRCC in a 20-year-old female without family history and no risk factors.Case Report:A 20-year-old African American female was admitted for hemoptysis with elevated blood pressure and was found to have left peri-hilar opacification on chest X-ray. Further radiological studies led to the discovery of a large complex left renal lesion within the collecting system, infiltrating the renal artery and causing severe hydronephrosis with para-aortic lymphadenopathy. An MRI also showed signal heterogeneity in the L2 and L3 vertebrae. Biopsies of the left renal mass and a right endobronchial lesion confirmed metastatic PRCC. Treatment was commenced with a tyrosine kinase inhibitor. Within a few weeks, the vertebral metastatic lesions progressed to cause spinal compression. After targeted radiotherapy, the patient was referred to Memorial Sloan Kettering Cancer Center for enrolment in a clinical trial.Conclusions:PRCC rarely occurs in the second decade of life and even then, most such early cases occur in family clusters. PRCC also has a relatively benign course, constituting less than 10% of all metastatic renal cell carcinomas, further making this case a unique presentation.
    American Journal of Case Reports 06/2014; 15:254-7. DOI:10.12659/AJCR.890424
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    • "Loss of activity of the Krebs cycle enzyme fumarase hydratase (FH) in some cases of papillary type II RCC may also result in HIF upregulation [46], potentially providing an avenue for utilization of similar treatments in patients with PRCC. Activation of the c-MET oncogene is characteristic of papillary RCC type I, particularly in the hereditary PRCC syndrome and a subset of sporadic PRCC [8]. This finding offers a clear opportunity to test newly developed inhibitors of this tyrosine kinase in this subset of RCC [44,47]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is known for its ability to metastasize synchronously or metachronously to various anatomic sites. Distinguishing histologic subtypes of metastatic RCC has become increasingly important, as prognosis and therapy can differ dramatically between subtypes. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping metastatic RCC in light of these potential therapeutic implications. Specimens from 103 cases of metastatic RCC were retrieved, including 32 cases originally diagnosed as metastatic clear cell renal cell carcinoma (CCRCC), 8 as metastatic papillary renal cell carcinoma (PRCC), and 63 metastatic RCC without a specific subtype. Immunohistochemistry was performed with antibodies against cytokeratin 7 (CK7) and alpha-methylacyl-CoA racemase (AMACR). Dual color interphase fluorescence in situ hybridization was utilized to assess for deletion of chromosome 3p and trisomy of chromosomes 7 and 17 in all tumors. Chromosome 3p deletion was detected in 41% of all metastatic RCC specimens, and trisomy of chromosomes 7 and/or 17 was detected in 16%. Of metastatic CCRCC, chromosome 3p deletion was detected in 63%. Of metastatic PRCC, 75% showed trisomy of chromosomes 7 and/or 17. Of the tumors not previously classified, 6% were positive for CK7, and 64% were positive for AMACR; 35% showed chromosome 3p deletion, and 16% showed trisomy of chromosomes 7 and/or 17. Combined analysis of immunohistochemistry and cytogenetics enabled reclassification of 52% of these metastatic tumors not previously classified. Our findings support the utility of immunohistochemistry and cytogenetics for subtyping metastatic RCC.
    Molecular Cancer 02/2014; 13(1):39. DOI:10.1186/1476-4598-13-39 · 4.26 Impact Factor
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    • "So called 'conventional' clear cell RCCs are recognised histologically by clear cell cytoplasm; morphological variants include granular and sarcomatoid carcinomas. Clear cell RCC can be diagnosed from hematoxylin and eosin-stained microscopy, but they are also associated with a typical immunohistochemical pattern with positivity for vimentin, cytokeratin, and CA-IX [21,22]. Genetically, clear cell RCC is characterised by loss of DNA in the short arm of chromosome 3 (3p), which has been shown to occur in 79-90% of cases, as detected by FISH [23]. "
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    ABSTRACT: Recent years have seen major advances in the management of metastatic renal cell carcinoma (mRCC). The tyrosine kinase and mammalian target of rapamycin inhibitors have resulted in disease control and improved survival for many patients with mRCC, but they have not led to preventive, predictive or personalised medicine (PPPM). Failure to achieve this rests ultimately with inadequate knowledge of tissue and molecular heterogeneity; discovery of these drugs was based upon identification of pathogenic molecular pathways in RCC, but research into molecular factors which underpin drug response, resistance and selection of therapy for individual patients has lagged well behind clinical trials of drug development. This review will provide an overview of the development of targeted drug therapies for mRCC, will discuss the challenges which currently impede the delivery of PPPM, including identification of biomarkers, drug resistance and molecular heterogeneity, and will propose research methodologies and technologies required to overcome these obstacles.
    EPMA Journal, The 12/2011; 3(1):1. DOI:10.1007/s13167-011-0137-3
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