Publications by authors named "Nandita Barnabas"

5 Publications

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Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Array-CGH shows amplification of 8q including MYC as the sole aberration in a leiomyosarcoma of the female lower genital tract.

Cytogenet Genome Res 2014 9;142(4):245-8. Epub 2014 May 9.

Department of Medical Genetics, Henry Ford Health System, Detroit, Mich., USA.

Leiomyosarcomas (LMS) are uncommon in the female genital tract, and the literature on LMS of the vagina consists mostly of case reports. We report the cytogenetic, FISH and array-CGH findings in a LMS of the vagina. Tumor microscopy showed a cellular spindle cell tumor composed of oval to spindly cells arranged in sheets or fascicles supported by a rich vascular network and stained positive for smooth muscle markers (SMA, HHF35). The majority of metaphase cells from the short-term cultures of tumor cells had 49 chromosomes including 3 copies of a derivative chromosome that consisted in most part of 8q material. The remaining cells had 4 copies of the derivative chromosome. FISH studies showed that each derivative chromosome consisted in its entirety of chromosome 8 material, had 2 copies of MYC and 8qter signals, lacked an 8pter signal, and was devoid of a centromeric alpha satellite or satellite III signal of any of the 24 chromosomes. Strong positive staining for MYC was demonstrated in tumor nuclei. Microarray-CGH study on DNA extracted from the tumor confirmed amplification of 8q12.1∼q22.2 and 8q24.13∼qter, and to a lesser extent 8q22.3∼q24.12, as the sole genetic abnormality in the tumor. The present report, to the best of our knowledge, is the first cytogenetically characterized primary LMS of the vagina, and our findings indicate that amplification of 8q including MYC is a primary genetic abnormality as well as a pathway of evolution in the tumor.
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http://dx.doi.org/10.1159/000362523DOI Listing
July 2014

Phenotypic and Molecular Characterization of MCF10DCIS and SUM Breast Cancer Cell Lines.

Int J Breast Cancer 2013 16;2013:872743. Epub 2013 Jan 16.

Asterand US, 440 Burroughs, Tech One Building, Suite 501, Detroit, MI 48202-3420, USA.

We reviewed the phenotypic and molecular characteristics of MCF10DCIS.com and the SUM cell lines based on numerous studies performed over the years. The major signaling pathways that give rise to the phenotype of these cells may serve as a good resource of information when researchers in drug discovery and development use these cells to identify novel targets and biomarkers. Major signaling pathways and mutations affecting the coding sequence are also described providing important information when using these cells as a model in a variety of studies.
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http://dx.doi.org/10.1155/2013/872743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562669PMC
February 2013

Chromosome 8 markers of metastatic prostate cancer in African American men: gain of the MIR151 gene and loss of the NKX3-1 gene.

Prostate 2011 Jun 17;71(8):857-71. Epub 2010 Nov 17.

Vattikuti Urology Institute, Henry Ford Hospital, Detroit, Michigan 48202-3450, USA.

Background: Radical prostatectomy (RP) is not curative if patients have undetected metastatic prostate cancer. Markers that indicate the presence of metastatic disease would identify men who may benefit from systemic adjuvant therapy. Our approach was to analyze the primary tumors of men with metastatic disease versus organ-confined disease to identify molecular changes that distinguish between these groups.

Methods: Patients were identified based on long-term follow-up of serum prostate specific antigen (PSA) levels following RP. We compared the tumors of African American (AA) men with undetectable serum PSA for >9 year after RP (good outcome) versus those of AA men with a rising PSA and recurrence after radiation or androgen ablation or both (poor outcome). We used real-time quantitative PCR to assay gene copy number alterations in tumor DNA relative to patient-matched non-tumor DNA isolated from paraffin-embedded tissue. We assayed several genes located in the specific regions of chromosome 8p and 8q that frequently undergo loss and/or gain, respectively, in prostate cancer, and the androgen receptor gene at Xq12.

Results: Gain of the MIR151 gene at 8q24.3 (in 33% of poor outcome vs. 6% of good outcome tumors) and/or loss of the NKX3-1 gene at 8p21.2 (in 39% of poor outcome vs. 11% of good outcome tumors) affected 67% of poor outcome tumors, compared to only 17% of good outcome tumors.

Conclusions: Copy number gain of the MIR151 gene and/or loss of the NKX3-1 gene in the primary tumor may indicate the presence of metastatic disease.
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http://dx.doi.org/10.1002/pros.21302DOI Listing
June 2011

Mutations in the von Hippel-Lindau (VHL) gene refine differential diagnostic criteria in renal cell carcinoma.

J Surg Oncol 2002 May;80(1):52-60

Department of Pathology, Henry Ford Health System, Detroit, Michigan 48202, USA.

Background And Objectives: Renal cell carcinomas (RCC) with abundant granular cytoplasm include oncocytomas, eosinophilic variants of chromophobe RCC, papillary RCC, collecting duct carcinoma, and some conventional (clear cell) RCC. Tumors with predominantly clear cell cytoplasm include typical chromophobe RCC and conventional (clear cell) RCC. The objective of this study was to determine if mutations in the VHL gene can serve as auxiliary diagnostic criteria in refining histology based subtyping of renal epithelial neoplasia.

Methods: The study cohort of 67 cases included 24 conventional RCC, 14 chromophobe RCC, 14 papillary RCC, and 15 oncocytomas. Single strand conformational polymorphism (SSCP) was used as a screening procedure for mutations followed by automated sequencing to identify mutations.

Results: Thirteen of the 14 mutations identified were novel, seven of which were in the coding region. In chromophobe RCC, mutations clustered in the 5'UTR/promoter region and have not been previously reported. Exon 3 appeared to favor conventional (clear cell) RCC and correlated with a more aggressive phenotype. Mutations were absent in the papillary and oncocytoma RCC subtypes.

Conclusions: Exon 3 mutations permitted a morphological distinction between conventional (clear cell) RCC and chromophobe RCC with clear cells. Mutations in the VHL gene refine histologic diagnostic criteria in RCC serving as adjuncts to the present morphology based diagnosis of RCC.
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http://dx.doi.org/10.1002/jso.10086DOI Listing
May 2002