Genomic investigation of etiologic heterogeneity: methodologic challenges Public Deposited

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Creator
  • Maranchie, Jodi K
    • Other Affiliation: Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
  • Choueiri, Toni K
    • Other Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  • Hsieh, James J
    • Other Affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Hakimi, A A
    • Other Affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Seshan, Venkatraman E
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Furberg, Helena
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Shen, Ronglai
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Begg, Colin B
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Karam, Jose A
    • Other Affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Signoretti, Sabina
    • Other Affiliation: Department of Pathology, Brigham and Womens’ Hospital, Harvard Medical School, Boston, MA, USA
  • Tamboli, Pheroze
    • Other Affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Arora, Arshi
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Rathmell, W. Kimryn
    • Affiliation: School of Medicine, Department of Genetics, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, Department of Medicine
  • Zabor, Emily C
    • Other Affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Nielsen, Matthew
    • Affiliation: Gillings School of Global Public Health, Department of Health Policy and Management, School of Medicine, Department of Surgery, Department of Epidemiology, Department of Urology
Abstract
  • Abstract Background The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. Methods We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. Results The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. Conclusions Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology.
Date of publication
Identifier
  • doi:10.1186/1471-2288-14-138
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Begg et al.; licensee BioMed Central.
Language
  • English
Bibliographic citation
  • BMC Medical Research Methodology. 2014 Dec 22;14(1):138
Publisher
  • BioMed Central
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