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Int J Clin Exp Pathol 2011;4(1):58-73

Review Article
Genetic and epigenetic alterations during renal carcinogenesis

Eri Arai, Yae Kanai

Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Received December 10, 2010; accepted December 11, 2010; Epub December 13, 2010; published January 1, 2011

Abstract: Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and
chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have
genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead
to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of
RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be
copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more
clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor
persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal
tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands
has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of
precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are
basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous
stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient
outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling
provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and
epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs.  
(IJCEP1012007).

Keywords: Renal cell carcinoma, copy number alteration, DNA methylation, precancerous condition, prognostication

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Address all correspondence to:
Yae Kanai, MD,PhD
Division of Molecular Pathology
National Cancer Center Research Institute
5-1-1 Tsukiji, Chuo-ku
Tokyo 104-0045, Japan.
Tel: 81-3-3542-2511; Fax: 81-3-3248-2463
E-mail:
ykanai@ncc.go.jp