Renal medullary carcinomas

Histopathologic phenotype associated with diverse genotypes

Zoran Gatalica, Stan L. Lilleberg, Federico A. Monzon, Manika Sapru Koul, Julia A. Bridge, Joseph Knezetic, Ben Legendre, Poonam K Sharma, Peter A. McCue

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Chromosomal abnormalities and gene mutations have become major determinants in the classification of kidney carcinomas. Most renal medullary carcinomas develop in patients with hereditary sickle cell disease, but sporadic cases unassociated with sickle cell disease have also been described, for which underlying genetic abnormality is unknown. We evaluated 3 patients with renal medullary carcinoma (1 patient with sickle cell disease and 2 patients without sickle cell disease) for germ line and somatic mutations in genes commonly involved in pathogenesis of renal carcinomas using denaturing high-performance liquid chromatography and direct sequencing. Chromosomal abnormalities were studied by the conventional cytogenetic and SNP arrays analysis. Expression of hypoxia-inducible factor 1α was examined using immunohistochemistry. Two new mutations in the gene for fumarate hydratase were identified in 1 case of medullary renal carcinoma without sickle cell disease: a germ line mutation in exon 6 (R233H) and an acquired (somatic) mutation in exon 8 (P374S). No fumarate hydratase mutations were identified in the other 2 patients. The second sporadic case of renal medullary carcinoma harbored double somatic mutations in von Hippel-Lindau gene, and renal medullary carcinoma in the patient with sickle cell disease showed von Hippel-Lindau gene promoter methylation (epigenetic silencing). No consistent pattern of chromosomal abnormalities was found between 2 cases tested. All 3 cases showed increased hypoxia-inducible factor 1α expression. Medullary renal carcinomas from patients with or without sickle cell disease show involvement of genes important in hypoxia-induced signaling pathways. Generalized cellular hypoxia (in sickle cell disease) or pseudohypoxia (in tumors with fumarate hydratase and von Hippel-Lindau mutations or epigenetic silencing) may act alone or in concert at the level of medullary tubular epithelium to promote development of this rare type of renal carcinoma, which could then be genetically reclassified as either fumarate hydratase-associated renal carcinomas or high-grade clear cell renal cell carcinomas.

Original languageEnglish
Pages (from-to)1979-1988
Number of pages10
JournalHuman Pathology
Volume42
Issue number12
DOIs
StatePublished - Dec 2011

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Medullary Carcinoma
Sickle Cell Anemia
Genotype
Phenotype
Kidney
Fumarate Hydratase
Mutation
Chromosome Aberrations
Genes
Carcinoma
Hypoxia-Inducible Factor 1
Germ-Line Mutation
Epigenomics
Exons
Cell Hypoxia
Renal Cell Carcinoma
Cytogenetics
Methylation
Single Nucleotide Polymorphism
Epithelium

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Gatalica, Z., Lilleberg, S. L., Monzon, F. A., Koul, M. S., Bridge, J. A., Knezetic, J., ... McCue, P. A. (2011). Renal medullary carcinomas: Histopathologic phenotype associated with diverse genotypes. Human Pathology, 42(12), 1979-1988. https://doi.org/10.1016/j.humpath.2011.02.026

Renal medullary carcinomas : Histopathologic phenotype associated with diverse genotypes. / Gatalica, Zoran; Lilleberg, Stan L.; Monzon, Federico A.; Koul, Manika Sapru; Bridge, Julia A.; Knezetic, Joseph; Legendre, Ben; Sharma, Poonam K; McCue, Peter A.

In: Human Pathology, Vol. 42, No. 12, 12.2011, p. 1979-1988.

Research output: Contribution to journalArticle

Gatalica, Z, Lilleberg, SL, Monzon, FA, Koul, MS, Bridge, JA, Knezetic, J, Legendre, B, Sharma, PK & McCue, PA 2011, 'Renal medullary carcinomas: Histopathologic phenotype associated with diverse genotypes', Human Pathology, vol. 42, no. 12, pp. 1979-1988. https://doi.org/10.1016/j.humpath.2011.02.026
Gatalica Z, Lilleberg SL, Monzon FA, Koul MS, Bridge JA, Knezetic J et al. Renal medullary carcinomas: Histopathologic phenotype associated with diverse genotypes. Human Pathology. 2011 Dec;42(12):1979-1988. https://doi.org/10.1016/j.humpath.2011.02.026
Gatalica, Zoran ; Lilleberg, Stan L. ; Monzon, Federico A. ; Koul, Manika Sapru ; Bridge, Julia A. ; Knezetic, Joseph ; Legendre, Ben ; Sharma, Poonam K ; McCue, Peter A. / Renal medullary carcinomas : Histopathologic phenotype associated with diverse genotypes. In: Human Pathology. 2011 ; Vol. 42, No. 12. pp. 1979-1988.
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