Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated EGLN2-mediated [corrected] oxygen-sensing response.
Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2 [corrected] a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 [corrected] in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma.
Koeman
Julie M
JM
Laboratory of Germline Modification and Cytogenetics, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Russell
Ryan C
RC
Tan
Min-Han
MH
Petillo
David
D
Westphal
Michael
M
Koelzer
Katherine
K
Metcalf
Julie L
JL
Zhang
Zhongfa
Z
Matsuda
Daisuke
D
Dykema
Karl J
KJ
Houseman
Heather L
HL
Kort
Eric J
EJ
Furge
Laura L
LL
Kahnoski
Richard J
RJ
Richard
Stéphane
S
Vieillefond
Annick
A
Swiatek
Pamela J
PJ
Teh
Bin Tean
BT
Ohh
Michael
M
Furge
Kyle A
KA
D018249:Adenoma, Oxyphilic / Q000235:genetics* / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D023902:Chromosome Pairing / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen
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