RGD Reference Report - Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. - Rat Genome Database

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Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma.

Authors: Hu, Q  Akatsuka, S  Yamashita, Y  Ohara, H  Nagai, H  Okazaki, Y  Takahashi, T  Toyokuni, S 
Citation: Hu Q, etal., Lab Invest. 2010 Mar;90(3):360-73. doi: 10.1038/labinvest.2009.140. Epub 2010 Jan 11.
RGD ID: 7248760
Pubmed: PMID:20065947   (View Abstract at PubMed)
DOI: DOI:10.1038/labinvest.2009.140   (Journal Full-text)

In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2'-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CDKN2AHumanMesothelioma  ISOCdkn2a (Rattus norvegicus)DNA:deletionRGD 
CDKN2BHumanMesothelioma  ISOCdkn2b (Rattus norvegicus)DNA:deletionRGD 
Cdkn2aMouseMesothelioma  ISOCdkn2a (Rattus norvegicus)DNA:deletionRGD 
Cdkn2aRatMesothelioma  IAGP DNA:deletionRGD 
Cdkn2bRatMesothelioma  IAGP DNA:deletionRGD 
Cdkn2bMouseMesothelioma  ISOCdkn2b (Rattus norvegicus)DNA:deletionRGD 
CDKN2AHumansarcomatoid mesothelioma  ISOCdkn2a (Rattus norvegicus)DNA:deletionRGD 
Cdkn2aRatsarcomatoid mesothelioma  IAGP DNA:deletionRGD 
Cdkn2aMousesarcomatoid mesothelioma  ISOCdkn2a (Rattus norvegicus)DNA:deletionRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cdkn2aRatincreased mesothelioma incidence  IAGP DNA:deletionRGD 
Cdkn2bRatincreased mesothelioma incidence  IAGP DNA:deletionRGD 
Objects Annotated

Genes (Rattus norvegicus)
Cdkn2a  (cyclin-dependent kinase inhibitor 2A)
Cdkn2b  (cyclin-dependent kinase inhibitor 2B)

Genes (Mus musculus)
Cdkn2a  (cyclin dependent kinase inhibitor 2A)
Cdkn2b  (cyclin dependent kinase inhibitor 2B)

Genes (Homo sapiens)
CDKN2A  (cyclin dependent kinase inhibitor 2A)
CDKN2B  (cyclin dependent kinase inhibitor 2B)


Additional Information