title: Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma.
abstract: 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.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Qian
authors.initials: Q
authors.lastname: Hu
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D005290:Ferric Compounds / Q000378:metabolism* / Q000494:pharmacology; D000077605:Ferric Oxide, Saccharated; D017353:Gene Deletion; D020869:Gene Expression Profiling; D019942:Genes, p16; D005937:Glucaric Acid; D006397:Hematinics; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D008654:Mesothelioma / Q000139:chemically induced / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009088:Mucoproteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010534:Peritoneal Neoplasms / Q000139:chemically induced / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D014157:Transcription Factors; D058949:Uromodulin
chemical_list: C493969:Cdkn2b protein, rat; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005290:Ferric Compounds; D006397:Hematinics; D009088:Mucoproteins; D014157:Transcription Factors; C548612:UMOD protein, human; C548614:Umod protein, rat; D058949:Uromodulin; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid