Mysterious link between iron overload and CDKN2A/2B

Our plain-English summary of Mysterious link between iron overload and CDKN2A/2B, by S. Toyokuni (Journal of Clinical Biochemistry and Nutrition, 2011).

The study

• Author: S. Toyokuni
• Journal: Journal of Clinical Biochemistry and Nutrition
• Published: 2011;48(1):46-9
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity.

In plain English

This article was a short narrative review by a single author, not a new study. It discussed iron overload and cancer, focusing on the genes CDKN2A/2B. In earlier work by the author's research group, about one third of rat kidney cancers caused by an iron compound (Fe-NTA) had homozygous deletion of these genes. The review cited another study reporting homozygous deletion of CDKN2A in as many as 74% of human malignant mesothelioma cases. The author mentioned an unpublished observation, without figures, of an even higher frequency of homozygous CDKN2A/2B deletion in rat peritoneal mesothelioma induced by chrysotile, crocidolite or amosite. The author's group also found that iron compounds alone caused mesothelioma in rats, at lower incidence and after a longer incubation period. In that study, 80% of sarcomatoid tumors had homozygous CDKN2A deletion. The review cited epidemiological studies suggesting that iron-containing asbestos fibers are more carcinogenic. The author hypothesized that excess iron causes deletion of CDKN2A/2B. The author suggested that lowering iron by blood donation, low iron diet or chelation may be a strategy to prevent cancer in healthy people without anemia.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review by a single author. It drew on published epidemiological studies and on animal experiments by the author's research group. It is not an original study.
• Who was studied: No study population of its own. The review discussed human epidemiological data and rat experiments, mainly from the author's research group.
• Exposure: Iron overload. This included iron compounds given to rats (ferric nitrilotriacetate, and ferric saccharate with nitrilotriacetate). It also included asbestos fibers (chrysotile, crocidolite, amosite) used to induce peritoneal mesothelioma in rats.
• Main results:
  • In the author's group's rat model of ferric nitrilotriacetate (Fe-NTA)-induced kidney (renal) cancer, approximately one third of cases had homozygous deletion of CDKN2A/2B.
  • Citing another study, the review stated that as many as 74% of human malignant mesothelioma cases had homozygous deletion of CDKN2A.
  • The author reported an unpublished observation of an even higher frequency of CDKN2A/2B homozygous deletion in rat peritoneal mesothelioma induced by chrysotile, crocidolite or amosite. No numbers were given.
  • Iron compounds alone (ferric saccharate with nitrilotriacetate) produced malignant mesothelioma in rats, at lower incidence and after a longer incubation period. Sarcomatoid types of these mesotheliomas had an 80% incidence of homozygous CDKN2A deletion.
  • The review cited epidemiological studies suggesting that asbestos fibers that contain iron are more carcinogenic.
  • Based on the three animal experiments, the author hypothesized that excess iron causes deletion of CDKN2A/2B.
• The authors' conclusion: The author concluded that iron modulation by phlebotomy (blood donation), low iron diet or chelation therapy may be a strategy to prevent cancer and possibly other diseases, provided the person is healthy and without anemia.

Topics

Medical terms in this study, explained in our Lexicon: CDKN2A, Oxidative Stress, Carcinogenesis, Carcinoma, Mesothelioma, Homozygous Deletion.

Related studies

• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis — S. Toyokuni (2014)
• Formation of asbestos bodies under the influence of parenteral iron overload — S. Narang, J.L. Kaw, et al. (1978)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Hyaluronan synthase 1: a mysterious enzyme with unexpected functions — H. Siiskonen, S. Oikari, et al. (2015)
• Mysterious pleural effusions — (1982)

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