Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors

Our plain-English summary of Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors, by M.A. Jackson, I. Lea, A. Rashid, et al (Toxicological Sciences, 2006).

The study

• Authors: M.A. Jackson, I. Lea, A. Rashid, S.D. Peddada, J.K. Dunnick
• Journal: Toxicological Sciences
• Published: 2006;90(2):400-18
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mutational incidence and spectra for genes examined in both human and mouse lung and liver tumors were analyzed using the National Institute of Environmental Health Sciences (NIEHS) Genetic Alterations in Cancer (GAC) knowledge system. GAC is a publicly available, web-based system for evaluating data obtained from peer-reviewed studies of genetic changes in tumors associated with exposure to chemical, physical, or biological agents, as well as spontaneous tumors. In mice, mutations in Kras2 and Hras-1 were the most common events reported for lung and liver tumors, respectively, whether chemically induced or spontaneous. There was a significant difference in Kras2 mutation incidence for spontaneous versus induced mouse lung tumors and in Hras-1 mutation incidence and spectrum for spontaneous versus induced mouse liver tumors. The major gene changes reported for human lung and liver tumors were in KRAS2 (lung only) and TP53. The KRAS2 mutation incidence was similar for spontaneous and asbestos-induced human lung tumors, while the TP53 mutation incidence differed significantly. Aflatoxin B1, hepatitis B virus, hepatitis C virus, and vinyl chloride all caused TP53 mutations in human liver tumors, but the mutation spectrum for each agent differed. The incidence of KRAS2 mutations in human compared to mouse lung tumors differed significantly, as did the incidence of Hras and p53 gene mutations in human compared to mouse liver tumors. Differences observed in the mutation spectra for agent-induced compared to spontaneous tumors and similarities in spectra for structurally similar agents support the concept that mutation spectra can serve as a "fingerprint" of exposure based on chemical structure.

In plain English

This article introduced the Genetic Alterations in Cancer (GAC) knowledge system, a web-based database of tumor gene mutations from published studies. The authors pooled lung and liver tumor data from 46 mouse lung, 38 mouse liver, 53 human lung and 106 human liver studies. Over 70% of mouse lung tumors had Kras2 mutations, compared with under 20% of human lung tumors, a statistically significant difference. The human lung-tumor analysis included 102 tumors from five studies reported as related to asbestos exposure, of which 20% had KRAS2 mutations; by their titles, two of the studies examined mesotheliomas. Kras2 mutation incidence in lung tumors did not differ statistically between spontaneous and induced tumors in either species. In human liver tumors, TP53 mutations occurred in 19% of spontaneous tumors (118/612) and 29% of tumors linked to aflatoxin B1, hepatitis B or C virus, or vinyl chloride (441/1541), a difference the authors called marginal. The authors concluded that estimating cancer potential from mutation patterns of structurally similar chemicals remains to be tested. They noted that strain, race and gender could not be modeled.

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: Pooled statistical analysis of gene-mutation data extracted from published studies and entered into a literature-based database (the GAC knowledge system)
• Who was studied: Tumors described in published studies: 46 studies of mouse lung tumors, 38 of mouse liver tumors, 53 of human lung tumors and 106 of human liver tumors. Each tumor was either linked to a specific agent or spontaneous.
• Exposure: Human lung tumors: asbestos exposure (fiber type not specified). Human liver tumors: aflatoxin B1, hepatitis B virus, hepatitis C virus and vinyl chloride. Mice: various chemicals (e.g. urethan, NNK, vinyl carbamate, diethylnitrosamine). Tumors with no reported exposure were treated as spontaneous.
• Main results:
  • The human lung-tumor analysis included 102 tumors from five studies reported to be related to asbestos exposure. Two of those studies, by their titles, examined mesotheliomas (Kitamura et al., 1998; Ni et al., 2000). Of the 102 tumors, 20% had KRAS2 mutations. Of those mutations, 52% were GC base changes at codon 12 and 33% were not described.
  • Kras2 mutation incidence in lung tumors was not statistically different for spontaneous versus induced tumors in either species. Spontaneous tumors were the main data source for human lung: about 90% were considered spontaneous and 10% were associated with asbestos exposure.
  • Over 70% of mouse lung tumors had Kras2 mutations, compared with under 20% of human lung tumors (difference p less than 0.0001). About 40% of human lung tumors had TP53 mutations, compared with under 10% (21/246) of mouse lung tumors.
  • In human liver tumors, TP53 mutation incidence was 19% (118/612; 34 studies) in spontaneous tumors and 29% (441/1541; 57 studies) in induced tumors. The authors described this difference (p = 0.0485) as marginal. The mutation spectra differed significantly (p less than 0.0001).
  • Hras-1 mutations were found in 31% (812/2605) of mouse liver tumors but in none of 111 human liver tumors. TP53 mutations were found in 26% (559/2153) of human liver tumors and 0% of 250 mouse liver tumors.
• The authors' conclusion: The authors concluded that structurally similar chemicals often produced similar mutation patterns. They stated that further development of the system should allow estimates of the cancer-causing potential of structurally similar chemicals based on mutation spectra, but that this remains to be tested.
• Limitations the authors state:
  • Covariates such as strain, race and gender were not modeled because of data limitations.
  • Some genes had been studied in only one or two studies.
  • The human spontaneous tumor group was heterogeneous; patients probably had various environmental exposures that were not reported.
  • Differences between humans and mice may reflect differences in the kinds of exposures rather than biology.
  • For some comparisons there was too little data for statistical testing.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

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