Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice

Timothy S. Fenske, Christine McMahon, Deepa Edwin, Joseph C. Jarvis, James M. Cheverud, Matthew Minn, Vikram Mathews, Molly A. Bogue, Michael A. Province, Howard L. McLeod, Timothy A. Graubert

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H2 = 0.25), T cell lymphoma (H2 = 0.19), and myeloid malignancies (H 2 = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.

Original languageEnglish (US)
Pages (from-to)5029-5038
Number of pages10
JournalCancer Research
Volume66
Issue number10
DOIs
StatePublished - May 15 2006
Externally publishedYes

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Neoplasm Genes
Alkylating Agents
Genome
Neoplasms
Carcinoma
Lung
Chromosomes, Human, Pair 6
Inbred Strains Mice
Chromosomes, Human, Pair 3
T-Cell Lymphoma
Quantitative Trait Loci
Incidence
Sarcoma
Carcinogens
Adenoma
Lymphoma
Histology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fenske, T. S., McMahon, C., Edwin, D., Jarvis, J. C., Cheverud, J. M., Minn, M., ... Graubert, T. A. (2006). Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. Cancer Research, 66(10), 5029-5038. https://doi.org/10.1158/0008-5472.CAN-05-3404

Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. / Fenske, Timothy S.; McMahon, Christine; Edwin, Deepa; Jarvis, Joseph C.; Cheverud, James M.; Minn, Matthew; Mathews, Vikram; Bogue, Molly A.; Province, Michael A.; McLeod, Howard L.; Graubert, Timothy A.

In: Cancer Research, Vol. 66, No. 10, 15.05.2006, p. 5029-5038.

Research output: Contribution to journalArticle

Fenske, TS, McMahon, C, Edwin, D, Jarvis, JC, Cheverud, JM, Minn, M, Mathews, V, Bogue, MA, Province, MA, McLeod, HL & Graubert, TA 2006, 'Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice', Cancer Research, vol. 66, no. 10, pp. 5029-5038. https://doi.org/10.1158/0008-5472.CAN-05-3404
Fenske, Timothy S. ; McMahon, Christine ; Edwin, Deepa ; Jarvis, Joseph C. ; Cheverud, James M. ; Minn, Matthew ; Mathews, Vikram ; Bogue, Molly A. ; Province, Michael A. ; McLeod, Howard L. ; Graubert, Timothy A. / Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. In: Cancer Research. 2006 ; Vol. 66, No. 10. pp. 5029-5038.
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