Reference SummaryDwyer-Nield LD, Int J Cancer 2010 Jan 1;126(1):125-32

Title

Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains.

Authors

Dwyer-Nield LD; McQuillan J; Hill-Baskin A; Radcliffe RA; You M; Nadeau JH; Malkinson AM

Journal

Int J Cancer

Volume

126

Issue

1

Year

2010

Pages

125-32

Abstract

Cancer susceptibility results from interactions between sensitivity and resistance alleles. We employed murine chromosome substitution strains to study how resistance alleles affected sensitive alleles during chemically-induced lung carcinogenesis. The C57BL/6J-Chr#(A/J) strains, constructed by selectively breeding sensitive A/J and resistant C57BL/6J (B6) mice, each contain one pair of A/J chromosomes within an otherwise B6 genome. Pas1, the major locus responsible for this differential strain response to urethane carcinogenesis, resides on Chr 6, but C57BL/6J-Chr6(A/J) mice (hereafter CSS-6) developed few tumors following a single urethane injection, which demonstrates epistatic interactions with other B6 alleles. CSS6 mice developed dozens of lung tumors after chronic urethane exposure, however, indicating that these epistatic interactions could be overcome by repeated carcinogen administration. Unlike A/J, but similar to B6 mice, CSS6 mice were resistant to lung carcinogenesis induced by 3-methylcholanthrene (MCA). Tumor multiplicity increased if BHT administration followed urethane exposure, showing that a Chr 6 gene(s) regulates sensitivity to chemically-induced tumor promotion. Unlike A/J tumors (predominantly codon 61 A-->T transversions), Kras mutations in tumors induced by urethane in CSS-6 mice were similar to B6 tumors (codon 61 A-->G transitions). DNA repair genes not located on Chr 6 may determine the nature of Kras mutations. CSS-6 mice are a valuable resource for testing the ability of candidate genes to modulate lung carcinogenesis.

Links

J:157052 – MGI References
19609923 – National Library of Medicine/PubMed

Strain Notes

Strain Note
A/J These mice were purchased from the Jackson Laboratory.
C57BL/6J These mice were purchased from the Jackson Laboratory.
C57BL/6J-Chr 10A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 11A/J/Na These mice were obtained from either Case Western Reserve University or the Jackson Laboratory (from the newly established colony derived from the Case Western colony).
C57BL/6J-Chr 14A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 15A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 17A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 18A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 19A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 4A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr 6A/J/Na These mice were obtained from either Case Western Reserve University or the Jackson Laboratory (from the newly established colony derived from the Case Western colony).
C57BL/6J-Chr 9A/J/Na These mice were obtained from Case Western Reserve University.
C57BL/6J-Chr YA/J/Na These mice were obtained from Case Western Reserve University.

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J Lung tumor
  • urethane (ethyl carbamate)
Lung

observed - 100

C57BL/6J Lung tumor
  • urethane (ethyl carbamate)
  • butylated hydroxytoluene (BHT)
Lung

100

C57BL/6J-Chr 4A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

24

C57BL/6J-Chr 6A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

observed - 100

C57BL/6J-Chr 6A/J/Na Lung tumor
  • urethane (ethyl carbamate)
  • butylated hydroxytoluene (BHT)
Lung

observed

C57BL/6J-Chr 6A/J/Na Lung tumor
  • 3-methylcholanthrene (MCA) (3-MC)
Lung

observed

C57BL/6J-Chr 6A/J/Na Lung tumor
  • 3-methylcholanthrene (MCA) (3-MC)
  • butylated hydroxytoluene (BHT)
Lung

observed

C57BL/6J-Chr 9A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

48

C57BL/6J-Chr 10A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

37

C57BL/6J-Chr 11A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

88 - 100

C57BL/6J-Chr 14A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

22

C57BL/6J-Chr 15A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

58

C57BL/6J-Chr 17A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

62

C57BL/6J-Chr 18A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

50

C57BL/6J-Chr 19A/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

64

C57BL/6J-Chr YA/J/Na Lung tumor
  • urethane (ethyl carbamate)
Lung

52

A/J Lung tumor
  • urethane (ethyl carbamate)
Lung

observed - 100

A/J Lung tumor
  • 3-methylcholanthrene (MCA) (3-MC)
Lung

observed

A/J Lung tumor
  • 3-methylcholanthrene (MCA) (3-MC)
  • butylated hydroxytoluene (BHT)
Lung

observed

(C57BL/6J x C57BL/6J-Chr 6A/J/NaJ)F1 Lung tumor
  • urethane (ethyl carbamate)
Lung

100