Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2.
The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ<-->BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation.
Lee
Gang-Hong
GH
Department of Pathology, Toramomon Hospital and Okinaka Memorial Institute for Medical Research 2-2-2 Toranomon, Minatoku, Tokyo 105-8470, Japan. lee@toranomon.gr.jp
Nishimori
Hiroyuki
H
Sasaki
Yasushi
Y
Matsushita
Hiroshi
H
Kitagawa
Tomoyuki
T
Tokino
Takashi
T
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics*; D000483:Alleles; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000818:Animals; D020296:Animals, Congenic; D002678:Chimera; D003062:Codon / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005260:Female; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D016678:Genome; D007113:Immunity, Innate; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000139:chemically induced / Q000235:genetics; D010641:Phenotype; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014520:Urethane; D000094769:DNA Polymerase iota
D003062:Codon; D018076:DNA, Complementary; D014520:Urethane; D004259:DNA-Directed DNA Polymerase; D000094769:DNA Polymerase iota