Modulation of patched-associated susceptibility to radiation induced tumorigenesis by genetic background.
We described previously a basal cell carcinoma (BCC) and medulloblastoma (MB) phenotype for CD1Ptch1(neo67/+) mice exposed to ionizing radiation. Ptch1 heterozygous mice mimic the predisposition to BCC and MB development of patients affected by nevoid BCC syndrome that inherit a mutant Patched (Ptch1) allele. To examine the impact of genetic background on development of BCCs and other tumors we used two outbred mouse lines characterized by extremely high, carcinogenesis-susceptible (Car-S), and low, carcinogenesis-resistant (Car-R), susceptibility to skin carcinogenesis. Crosses between Ptch1(neo67/+) mice and Car-S (F1S) or Car-R mice (F1R) were exposed to ionizing radiation. F1SPtch1(neo67/+) mice were highly susceptible to radiation-induced BCCs, whereas F1RPtch1(neo67/+) mice were completely resistant, indicating that tumor penetrance can be modulated by genetic background. Development of microscopic and macroscopic BCC lesions was influenced by Car-S and Car-R genotypes, suggesting a genetic-background effect on both initiation and progression of BCC. Susceptibility was additionally increased in N2 backcross mice (Car-S x F1SPtch1(neo67/+)), showing a contribution from recessive-acting Car-S modifiers. The modifying effects of Car-S-derived susceptibility alleles were tissue specific. In fact, despite higher susceptibility to BCC induction, Car-S-derived lines had lower MB incidence compared with CD1Ptch1(neo67/+) mice. BCC-associated somatic events were not influenced by genetic background, as shown by similar rate of wild-type Ptch1 loss in BCCs from F1SPtch1(neo67/+) (93%) and CD1Ptch1(neo67/+) mice (100%). Finally, microsatellite analysis of BCCs showed Ptch1 loss through interstitial deletion. These results are relevant to humans, in which BCC is the commonest malignancy, because this model system may be used to study genes modifying BCC development.
Pazzaglia
Simonetta
S
Biotechnology Unit, ENEA-Ente per le Nuove tecnologie, l'Energia e l'Ambiente, Centro Ricerche Casaccia, Casaccia, Rome, Italy. pazzaglia@casaccia.enea.it
Mancuso
Mariateresa
M
Tanori
Mirella
M
Atkinson
Michael J
MJ
Merola
Paola
P
Rebessi
Simonetta
S
Di Majo
Vincenzo
V
Covelli
Vincenzo
V
Hahn
Heidi
H
Saran
Anna
A
D015127:9,10-Dimethyl-1,2-benzanthracene; D022981:Allelic Imbalance; D000818:Animals; D002273:Carcinogens; D002280:Basal Cell Carcinoma / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D007178:Inbreeding; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate