Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice.
Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1(+/-) mice versus that in Ptch1(+/-) mice carrying mutant Blm alleles. We found that BCCs in Ptch1(+/-) Blm(tm3Brd/tm3Brd) mice had a trend toward greater genomic instability as measured by array comprehensive genomic hybridization and that these mice developed significantly more microscopic BCCs than did Ptch1(+/-) Blm(+/tm3Brd) or Ptch1(+/-) Blm(+/+) mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMSs), another cancer to which Ptch1(+/)(-) mice and PTCH1(+/)(-) (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci, respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualititative difference in the BCC or RMS tumors associated with the mutant Blm genotype.
Davari
Parastoo
P
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Hebert
Jennifer L
JL
Albertson
Donna G
DG
Huey
Bing
B
Roy
Ritu
R
Mancianti
Maria L
ML
Horvai
Andrew E
AE
McDaniel
Lisa D
LD
Schultz
Roger A
RA
Epstein
Ervin H
EH
D000483:Alleles; D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D053484:RecQ Helicases / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics*
C097151:Bloom syndrome protein; D053484:RecQ Helicases