Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis.
Chromosome 3p and 1p deletions are among the most frequent genetic changes in human lung cancer and although candidate tumor suppressor genes have been identified in these regions, no causative correlations have been drawn between deletion or mutation of these and lung carcinogenesis. We identify XPC and Gadd45a as genes within each of these regions involved in lung tumor initiation and progression, respectively. One hundred percent of XPC-/- mice develop multiple spontaneous lung tumors with a minority progressing to non-small cell lung adenocarcinoma, occasionally with metastasis to adjacent lymph nodes. Deletion of Gadd45a alone does not lead to increased lung tumors in mice, but coupled with an XPC deletion, it results in lung tumor progression. Analysis of published data indicated allelic loss of XPC in most human lung tumors and allelic loss of Gadd45a in some human lung and other cancer types. Because DNA repair capacity is compromised in XPC+/- cells, it is possible that the loss of a single XPC allele in the human lung might confer a mutator phenotype. Coupled with cigarette carcinogens, decreased DNA repair would lead to additional mutations in genes such as p53 that are frequent targets in lung cancer.
Hollander
M Christine
MC
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ch96b@nih.gov
Philburn
Robyn T
RT
Patterson
Andrew D
AD
Velasco-Miguel
Susana
S
Friedberg
Errol C
EC
Linnoila
R Ilona
RI
Fornace
Albert J
AJ
D000483:Alleles; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002893:Chromosomes, Human, Pair 3; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499072:Gadd45a protein, mouse; C501002:Xpc protein, mouse; C086984:XPC protein, human