Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis.
Cutaneous malignant melanoma (CMM), already known for its highly aggressive behavior and resistance to conventional therapy, has evolved into a health crisis by virtue of a dramatic elevation in incidence. The underlying genetic basis for CMM, as well as the fundamental role for UV radiation in its etiology, is now widely accepted. However, the only bona fide genetic locus to emerge from extensive analysis of CMM suppressor candidates is INK4a/ARF at 9p21, which is lost frequently in familial and occasionally in somatic CMM. The functional relationship between INK4a/ARF and UV radiation in the pathogenesis of CMM is largely unknown. Recently, we reported that hepatocyte growth factor/scatter factor (HGF/SF)-transgenic mice develop melanomas after a single erythemal dose of neonatal UV radiation, supporting epidemiological data implicating childhood sunburn in CMM. Here we show that neonatal UV irradiation induces a full spectrum of melanocyte pathology from early premalignant lesions through distant metastases. Cutaneous melanomas arise with histopathological and molecular pathogenetic features remarkably similar to CMM, including loss of ink4a/arf. A role for ink4a/arf in UV-induced melanomagenesis was directly assessed by placing the HGF/SF transgene on a genetic background devoid of ink4a/arf. Median time to melanoma development induced by UV radiation was only 50 days in HGF/SF ink4a/arf(-/-) mice, compared with 152 and 238 days in HGF/SF ink4a/arf(+/-) and HGF/SF ink4a/arf(+/+) mice, respectively. These studies provide experimental evidence that ink4a/arf plays a critical role in UV-induced melanomagenesis and strongly suggest that sunburn is a highly significant risk factor, particularly in families harboring germ-line mutations in INK4a/ARF.
Recio
Juan A
JA
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892-4264, USA.
Noonan
Frances P
FP
Takayama
Hisashi
H
Anver
Miriam R
MR
Duray
Paul
P
Rush
Walter L
WL
Lindner
Gerd
G
De Fabo
Edward C
EC
DePinho
Ronald A
RA
Merlino
Glenn
G
D000818:Animals; D003043:Cocarcinogenesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D008546:Melanoma, Experimental / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014466:Ultraviolet Rays / Q000009:adverse effects*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017228:Hepatocyte Growth Factor