PMID- 12438273
OWN - NLM
STAT- MEDLINE
DCOM- 20021217
LR  - 20071114
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 62
IP  - 22
DP  - 2002 Nov 15
TI  - Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis.
PG  - 6724-30
AB  - 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.
FAU - Recio, Juan A
AU  - Recio JA
AD  - Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 
      20892-4264, USA.
FAU - Noonan, Frances P
AU  - Noonan FP
FAU - Takayama, Hisashi
AU  - Takayama H
FAU - Anver, Miriam R
AU  - Anver MR
FAU - Duray, Paul
AU  - Duray P
FAU - Rush, Walter L
AU  - Rush WL
FAU - Lindner, Gerd
AU  - Lindner G
FAU - De Fabo, Edward C
AU  - De Fabo EC
FAU - DePinho, Ronald A
AU  - DePinho RA
FAU - Merlino, Glenn
AU  - Merlino G
LA  - eng
GR  - CA-92258/CA/NCI NIH HHS/United States
GR  - N0I-CO-56000/CO/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
SB  - IM
MH  - Animals
MH  - *Cocarcinogenesis
MH  - Cyclin-Dependent Kinase Inhibitor p16/*deficiency/genetics
MH  - Disease Models, Animal
MH  - Hepatocyte Growth Factor/genetics
MH  - Humans
MH  - Melanoma, Experimental/*etiology/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Ultraviolet Rays/*adverse effects
EDAT- 2002/11/20 04:00
MHDA- 2002/12/18 04:00
CRDT- 2002/11/20 04:00
PHST- 2002/11/20 04:00 [pubmed]
PHST- 2002/12/18 04:00 [medline]
PHST- 2002/11/20 04:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2002 Nov 15;62(22):6724-30.