Molecular alterations in the mismatch repair system suggest that this mechanism may be important in the evolution of cutaneous melanoma. Our current study evaluated the expression of two mismatch repair proteins, hMLH1 and hMSH2, in dysplastic nevi (DN) and cutaneous melanoma (CM). Immunohistochemical staining of these proteins was performed on 55 CM and 30 DN specimens. The staining results were divided into three groups: negative, partially positive and strongly positive. Normal adjacent skin cells served as an internal control for positive immunostaining. Altered immunoreactivity of one of the proteins was found in four (13.4%) DN and seven (12.7%) CM. Lack of staining for hMLH1 was observed in two (6.7%) cases of DN and five (9.1%) cases of CM; staining for hMSH2 was absent in two (6.7%) of the DN and two (3.6%) of the CM specimens. Partially positive staining was found in 33.3% and 53.3% for hMLH1 and hMSH2, respectively, in DN, and in 54.5% and 69.1%, respectively, in CMM. Our study shows that complete or partial loss of MMR protein expression occurs in a subset of both DN and CM and may represent a distinct pathway in the development of some DN and CM.
EshlemanJ.R., MarkowitzS.D.. Mismatch repair defects in human carcinogenesis.Hum Molec Genet1996; 5: 1489–94.
2.
AaltonenL.A., PeltomäkiP., LeachF.S.. Clues to the pathogenesis of familial colorectal cancer.Science1993; 260: 812–6.
3.
BolandC.R., ThibodeauS.N., HamiltonS.R.. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for determination of microsatellite instability in colorectal cancer.Cancer Res1998; 58: 5248–57.
4.
PeltomäkiP.. Deficient DNA mismatch repair: a common etiologic factor for colon cancer.Hum Mol Genet2001; 10: 735–40.
CawkwellL., GrayS., MurgatroidH.. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair.Gut1999; 45: 409–15.
7.
ChavesP., CruzC., LageP.. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype.J Pathol2000; 191: 355–60.
8.
LindorN.M., BurgartL.J., LeontovichO.. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors.J Clin Oncol2002; 20: 897–9.
9.
TuckerM.A., HalpernA., HollyE.A.. Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma.JAMA1997; 277: 1439–44.
10.
KanzlerM.H., Mraz-GernhardS.. Primary cutaneous melanoma and its precursor lesions: diagnostic and therapeutic overview.J Am Acad Dermatol2001; 45: 260–76.
11.
StaeblerA., LaxS.F., EllensonL.H.. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability.Hum Pathol2000; 31: 354–8.
12.
MarkusV.A., MadlenskyL., GryfeR.. Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.Am J Surg Pathol1999; 23: 1248–55.
13.
ChiaravalliA.M., FurlanD., FaccoC.. Immunohistochemical pattern of hMLH1/hMSH2 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences.Virch Arch2001; 438: 39–48.
14.
HusseinM.R., SunM., TuthillR.J.. Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi.J Clin Pathol2001; 28: 343–50.
BirindelliS., TragniG., BartoliC.. Detection of microsatellite alterations in the spectrum of melanocytic nevi in patients with or without individual or family history of melanoma.Int J Cancer2001; 86: 255–61.
17.
HusseinM.R., WoodG.S.. hMLH1 and hMSH2 gene mutations are present in radial growth-phase cutaneous melanoma cell lines and can be induced further by ultraviolet-B irradiation.Exp Dermatol2003; 12: 872–5.
18.
KorabiowskaM., ViehoverM., SchlottT., BergerH., DroeseM., BrinckU.. Relationship between DNA ploidy-related parameters and the deletions in mismatch repair genes MLH1 and MSH2 in lentigo maligna and malignant melanomas.Arch Dermatol Res2001; 293: 219–25.
19.
KorabiowskaM., BrinkU., RuschenbergI., HönigJ.F., StachuraJ., DroeseM.. Loss of DNA-mismatch repair gene expression in oral melanomas.Oncol Reports1999; 6: 921–3.
20.
CastigliaD., PaganiE., AlvinoE.. Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma.Genes Chromosomes Cancer2003; 37: 165–75.
21.
HusseinM.R., RoggeroE., SudilovskyE.C.. Alterations of mismatch repair protein expression in benign melanocytic nevi, melanocytic dysplastic nevi and cutaneous malignant melanoma.Am J Dermatol2001; 23: 308–14.
22.
LandiM.T., BaccarelliA., TaroneR.E.. DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.J Natl Cancer Inst2002; 94: 94–101.
23.
WeiQ., LeeJ.E., GershenwaldJ.E.. Repair of UV light-induced DNA damage and risk of cutaneous malignant melanoma.J Natl Cancer Inst2003; 95: 308–15.
24.
MuD., TursunM., DuckettD.R., DrummondJ.T., ModrichP., SancarA.. Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems.Molec Cell Biol1997; 17: 760–9.
25.
MellonI., RajpalG., KoiM., BolandC.R., ChampeG.N.. Transcription-coupled repair deficiency and mutations in human mismatch repair genes.Science1996; 272: 557–60.
