Sebaceous carcinoma. Tumor progression through mutational inactivation of p53.
BACKGROUND
Sebaceous carcinoma may masquerade for years as an inflammatory condition. In many cases, this may be because of the presence of longstanding intraepithelial disease (e.g., dysplasia or carcinoma in situ), which eventually progresses to invasive carcinoma recognized through tumefaction and a worsening clinical presentation. The mechanism for this tumor progression is unknown. In the Far East, human papilloma virus (HPV) has been suggested to play a role in the development of sebaceous carcinoma by inactivating tumor suppressor gene p53. Here, the authors explore the molecular basis of the progression of ocular sebaceous carcinoma.


METHODS
Cases of sebaceous carcinoma seen at the University of Virginia, Department of Ophthalmology, during the period from 1989 to 1996 were analyzed for HPV infection by in situ hybridization and polymerase chain reaction. The expression of p53, p21WAF-1, Bcl-2, and epithelial membrane antigen was examined by immunohistochemistry. In one of the cases, frozen tumor was available, allowing exons 5 through 9 of the p53 gene to be sequenced.


RESULTS
Seven cases were identified, all of which were from women. All were negative for HPV. In cases in which disease was restricted to dysplasia (carcinoma in situ), p53 but not p21WAF-1 was negative. In contrast, cases that contained a component of invasive or metastatic carcinoma showed striking hyperexpression of nuclear p53 in all of the malignant cells. In one of these cases, a G:C-->T:A transversion was found in the p53 gene. This mutation, characteristic of bulky carcinogens, substituted phenylalanine for cysteine 277, a residue that participates in hydrogen bonding to the p53 DNA binding consensus sequence.


CONCLUSIONS
Mutational inactivation of p53 may be involved in the progression of sebaceous carcinoma.
Gonzalez-Fernandez
F
F
Department of Ophthalmology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Kaltreider
S A
SA
Patnaik
B D
BD
Retief
J D
JD
Bao
Y
Y
Newman
S
S
Stoler
M H
MH
Levine
P A
PA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D005142:Eyelid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012367:RNA, Viral / Q000032:analysis; D012626:Sebaceous Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D019253:Proto-Oncogene Proteins c-bcl-2; D012367:RNA, Viral; D016159:Tumor Suppressor Protein p53