Protein p16 as a marker of dysplastic and neoplastic alterations in cervical epithelial cells.
BACKGROUND
Cervical carcinomas are second most frequent type of women cancer. Success in diagnostics of this disease is due to the use of Pap-test (cytological smear analysis). However Pap-test gives significant portion of both false-positive and false-negative conclusions. Amendments of the diagnostic procedure are desirable. Aetiological role of papillomaviruses in cervical cancer is established while the role of cellular gene alterations in the course of tumor progression is less clear. Several research groups including us have recently named the protein p16INK4a as a possible diagnostic marker of cervical cancer. To evaluate whether the specificity of p16INK4a expression in dysplastic and neoplastic cervical epithelium is sufficient for such application we undertook a broader immunochistochemical registration of this protein with a highly p16INK4a-specific monoclonal antibody.


METHODS
Paraffin-embedded samples of diagnostic biopsies and surgical materials were used. Control group included vaginal smears of healthy women and biopsy samples from patients with cervical ectopia. We examined 197 samples in total. Monoclonal antibody E6H4 (MTM Laboratories, Germany) was used.


RESULTS
In control samples we did not find any p16INK4a-positive cells. Overexpression of p16INK4a was detected in samples of cervical dysplasia (CINs) and carcinomas. The portion of p16INK4a-positive samples increased in the row: CIN I - CIN II - CIN III - invasive carcinoma. For all stages the samples were found to be heterogeneous with respect to p16INK4a-expression. Every third of CINs III and one invasive squamous cell carcinoma (out of 21 analyzed) were negative.


CONCLUSIONS
Overexpression of the protein p16INK4a is typical for dysplastic and neoplastic epithelium of cervix uteri. However p16INK4a-negative CINs and carcinomas do exist. All stages of CINs and carcinomas analyzed are heterogeneous with respect to p16INK4a expression. So p16INK4a-negativity is not a sufficient reason to exclude a patient from the high risk group. As far as normal cervical epithelium is p16INK4a-negative and the ratio p16INK4a-positive/ p16INK4a-negative samples increases at the advanced stages application of immunohisto-/cytochemical test for p16INK4a may be regarded as a supplementary test for early diagnostics of cervical cancer.
Volgareva
Galina
G
Institute of Carcinogenesis, N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia. gmvolgareva@front.ru
Zavalishina
Larisa
L
Andreeva
Yulia
Y
Frank
Georgy
G
Krutikova
Ella
E
Golovina
Darya
D
Bliev
Alexander
A
Spitkovsky
Dimitry
D
Ermilova
Valeriya
V
Kisseljov
Fjodor
F
D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D003593:Cytoplasm / Q000473:pathology; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D005188:False Negative Reactions; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D009215:Myometrium / Q000166:cytology / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012016:Reference Values; D012680:Sensitivity and Specificity; D002578:Uterine Cervical Dysplasia / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000473:pathology*; D014621:Vagina / Q000166:cytology; D014626:Vaginal Smears
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16