Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix.
BACKGROUND
Claspin is a nuclear protein involved in DNA replication and damage response and is a key mediator for the S-phase checkpoint. Claspin expression is significantly high in several human solid tumors. Furthermore, high levels of claspin have been found in cervical cancer cell lines. Nevertheless, no data are available regarding claspin expression in cervical tissues.


METHODS
In order to investigate whether claspin immunoreactivity is related to the lesion severity and High-Risk (HR) HPV infection, we analyzed claspin expression by immunohistochemistry in a series of cervical biopsies which represent the steps occurring during cervical carcinogenesis (normal tissues, Cervical Intraepithelial Neoplasias 1, 2 and 3, Squamous Cell Carcinomas). All patients also had a cervico-vaginal sample for HPV testing, collected immediately before the colposcopy-guided biopsy. The HR-HPV DNA detection was performed by the HR-HPV Hybrid Capture 2 test. HPV genotyping was performed using the Linear Array HPV Genotyping Test.


RESULTS
Our results evidenced a constant and significant increase of the rate of claspin positivity from the normal tissues to carcinomas (pχ2(trend) < 0.0001). In fact, the normal tissues displayed either no or faint claspin immunoreactivity, whereas a moderate/high positivity was observed in 16% of the CIN1, 76% of the CIN2, 87.5% of the CIN3 and 93.3% of the cancers. Moreover, we found a statistically significant correlation between claspin expression and HR-HPV infection (pχ2 < 0.0001), irrespective of the genotype. Finally, we demonstrated the feasibility of claspin immunostaining in cervical cytology.


CONCLUSIONS
Our findings indicate that in vivo claspin expression is significantly related to HR-HPV infection and lesion grade both in histological and cytological samples. Therefore, the analysis of claspin expression could be clinically relevant in the diagnosis of HPV-related cervical lesions, in particular when applied to cervico-vaginal cytology. Moreover, giving information on the proliferation rate of each lesion, claspin immunostaining may contribute to the evaluation of progression risk, thus being helpful in patient management. Nevertheless, only large prospective studies may clarify the true clinical usefulness of claspin expression in distinguishing lesions with different progression potential.
Pathology Department, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. benevolo@ifo.it
Maria
M
Benevolo
Antonio
A
Musio
Amina
A
Vocaturo
Maria Gabriella
MG
Donà
Francesca
F
Rollo
Irene
I
Terrenato
Mariantonia
M
Carosi
Edoardo
E
Pescarmona
Giuseppe
G
Vocaturo
Marcella
M
Mottolese
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D052685:Alphapapillomavirus / Q000235:genetics / Q000472:pathogenicity*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000821:virology*
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C488158:CLSPN protein, human; D004279:DNA, Viral