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Cervical cancer originates with human papillomavirus (HPV) infection and progresses via histologically-defined premalignant stages. Here we compare normal cervical epithelium and patientmatched high grade squamous intraepithelial lesions (HSIL) with cervical carcinoma tissue from the same patient population (n=10 per group). Specimens were analyzed by combined laser capture microdissection and 2D-DIGE. Significant expression changes were seen with 53 spots resulting in identification of 23 unique proteins at the molecular level. These include eight that uniquely distinguish normal epithelium and HSIL and four that uniquely distinguish HSIL and carcinoma. In addition, one protein, cornulin, distinguishes all three states. Other identified proteins included differentiation markers, oncogene DJ-1, serpins, stress and interferon-responsive proteins, detoxifying enzymes, and serum transporters. A literature review, performed for all identified proteins, allowed most changes to be assigned to one of three causes: direct or indirect HPV oncoprotein interactions, growth selection during latency, or interactions in the lesion microenvironment. Selected findings were confirmed by immunohistochemistry using either frozen sections from the same cohort or formalin fixed paraffin embedded samples from a tissue microarray. Novel markers described here have potential applications for increasing the predictive value of current screening methods.

Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies International Collaboration of Epidemiological Studies of Cervical CancerThe International Collaboration of Epidemiological Studies of Cervical Cancer has combined individual data on 11,161 women with invasive carcinoma, 5,402 women with cervical intraepithelial neoplasia (CIN)3/carcinoma in situ and 33,542 women without cervical carcinoma from 25 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of cervical carcinoma in relation to number of full-term pregnancies, and age at first fullterm pregnancy, were calculated conditioning by study, age, lifetime number of sexual partners and age at first sexual intercourse. Number of full-term pregnancies was associated with a risk of invasive cervical carcinoma. After controlling for age at first fullterm pregnancy, the RR for invasive cervical carcinoma among parous women was 1.76 (95% CI: 1.53-2.02) for 7 full-term pregnancies compared with 1-2. For CIN3/carcinoma in situ, no significant trend was found with increasing number of births after controlling for age at first full-term pregnancy among parous women. Early age at first full-term pregnancy was also associated with risk of both invasive cervical carcinoma and CIN3/carcinoma in situ. After controlling for number of full-term pregnancies, the RR for first full-term pregnancy at age <17 years compared with 25 years was 1.77 (95% CI: 1.42-2.23) for invasive cervical carcinoma, and 1.78 (95% CI: 1.26-2.51) for CIN3/carcinoma in situ. Results were similar in analyses restricted to high-risk human papilloma virus (HPV)-positive cases and controls. No relationship was found between cervical HPV positivity and number of fullterm pregnancies, or age at first full-term pregnancy among controls. Differences in reproductive habits may have contributed to differences in cervical cancer incidence between developed and developing countries. ' 2006 Wiley-Liss, Inc.Key words: cervical carcinoma; cervical intraepithelial neoplasia; reproductive factors; full-term pregnancy; age at first full-term pregnancy; collaborative reanalysis; relative risk Parity was one of the earliest risk factors to be associated with cancer risk. Already in 1842, on the basis of death certificates in Verona, Italy, Rigoni-Stern observed that cancers of the uterus (which at that time chiefly originated from the cervix) were more frequent in married women, who tended to be multiparous, whereas breast neoplasms were more common in nulliparae, including nuns. 1Epidemiological studies conducted in the 1950's and 1960's pointed to sexual habits, and subsequent studies to sexual infections, specifically high-risk human papillomavirus (HPV) types, 2 as the key factor in cervical carcinogenesis. Consequently, they tended to consider that the association between reproductive factors and cervical cancer was chiefly accounted for by...

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