Cervical cancer is linked to infection with human papillomaviruses (HPV) and isThe human papillomaviruses (HPV) comprise a heterogeneous group of more than 80 epitheliotropic genotypes. The clear link between infection with "high-risk" HPV types and the development of malignant diseases was established in numerous epidemiological and molecular studies (for reviews, see references 15, 24, and 49). Worldwide, HPV are responsible for approximately half a million new cervical cancer cases every year, as HPV DNA of high-risk genotypes can be found in more than 95% of these cancers. About half of these cases are associated with infections with HPV type 16 (HPV-16) (2, 31).Despite improved abilities to detect and cure premalignant lesions, a high percentage of patients still develops persistent or metastatic disease for which no effective therapy is available. Therefore, there is urgent need to develop a prophylactic subviral vaccine for preventing infection with HPV and thereby, most likely, the development of cervical cancer (40).The fact that for a long time it was not possible to produce papillomaviruses under cell culture conditions has hindered

The gene coding for the human homologue of the Drosophila segment polarity gene patched (PTCH1) is mutated in several common human tumors. In mice, haplodeficiency at the Ptch1 locus results in severe histologic defects in mammary ductal structure. We found no mutations within the coding region of PTCH1 in 17 human primary breast carcinomas. However, the biallelic Pro1315Leu (C3944T ) polymorphism of PTCH1 was significantly associated with breast cancer in 41 Bavarian patients compared to 85 healthy controls. We investigated whether this variant influences susceptibility for breast cancer in 611 breast cancer patients diagnosed by age 50 years and 1,057 controls matched by age and study region in Germany and in 1,093 breast cancer patients from the United Kingdom. Allele and genotype frequencies were not different between cases and controls. However, multivariate logistic regression analysis revealed an effect modification of oral contraceptive use (OC) on breast cancer risk by Leu-carrier status. Compared to women who have Pro/Pro and never used OC, Pro/Pro OC users had an increased odds ratio for breast cancer of 1.7. The odds ratio was also 1.7 for Leu-carriers who never used OC, but this was attenuated among Leu-carriers who ever used OC by 20%. Key words: genetic polymorphism; breast cancer; gene-environment interaction; oral contraceptivesThe tumor suppressor gene PTCH1 is a downstream receptor in the hedgehog family of cell signaling proteins and plays an essential role in many aspects of cell growth and cell differentiation. Germline mutations in PTCH1 have been detected in patients with nevoid basal cell carcinoma syndrome (NBCCS), in which patients are predisposed to developmental abnormalities and a variety of neoplasms including basal cell carcinoma and medulloblastoma. 1,2 In addition, somatic mutations in PTCH1 have been identified in sporadic cases of basal cell carcinomas and of medulloblastoma and in a variety of other tumors (see review). 3,4 Interestingly, nonsense mutations in PTCH1 have been reported in 2 of 7 breast carcinomas, 5 suggesting an involvement of the SHH/PTCH1 signaling pathway in development of this kind of tumor. Although a similar study in a larger sample of 45 breast carcinomas did not reveal any inactivating PTCH1 mutations, 6 the possible involvement of this gene in the formation of breast carcinoma has also been demonstrated in an animal model for Ptch1 haplodeficiency. 7 All postpubescent virgin mice heterozygous for Ptch1 developed ductal hyperplasia and dysplasia of the mammary glands, which reverted during late pregnancy and lactation but returned upon involution and gland remodeling. Treatment with estradiol and progesterone enhanced the mutant histologic phenotype. These data suggest a role for the Ptch1 signaling network in mammary growth and differentiation.To obtain further insights into the involvement of PTCH1 in breast carcinoma formation, we analyzed a series of breast carcinomas for PTCH1 mutations. In the process we observed that the biallelic Pro1315Leu (...

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