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Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case–parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3’ UTR SNP (OR=1.76, 95% CI=1.15–2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26–0.82; rs2229546, OR=0.43, 95% CI=0.21–0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26–3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12–2.05). Finally, the minor allele of the IL12B rs3181224 3’ UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12–0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

Human papillomavirus (HPV) is the central etiologic factor for cervical cancer, and prior studies suggested C. trachomatis may act as an HPV cofactor. We examined the C. trachomatis-cervical cancer association by serotype, histology, HPV type in the tumor, and other HPV cofactors. We conducted a population-based study in the Seattle-Puget Sound area of 302 women with invasive squamous cell carcinomas (SCC), 185 women with adenocarcinomas of the cervix (AC), and 318 HPV seropositive control women. The risk of SCC associated with antibodies to C. trachomatis was increased (OR 1.6, 95% CI 1.1-2.2) but not for AC (OR 1.0, 95% CI 0.6-1.5). This association was independent of HPV type in the SCC tumor tissue. There was an association between specific serotypes of C. trachomatis and SCC for 6 of the 10 serotypes: B (OR 3.6, 95% CI 1.5-8.4), D (OR 2.1, 95% CI, 1.2-3.5), E (OR 2.4, 95% CI, 1.4-3.9), G (OR 3.0, 95% CI, 1.1-7.9), I (OR 4.2, 95% CI, 1.5-11.7), and J (OR 2.3, 95% CI, 1.0-5.1), but not for the 4 types (C, F, H, and K) that were present at very low prevalence in this population. There was an increased risk of SCC, but not AC, associated with antibodies to C. trachomatis that was not serotype specific.

Use of combined estrogen-progestin hormone replacement therapy appears to be associated with an increased risk of invasive lobular breast carcinomas (ILC) and, to a lesser degree, with risk of invasive ductal carcinoma (IDC). Conceivably, ILCs are more hormonally responsive and so may be more strongly associated than IDCs with reproductive and anthropometric characteristics that can influence hormone levels. However, few epidemiologic studies of breast cancer have evaluated these factors by histologic type. We conducted a population-based case-control study of women aged 65–79 years in western Washington State. Responses from 975 women diagnosed with breast cancer during 1997–1999 were compared to those of 1,007 controls. Associations between various reproductive and anthropometric factors and risks of IDC (n = 656) and ILC (n = 196) were evaluated using polytomous logistic regression. Earlier age at menarche, later age at menopause and obesity were more strongly associated with elevated risks of IDC than ILC. Alternatively, oral contraceptive use was associated with an increased risk of ILC but not IDC. Thus, the pattern of results that we observed suggest that factors influencing endogenous hormones and duration of ovarian function may be more strongly associated with IDC risk, while exogenous hormones may be more strongly associated with ILC risk. © 2003 Wiley-Liss, Inc.

HPV infections have been previously observed in oral cancers, and inactivation of the p53 gene has been shown to be one of the most common genetic alterations in human tumors. We examined 179 oral specimens from 70 individuals with histologic findings of either normal mucosa (n = 6) or oral disease that ranged from mild dysplasia to invasive squamous-cell carcinoma (n = 64) to determine the occurrence of both HPV infection and p53 mutations and their relationship with several clinical factors. HPV infection was detected by PCR amplification of viral DNA, and the presence of p53 mutations was assayed using the single-strand conformation polymorphism (SSCP)-PCR technique. HPV infection was found in 31% of individuals with oral disease and was not seen in healthy individuals. Mutations in exons 5, 6, 7 or 8 of the p53 gene were detected in 37.5% of patients with oral lesions and in a biopsy from 1 healthy individual who was a heavy smoker. Approximately one-third of lesions classified as pre-malignant (dysplasia and carcinoma in situ) and 42% of invasive carcinomas contained p53 mutations. The majority of these mutations were G:T transversions located within exons 7 and 8. Tumor tissues from 6 patients with oral lesions were found both to be HPV-16-positive and to contain p53 mutations; of these, 4 were poorly differentiated carcinomas that were diagnosed as late-stage disease. In this study, p53 mutations were detected in the early stages of cancer development. © 1996 Wiley-Liss, Inc.

To determine whether the occurrence of one or more histologic types of uterine sarcoma is related to events in a woman's reproductive life, a population-based case-control study was conducted. One-hundred sixty-seven women newly diagnosed with uterine sarcoma among residents of 6 geographic regions were compared to 208 women selected at random from the same populations with regard to histories of menstruation, pregnancy and childbearing, and breast feeding, as reported during a telephone interview. Compared to women whose menstrual periods began at age 13, women whose menses began earlier were at increased risk of leiomyosarcoma (OR = 2.0, 95% CI 0.9, 4.3); other histologic types were less strongly associated with early age at menarche. Women with leiomyosarcoma and endometrial stromal sarcoma, but not malignant mixed Müllerian tumors, tended to have ceased menstruating 2-3 years later than controls. None of the histologic types was clearly related to parity or to age at first live birth, but each was inversely related to age at last live birth. Associations were observed between leiomyosarcoma and histories of an induced abortion (OR = 4.2, 95% CI 1.2, 14.2) and of breast feeding after a live birth (OR = 0.5, 95% CI 0.3, 1.0); these relationships were not observed for other morphologic variants. These results suggest possible similarities and differences in menstrual and reproductive risk factors among histologic types of uterine sarcoma, and between these malignancies and the more common breast, endometrial and ovarian carcinomas.

Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers, 1,164 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology.

Few population-based case-control studies have assessed etiologic factors for penile cancer. Past infection with high-risk human papillomavirus (HPV) is a known risk factor for penile cancer; however, few previous studies have related the HPV DNA status of the tumor to potential demographic and behavioral risk factors for the disease or evaluated whether in situ and invasive penile cancer share risk factors. Little information is available on the role and timing of circumcision in the etiology of penile cancer. We conducted a population-based case-control study in western Washington state that included 137 men diagnosed with in situ (n = 75) or invasive (n = 62) penile cancer between January 1, 1979, and December 31, 1998, and 671 control men identified through random digit dialing. Cases and controls were interviewed in person and provided peripheral blood samples. Case and control blood samples were tested for antibodies to HPV16 and HSV-2, and tumor specimens from cases were tested for HPV DNA. Men not circumcised during childhood were at increased risk of invasive (OR = 2.3, 95% CI 1.3-4.1) but not in situ (OR = 1.1, 95% CI 0.6-1.8) penile cancer. Approximately 35% of men with penile cancer who had not been circumcised in childhood reported a history of phimosis compared to 7.6% of controls (OR = 7.4, 95% CI 3.7-15.0). Penile conditions such as tear, rash and injury were associated with increased risk of disease. Among men not circumcised in childhood, phimosis was strongly associated with development of invasive penile cancer (OR = 11.4, 95% CI 5.0-25.9). When we restricted our analysis to men who did not have phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was not elevated (OR = 0.5, 95% CI 0.1-2.5). Cigarette smoking was associated with a 4.5-fold risk (95% CI 2.0-10.1) of invasive penile cancer. HPV DNA was detected in 79.8% of tumor specimens, and 69.1% of tumors were HPV16-positive. The proportion of HPV DNA-positive tumors did not vary by any risk factors evaluated. Many risk factors were common for both in situ and invasive disease. However, 3 factors that did not increase the risk for in situ cancer proved significant risk factors for invasive penile cancer: lack of circumcision during childhood, phimosis and cigarette smoking. The high percentage of HPV DNA-positive tumors in our study is consistent with a strong association between HPV infection and the development of penile cancer regardless of circumcision status. Circumcision in early childhood may help prevent penile cancer by eliminating phimosis, a significant risk factor for the disease.

To investigate the possible association between residential formaldehyde exposures and risk of cancer of the oro- and hypopharynx (OHPC, N = 205), nasopharynx (NPC, N = 27) and sinus and nasal cavity (SNC, N = 53), a population-based case-control investigation was carried out in 13 counties of western Washington. Controls (N = 552) were selected by random digit dialing. Subjects' residential histories, including type of dwelling, were determined from a structured telephone interview which also collected smoking, alcohol and demographic information. Multiple logistic regression was used to estimate exposure odds ratios (OR) while adjusting for known risk factors. A strong association was found between a history of having lived in a mobile home and NPC, but not OHPC or SNC. The NPC risk increased with the number of years lived in a mobile home: for those with 1 to 9 years the OR = 2.1 (95% confidence interval = 0.7-6.6), and for those with 10 or more years, the OR = 5.5 (95% CI = 1.6-19.4). No associations were found between any of the cancers and a history of exposure to new constructions containing particle board and plywood, or to urea-formaldehyde foam insulation. The association found with living in a mobile home must be interpreted with caution since it is based on a small number of cases, and may be due to factors other than formaldehyde. This report emphasizes the need for additional studies focusing on potential associations between indoor air pollutants and respiratory cancers.

To study the association of human papillomavirus (HPV) infection with anal cancer, we examined tissue specimens from 126 patients with malignant lesions of the anal skin or mucosa. The patients were enrolled in a population-based, case-control study of ano-rectal cancer which is being conducted in the state of Washington and the Province of British Columbia. Histologic sections from formalin-fixed, paraffin-embedded tissues were tested for the presence of HPV DNA by in situ hybridization with biotin-labelled HPV 6, 11, 16, 18 and 31 DNA probes. HPV DNA sequences were found in tumor tissues from 24 of the 126 subjects (19.0%). When only squamous neoplasms are considered, 23 of 70 subjects (32.9%) had lesions which contained detectable HPV DNA. One HPV-positive patient had a cloacogenic carcinoma that contained regions of squamous differentiation and it was in these squamous cells that HPV DNA was localized. Of the 23 squamous lesions that harbored detectable HPV DNA, 8 contained HPV 6, 10 contained HPV 16, 1 contained HPV 18 and 4 contained an unclassified virus type(s). HPV DNA was found in tissues from 14 patients with carcinoma-in situ and 10 subjects with invasive carcinoma. These results demonstrate that some malignant tumors of the anus, in both men and women, are associated with HPV infection. We conclude that the anal squamous epithelium is another site where infection with the common genital tract HPVs may carry a risk of malignant transformation.

Female residents of six counties in Washington and Utah in whom a diagnosis of ovarian cancer was made during 1975-79 were interviewed concerning prior use of oral contraceptives. Interviews with a random sample of women drawn from these same counties were obtained for comparison. A smaller proportion of women with epithelial ovarian tumors had taken oral contraceptives than had controls: the estimated risk of ovarian cancer in uses relative to that in non-users was 0.57 (p = 0.04). The magnitude of the decreased risk depended on the duration over which oral contraceptives had been taken, as the negative association was present only after 4 or more years of use. In many ways, the use of oral contraceptives mimics the physiologic effects of pregnancy. The results of the present investigation, when interpreted together with those from other epidemiologic studies and from experiments in animals, suggest that, like pregnancy, the use of oral contraceptives has a protective effect against the development of ovarian cancer.

A population-based case-control study was undertaken in 13 counties of western Washington to determine if occupational formaldehyde exposure was related to cancer of the oro- and hypopharynx (OHPC, N = 205), nasopharynx (NPC, N = 27) or sinus and nasal cavity (SNC, N = 53). Controls were selected by random digit dialing (N = 552). A telephone interview inquired about lifetime occupational history as well as a number of potential confounding factors, including smoking and drinking. Approximately half (N = 143) of the case interviews were with next-of-kin. Occupational formaldehyde exposures were assessed by application of job-exposure matrix developed for this study which classified unique job codes into 4 categories based on judgement of likelihood and intensity of formaldehyde exposure. Exposure scores were calculated by weighing the number of years in a formaldehyde-associated job by the assigned exposure level. The effects assuming a 15-year induction period were also investigated. Logistic regression was used to estimate exposure odds ratios (OR) while taking into account multiple risk factors for each site. No significant associations were found between occupational formaldehyde exposure and any of the cancer sites under study. However, relative risk estimates associated with the highest exposure score categories were elevated for OHPC (OR = 1.3, 95% Confidence Interval = 0.6-3.1) and NPC (OR = 2.1, 95% CI = 0.4-10.0) when an induction period was accounted for. When only live interviews were considered, the odds ratios for OHPC and NPC increased to 1.7 and 3.1 respectively. Several limitations in the study tend to conservatively bias the results and must be taken into account in its interpretation.