Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Cancer occurrence after cosmetic breast implantation in Denmark.

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973-1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17-2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76-1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78-1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5-2.2) among private clinic patients and 0.9 (95% CI = 0.4-1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted.

Comparison of human papillomavirus genotypes in archival cervical cancer specimens from Alaska natives, Greenland natives and Danish Caucasians.

Archival, formalin-fixed, paraffin-embedded cervical cancer specimens from 53 Alaska natives, 32 Greenland natives and 34 Danish Caucasians were analyzed for human papillomavirus (HPV) genotypes 16, 18, 31, 33, 35 and 45 and unidentified genotypes (HPV X) using PCR. The specimens were from the time period 1980-1989. No significant differences were observed in the overall HPV detection rates among cases from Alaska (98.1%), Greenland (84.4%) and Denmark (85.3%). HPV genotype 16 was the most prevalent type: 78.8% in Alaska natives, 96.3% in Greenland natives and 82.8% in Danish Caucasians. A prevalence of 21.2% HPV 31 and 30.8% HPV 33 was found in Alaska natives, of which most were coinfections with HPV 16. Only 3.7% HPV 31 and 3.7% HPV 33 were found in Greenland natives and no HPV 31 and 6.9% HPV 33 were found in Danish Caucasians. HPV 18 was only detected in Alaska natives and HPV 35 and 45 were not detected in any of the three populations. Infections with multiple genotypes were prevalent in Alaskan (36.5%) but not in Greenland natives (3. 7%) and Danish Caucasians (6.9%). The Eskimo subgroup of the Alaska native population has a significantly higher prevalence of HPV genotypes 31 and 33 associated with mixed infections in invasive cancer than the two other native subgroups (P = 0.04) and Greenland and Danish populations, reflecting genotype distributions in dysplasia and normal cervical cytology. The reason for HPV genotype diversity, although unknown, may be relevant to the current development of HPV vaccines.

Pooling of urine specimens for detection of asymptomatic Chlamydia trachomatis infections by PCR in a low-prevalence population: cost-saving strategy for epidemiological studies and screening programs.

Pooling, in groups of five, of urine specimens from asymptomatically infected men in a population with 4% prevalence, as determined by case finding, is 100% sensitive and specific and results in a 60.5% reduction in the number of tests needed. Pooling of urine specimens in groups of 10 for the estimation of population-based prevalence is 96.1% sensitive and 100% specific and saves 90% of the test costs.

Cancer risk in close relatives of women with early-onset breast cancer--a population-based incidence study.

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs. 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs. 24.5) and for ovarian cancer (20 vs. 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast-ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5-7.4) and especially brothers (29; 7.7-74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer.

Different risk factor patterns for high-grade and low-grade intraepithelial lesions on the cervix among HPV-positive and HPV-negative young women.

Risk factors for cervical intraepithelial neoplasia have most often been studied in high-grade lesions. Furthermore, in a high proportion of the studies, human papillomavirus (HPV), the most significant risk determinant of cervical neoplasia, was not taken into account when evaluating other risk factors. To compare risk factors for ASCUS (atypical cells of undetermined significance), LSIL (low-grade squamous intraepithelial lesion) and HSIL (high-grade squamous intraepithelial lesion), we conducted a case-control study among 20 to 29 year-old women participating in a prospective cohort study in Copenhagen. It included 131 women with ASCUS, 120 women with LSIL, 79 women with HSIL and 1,000 randomly chosen, cytologically normal, control women. All participants had a personal interview and a gynecological examination including a Pap smear and cervical swabs for HPV DNA detection using general primer-mediated polymerase chain reaction. The most significant risk determinant of all 3 disease categories was the presence of genital HPV DNA. The risk factor pattern was nearly identical for ASCUS and LSIL, but differed significantly from that for HSIL. Stratified analysis by HPV-status showed that, apart from, respectively, smoking and parity among HPV-positive women, and smoking and number of sex partners among HPV-negative women, no additional risk factors were observed for ASCUS and LSIL. In contrast, among HPV-negative women with HSIL, long-term use of oral contraceptives was the most important risk factor. However, our result should be taken with great caution as it is based on very small numbers, and as it is unknown whether the HPV-negative lesions constitute a true entity. Among HPV-positive women, the risk of HSIL was associated with e.g., years of sex life without barrier contraceptive use, early age at first genital warts and smoking. Whether the risk factors that are applicable only to HSIL represent factors related to progression remains unknown.

Reproducibility and relative validity of a self-administered semiquantitative food frequency questionnaire applied to younger women.

We have evaluated the reproducibility and relative validity of a semiquantitative food frequency questionnaire (FFQ) used in a prospective study of risk factors for cervical neoplasia. The questionnaire is a modified version of one developed and evaluated in a middle-aged Danish population. In the present study, 122 women from the general population of Copenhagen, aged 20-29 years, completed the FFQ twice at a 1-year interval, and provided three 4-day dietary records during the intervening year. The mean nutrient intakes calculated from the first and second questionnaire were similar and, for most nutrients, close to those obtained from the dietary records. The Pearson correlation coefficients between the mean nutrient intakes from the two questionnaires ranged from 0.53 (95% CI, 0.39-0.65) for vitamin E to 0.76 (95% CI, 0.67-0.83) for vitamin B12 (median, 0.67 [95% CI, 0.56-0.76]). In comparisons between the second FFQ and the dietary records, the correlations ranged from 0.24 (95% CI, 0.07-0.40) for vitamin D to 0.63 (95% CI, 0.51-0.73) for sucrose (median, 0.42 [95% CI, 0.26-0.561). The correlations between FFQ and dietary records were generally higher after adjustment for energy intake (median, 0.53 [95% CI, 0.39-0.65]) and within-person variability (median, 0.64 [95% CI, 0.52-0.73]). On average, 71% of the women were classified in the same (+/- 1) quintile in the second FFQ and the dietary records. An average of 3.8% of the women were grossly misclassified into the highest and lowest quintiles by the dietary records. The relative validity of the FFQ in this population was similar to that reported earlier. It is concluded that the FFQ is reproducible and provides a useful scale for categorizing individuals according to their intake of energy and nutrients.

Seroreactivity to HPV16 virus-like particles as a marker for cervical cancer risk in high-risk populations.

Sexually transmitted genital human papillomavirus (HPV) infection, most often HPV 16, is considered the major etiologic determinant of cervical cancer. However, some studies have found relatively low prevalences of genital tract HPV DNA in some geographical areas, such as Greenland, that have high rates of cervical cancer. We sought to evaluate HPV 16 infection in high-risk cohorts using a serologic assay that assesses prior exposure as well as current infection and to compare the results with those obtained using a sensitive PCR-based HPV DNA assay. An ELISA based on HPV 16 virus-like particles was used to detect IgG serum antibodies in women attending sexually transmitted disease (STD) clinics in Nuuk, Greenland and Copenhagen, Denmark. Using a preassigned cut-off, 56% of Greenlandic and 41% of Danish women were seropositive (p = 0.02). In Greenlandic women, there was a non-significant increase in seropositivity with age, and odds ratios for seropositivity were similar for women with more than 5 lifetime sex partners. Seropositivity in the Danish women, however, increased linearly with increases in these 2 factors, which are likely correlates of lifetime exposure to genital HPVs. In contrast, any genital HPV DNA (HPV16 specifically) was detected in 24% and 36% of Greenlandic and Danish women, respectively and was most frequently detected in women below 20. The finding that HPV DNA prevalences, unlike seroprevalences, tended to decrease with increased lifetime risk of infection, provides an explanation for the lack of correlation between HPV DNA prevalences and cervical cancer risk in previous studies of high-risk populations.

Microsurgical reversal of female sterilization.

Between 1979 and 1985, 25 consecutive, unselected women (age 28-40 years, median 34) underwent microsurgical tubo-tubal anastomosis for reversal of sterilization. The overall pregnancy rate was 44%. The incidence of pregnancy was correlated to the tubal length after reversal. Of 12 women with tubal lengths exceeding 5.5 cm, 8 (67%) became pregnant. Of the 13 women with tubal lengths under 5.5 cm only 3 (23%) conceived (p less than 0.04). There was no significant correlation between pregnancy rate and age, interval since sterilization, or the sterilization procedure itself.

PIP: Between 1979 and 1985, 25 women aged 28-40 years of age underwent microsurgical tubotubal anastomosis at the University of Copenhagen's Hvidovre Hospital for reversal of sterilization. The interval between sterilization and reversal ranged from 2-8 years (mean, 5 years). All procedures were performed by the same surgeon. Tubotubal anastomosis was performed bilaterally in 23 women and unilaterally in 2. Equipment included magnifying glasses, microsurgical instruments, unipolar electrocoagulator for hemostasis, and unipolar microcautery needle for cutting. The tubal scars from the proximal and distal occluded ends were removed and anastomosis was performed in 2 layers. The tubal length after refertilization varied from 2-7.5 cm (mean, 5.5 cm). Tubal length was not correlated with the sterilization procedure. 11 women (44%) in this series became pregnant 2-32 months (mean, 6 months) after reversal. 2 of these women had an ectopic pregnancy, while the remaining 9 had a normal intrauterine pregnancy with term delivery. There was no significant difference in pregnancy rate or mean time to pregnancy in relation to age, duration of interval since sterilization, or sterilization procedure. However, the incidence of pregnancy was associated with tubal length after reversal. 67% of the 12 women with tubal length exceeding 5.5 cm became pregnant compared with 23% of the 13 women with tubal length under 5.5 cm. Thus, all sterilization procedures should seek to damage or remove as little as possible of the tubes to afford optimal conditions for subsequent reversal. For women with badly damaged fallopian tubes, in vitro fertilization and embryo transfer should be considered as an alternative.