Breast cancer, cytomegalovirus and Epstein-Barr virus: a nested case-control study.

BACKGROUND: We investigated whether elevation in serum cytomegalovirus (CMV) or Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels precedes the development of breast cancer. METHODS: A nested case-control study was carried out within the Janus Serum Bank cohort. Two serum samples, one taken at least 4 years before diagnosis (sample 2) and an earlier sample (sample 1) from 399 women with invasive breast cancer and from 399 controls, matched for date of blood samples and age were tested for CMV and EBV IgG antibodies. Odds ratios (ORs) with 95% confidence intervals (CIs) for CMV and EBV seroconversion between the samples and unit changes in IgG optical density (OD) examined as a continuous variable were calculated using conditional logistic regression. RESULTS: Eleven cases and three controls seroconverted for CMV IgG between the first and second blood samples, with an adjusted OR for CMV IgG seroconversion of 4.0 (95% CI=1.1-14.4). The risk of breast cancer, adjusted for parity, increased per unit difference in CMV OD between samples (OR=1.7, 95% CI=1.1-2.5). In an analysis restricted to parous cases and age-matched parous controls, the OR for CMV seroconversion for IgG between the two samples, adjusted for parity and age at first birth, was 9.7 (95% CI=1.2-77.3). The EBV seroconversion or change in EBV OD was not associated with risk of breast cancer. CONCLUSION: Our hypothesis that elevation in serum CMV IgG antibody levels precedes the development of breast cancer in some women is supported by the results of this study. Changes in EBV IgG antibody are not associated with risk of breast cancer.

Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors.

OBJECTIVE: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). METHODS: Case-control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein-Barr virus and parvovirus B19. RESULTS: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein-Barr virus and parvovirus B19 did not differ significantly between case and control sera. CONCLUSIONS: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

Prospective seroepidemiologic study of human papillomavirus infection as a risk factor for invasive cervical cancer.

BACKGROUND: Major risk factors for invasive cervical cancer include infection with human papillomavirus (HPV), infection with other sexually transmitted pathogens (e.g., Chlamydia trachomatis), and smoking. Since exposures to these risk factors can be related, the contribution of any single factor to cervical carcinogenesis has been difficult to assess. We conducted a prospective study to define the role of HPV infection in cervical carcinogenesis, with invasive cancer as an end point. METHODS: A nested case-control study within a joint cohort of 700,000 Nordic subjects was performed. The 182 women who developed invasive cervical cancer during a mean follow-up of 5 years were matched with 538 control women on the basis of age and time of enrollment. Serum samples taken at enrollment were analyzed for evidence of tobacco use (i.e., cotinine levels); for antibodies against HPV types 16, 18, and 33; and for antibodies against C. trachomatis. Relative risks (RRs) were estimated by use of conditional logistic regression. RESULTS: Presence of antibodies against HPV in serum (seropositivity) was associated with an increased risk of cervical cancer, and adjustment for smoking and for C. trachomatis seropositivity did not affect this finding (RR = 2.4; 95% confidence interval [CI] = 1.6-3.7). HPV16 seropositivity was associated primarily with an increased risk of squamous cell carcinoma (RR = 3.2; 95% CI = 1.7-6.2). In contrast, risk associated with HPV18 seropositivity tended to be higher for cervical adenocarcinoma (RR = 3.4; 95% CI = 0.8-14.9). In populations with a low prevalence of antibodies against C. trachomatis, the HPV16-associated risk of cervical cancer was very high (RR = 11.8; 95% CI = 3.7-37.0); in contrast, in populations with a high prevalence of antibodies against C. trachomatis, no excess risk was found. CONCLUSION: Past infection with HPV16 increases the risk of invasive cervical squamous cell carcinoma, most clearly seen in populations with a low prevalence of sexually transmitted diseases.

Joint Nordic prospective study on human herpesvirus 8 and multiple myeloma risk.

An association between human herpesvirus 8 (HHV8) and multiple myeloma (MM) has been reported, though most studies have not confirmed such association. To follow-up on a previous prospective seroepidemiological study, where HHV8 tended to associate with MM risk, we linked five large serum banks in the Nordic countries with the Nordic cancer registries and 329 prospectively occurring cases of MM were identified, together with 1631 control subjects matched by age and gender. The HHV8 seroprevalences among cases and controls were similar (12 and 15%, respectively) and HHV8 seropositivity did not associate with the risk of MM, neither when considering positivity for lytic antibodies (relative risk (RR) = 0.8, 95% confidence interval (CI) = 0.5-1.1) nor for latent antibodies (RR = 0.6, 95% CI = 0.1-2.7). Similar risks were seen when analysis was restricted to case-control sets with at least 2 years lag before diagnosis (RR = 0.8, 95% CI = 0.5-1.2 and RR = 0.9, 95% CI = 0.1-4.2). In conclusion, the data indicate that HHV8 infection is not associated with MM.

Constant region of a kappa III immunoglobulin light chain as a major AL-amyloid protein.

AL-amyloidoses are generally described as a group of disorders in which N-terminal fragments of monoclonal immunoglobulin light chains are transferred into amyloid fibrils. We have, by amino acid sequence analyses and immunological methods, characterized the Bence-Jones protein and the corresponding AL protein as a kappa III immunoglobulin light chain from material of a patient with systemic AL-amyloidosis presenting as a local inguinal tumour. The two proteins showed some unique features. The major part of the AL amyloid fibril protein consisted of C-terminal fragments of the Bence-Jones protein. Furthermore, both the Bence-Jones protein and the AL protein were glycosylated, with possibly a glycosylation in the constant part of the light chain.

BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case-control study.

The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.

Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study.

Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case-cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1-8.2) and HPV 18 (OR=4.4; 95%CI=1.1-17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.