Anne O. Olsen

P53 polymorphism and risk of cervical cancer

Storey and co-workers recently presented results indicating that the allele encoding arginine in the codon-72 polymorphism of the p53 gene represents a significant risk factor in the development of cancers associated with human papilloma virus (HPV). The form of the p53 protein carrying an arginine residue at this position was found to be significantly more susceptible to degradation by the HPV E6 protein than by the proline form. Genotype analysis of 30 cervical tumours and 12 skin carcinomas revealed that the homozygous Arg/Arg genotype was overrepresented compared with 41 controls. We have now analysed this polymorphism in leukocyte DNA from a larger sample of cancer patients and controls but have found no significant overrepresentation of this genotype.

DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%–80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4+ and CD8+ cells using Illuminas HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4+ cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease.

An increased risk of cervical intra-epithelial neoplasia grade II-III among human papillomavirus positive patients with the HLA-DQA1*0102-DQB1*0602 haplotype: A population-based case–control study of Norwegian women

Several recent studies have reported different associations between HLA specificities and human papillomavirus (HPV)‐associated disease of the cervix. We report the distribution of DQA1 and DQB1 genes and HPV infection in a population‐based case–control study including 92 patients with histologically verified cervical intraepithelial neoplasia grade II‐III (CIN II‐III) (thus including moderate and severe dysplasia and carcinoma in situ) and 225 control subjects. We found an overrepresentation of the DQA1*0102‐DQB1*0602 haplotype among HPV‐positive cases compared with controls. The association was even stronger when comparing HPV‐16–positive cases with HPV‐16–positive controls. In addition, among HPV‐16–positive individuals, we observed a decreased frequency of DQA1*0102‐DQB1*0604 in cases compared with controls. We were not able to detect any association between CIN II‐III and DQB1*03. Compared with previous findings in cervical cancer, our data indicate that carrying the DQA1*0102‐DQB1*0602 haplotype gives an increased risk of developing CIN when infected with HPV‐16, without influencing progression to cancer. Int. J. Cancer 76:19–24, 1998.© 1998 Wiley‐Liss, Inc.

The complete sequence of human chromosome 5

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.

Combined effect of smoking and human papillomavirus type 16 infection in cervical carcinogenesis.

To study the combined effect of smoking and human papillomavirus (HPV) type 16 infection in high-grade cervical intraepithelial neoplasia, we analyzed data from a Norwegian population-based case-control study including 90 patients and 216 controls, 20-44 years of age. We assessed HPV-16 status both by polymerase chain reaction detecting virus DNA and by enzyme-linked immunosorbent assay detecting antibodies against virus capsid. Smoking was associated with cervical intraepithelial neoplasia grade II-III in HPV-16-positive individuals. Using the jointly unexposed (HPV-16 DNA-negative never-smokers) as the reference group, we determined the risk of cervical intraepithelial neoplasia grade II-III in HPV-16 DNA-positive never-smokers and HPV-16 DNA-positive ever-smokers (odds ratio = 15.7; 95% confidence limits = 3.2, 76.5, and odds ratio = 65.9; 95% confidence limits = 22.3, 194.3, respectively). The estimated proportion of cases among HPV-16-positive smokers that is attributable to the interaction between the two causes is 74%, based on HPV-16 DNA positivity.

Psoriasis in Norwegian twins: contribution of genetic and environmental effects.

Background  Psoriasis is a chronic T‐cell‐mediated immunological skin disease with a complex pathogenesis where both genetic and environmental factors are involved.

Seropositivity against HPV 16 capsids: a better marker of past sexual behaviour than presence of HPV DNA.

OBJECTIVES: To assess if seropositivity to human papillomavirus type 16 capsids is a better marker of sexual history than the presence of HPV DNA. STUDY DESIGN: A population based age stratified random sample of 234 Norwegian women (mean age 32.8 years, range 20-44) was examined for HPV serum antibodies, cervical HPV DNA, cytology and age in relation to sexual behaviour. RESULTS: Neither age nor age at first sexual intercourse was associated with HPV 16 antibodies. Adjusted ORs for 4-5; 6-10 and > 10 versus 0-1 lifetime sexual partners, were 13.1 (95% CI 1.5-110.8), 8.2 (1.0-69.6) and 10.5 (1.2-94.0) for HPV 16 seropositivity, respectively; and 2.6 (0.2-27.8), 3.4 (0.4-31.7) and 4.1 (0.4-42.8) for HPV 16 DNA positivity, respectively. CONCLUSION: Seropositivity to HPV 16 capsids is positively associated with the number of sexual partners, suggesting that HPV 16 is predominantly sexually transmitted. The fact that serology had a stronger association with number of sexual partners than viral DNA suggests that seroreactivity is a better measure of lifetime history of HPV infection.

Neisseria gonorrhoeae Strain with High-Level Resistance to Spectinomycin Due to a Novel Resistance Mechanism (Mutated Ribosomal Protein S5) Verified in Norway

ABSTRACT Gonorrhea may become untreatable, and new treatment options are essential. Verified resistance to spectinomycin is exceedingly rare. However, we describe a high-level spectinomycin-resistant (MIC, >1,024 μg/ml) Neisseria gonorrhoeae strain from Norway with a novel resistance mechanism. The resistance determinant was a deletion of codon 27 (valine) and a K28E alteration in the ribosomal protein 5S. The traditional spectinomycin resistance gene (16S rRNA) was wild type. Despite this exceedingly rare finding, spectinomycin available for treatment of ceftriaxone-resistant urogenital gonorrhea would be very valuable.

Herpes simplex virus and human papillomavirus in a population-based case-control study of cervical intraepithelial neoplasia grade II-III

In order to evaluate the association between seropositivity for herpes simplex virus (type 1 and type 2) and cervical intraepithelial neoplacia (CIN), we analysed data from a population‐based case‐control study of CIN grade II‐III which included Norwegian women aged 20 to 44 years, 94 cases and 228 controls. Our objectives were to determine if HSV‐1 and/or HSV‐2 seropositivity were independent risk factors for CIN, taking human papillomavirus exposure into account, and to elucidate the combined effect of HPV positivity and seropositivity for HSV. In logistic regression analyses, the association between HSV‐2 or HSV‐1 seropositivity and CIN II‐III was not explained by HPV (adjusted OR 3.0; 95% CI 1.3–7.2 and adjusted OR 3.3; 95% CI 1.3–8.4, respectively). In analyses restricted to HPV‐16 DNA‐positive individuals, seropositivity for HSV‐2 increased the risk of CIN (OR 11.1; 95% CI 1.2–105.7), whereas HSV‐1 seropositivity was not significantly associated with CIN. In women positive for other HPV types, only HSV‐1 seropositivity was associated with CIN (OR 8.5; 95% CI 1.3–55.8). In analyses of the HPV‐16‐seropositive individuals, neither HSV‐1 nor HSV‐2 seropositivity was associated with CIN. Compared to the reference group of jointly unexposed subjects, the HPV‐16 DNA‐positive women who were anti‐HSV‐2 negative had an increased risk of CIN (OR 29; 95% CI 12–67), whereas the risk in women who were both HPV‐16 DNA‐positive and HSV‐2 was OR = 247 (95% CI 31–1996). The estimate of interaction was strong, but did not reach significance, and our findings may suggest that the combined effect of the two viruses is of aetiological importance in cervical carcinogenesis. Furthermore, the results indicate that HPV DNA positivity is not sufficient to explain the sexual behaviour‐associated risk of cervical neoplasia and that further studies on the role of genital HSV (type 1 as well as type 2) and other STDs are warranted.

Screening for ESR mutations in breast and ovarian cancer patients

In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR). Three patients with a family history of cancer were carrying a Gly160Cys germline substitution. This alteration was also detected in eight (four females and four males) of 729 controls (366 female, 363 males), indicating that the substitution probably represents a polymorphism. However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele. Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated. Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor‐positive breast carcinomas. Hum. Mutat. 9:531–536, 1997.