Human papillomavirus types in cervical high-grade lesions or cancer among Nordic women - Potential for prevention

Publisher's version (útgefin grein)It is valuable to establish a population‐based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high‐grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high‐grade precancerous cervical lesions (n = 1240) during 2004‐2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0‐86.4) in CIN2, 91.6% (95% CI 89.7‐93.5) in CIN3, and 86.4% (95% CI 83.7‐89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2‐40.6; CIN3: 50.2%, 95% CI 46.8‐53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8‐13.9; CIN3: 12.1%, 95% CI 9.9‐14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9‐52.7 and 15.3%, 95% CI 12.5‐18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0‐46.7) of CIN2, 57% (95% CI 53.8‐60.5) of CIN3 and 64% (95% CI 60.3‐67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0‐72.2) in CIN2, 85% (95% CI 82.4‐87.2) in CIN3 and 80% (95% CI 77.0‐83.2) in cervical cancer. This study provides large‐scale and representative baselines for assessing and evaluating the population‐based preventive impact of HPV vaccination.We thank Cecilia Wahlström and Kia Sjölin for assistance with the HPV genotyping. SKK received lecture fee from Merck and Sanofi Pasteur MSD, scientific advisory board fee from Merck, and unrestricted research grants through her institution from Merck. JD reports having received research grants to his institution for the funding of the study. CM received lecture fees and travel grants from Sanofi Pasteur MSD. CL and MH report that their institution received a grant from Merck. KLL is a full‐time employee of Merck & Co. Inc and owns stocks and options of Merck. MN received research grants from MSD Norway/Merck through the affiliating institute. CDC, SG, LT, KS, and BTH report no conflicts of interest.Peer Reviewe

Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities Implications for LAST Terminology

Allen Press, Open AccessInformation reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health under award number U19AI113187 and through its Developmental Research Pilot (DRP) program. Roche Molecular Systems and Ventana, a Roche Company, provided reagents and equipment at no cost. PEC has received HPV tests and assays for research at a reduced or no cost from Roche, Cepheid, Becton Dickinson, and Arbor Vita Corporation. JC has received funds from grants, cooperative agreements, or subcontracts related to cervical screening and triage through his institution. JC reports grants and personal fees from Qiagen, grants from Hologic, grants and personal fees from Becton Dickinson, grants and personal fees from Genera Biosystems, grants from Gene First, and grants from Trovagene, outside the submitted work. NW is an employee of the National Cancer Institute, which has received HPV tests at reduced cost from BD and Roche. MHS is a consultant and has received fees for clinical trial development and as an expert pathologist in clinical trials for Merck, Roche/Ventana Medical Systems, Becton Dickinson (BD), Hologic/Gen Probe, Cepheid, and Inovio Pharmaceuticals and was Co-Lead of Work Group 4 and an author of the College of American Pathologists (CAP)–American Society of Colposcopy and Cervical Pathology (ASCCP) LAST Project. BMR received consulting fees from Merck as a member of pathology adjudication panel for HPV vaccine trials. TMD has received consultant fees from BD, Roche, Antiva, and Thevax; research supplies for anal cytology from Hologic; and was lead author on the CAP-ASCCP LAST Project. CMW has received funds from grants and cooperative agreements related to cervical screening and triage through her institution

Role of HPV Genotype, Multiple Infections, and Viral Load on the Risk of High-Grade Cervical Neoplasia

Background:HPV testing provides a much more sensitive method of detection for high-grade lesions than cytology, but specificity is low. Here we explore the extent to which full HPV genotyping, viral load and multiplicity of types can be used to improve specificity. Methods:A population-based sample of 47,120 women undergoing cervical screening were tested for 13 high-risk HPV genotypes. Positive predictive values (PPV) for CIN grade 2 or worse (CIN2+; N=3449) and CIN3 or worse (CIN3+; N=1475) over three years of follow-up were estimated for HPV genotype and viral load. Weighted multivariate logistic regression models were used to estimate the odds of CIN2+ or CIN3+ according to genotype, multiplicity of types and viral load. Results:High-risk HPV was detected in 15.4% of women. A hierarchy of HPV genotypes based on sequentially maximizing PPVs for CIN3+ found HPV16>33>31 to be the most predictive, followed sequentially by HPV18>35>58>45>52>59>51>39>56>68. After adjusting for higher ranked genotypes, multiple HPV infections added little to risk prediction. High viral loads for HPV18, 35, 52 and 58 carried more risk than low viral loads for HPV16, 31 and 33. High viral load for HPV16 was significantly more associated with CIN3+ than low viral load. Conclusions:HPV genotype and viral load, but not multiplicity of HPV infections, are important predictors of CIN2+ and CIN3+. Impact:The ability to identify women at higher risk of CIN2+ and CIN3+ based on both HPV genotype and viral load could be important for individualising triage plans, particularly as HPV becomes the primary screening test

Differential Epigenetic Regulation of TOX Subfamily High Mobility Group Box Genes in Lung and Breast Cancers

Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment

Facultative polyandry and the role of infant-carrying in wild saddle-back tamarins ( Saguinus fuscicollis )

Wild saddle-back tamarins ( Saguinus fuscicollis ) in southeastern Peru have a variable mating system that can differ both between territories at any one time and within territories over time. Groups are usually monogamous or cooperatively polyandrous, but are occasionally even polygynous. This study addressed the following questions: why does this population contain both monogamous and polyandrous groups simultaneously? What factors determine whether specific groups are monogamous or polyandrous? The data from this study population tentatively support the hypothesis that adults should mate monogramously only if they have nonreproductive helpers (usually older offspring) to help rear infants. Without helpers, the reproductive success of both males and females is hypothesized to be higher, on average, if they mate polyandrously than if they mate monogamously. The proposed benefits of polyandry to males and females differ quantitatively, but in both cases benefits stem from the help that males provide in rearing young. The following results support this hypothesis. (1) Lone pairs were never seen to attempt breeding, and calculations suggest that the costs of lactation and infant-carrying are too great for lone pairs to have a high probability of being able to raise twin offspring (the normal litter size). (2) Polyandrous males and nonreproductive offspring contributed substantially to infant care, particularly infant-carrying (fig. 2). (3) Adult males carried infants approximately twice as often as did lactating females, presumably because of the combined costs of (a) lactation (Fig. 3) and (b) infant-carrying (Fig. 4). The proximate causes of cooperative polyandry in S. fuscicollis appear to be different from those responsible in several bird species, showing that cooperative polyandry is a complex phenomenon.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46876/1/265_2004_Article_BF00572631.pd

Social relationships in a cooperatively polyandrous group of tamarins ( Saguinus fuscicollis )

This paper presents detailed data on the social relationships among the adults, and between the adults and young, of a cooperatively polyandrous saddle-back tamarin ( Saguinus fusciollis ; Callitrichidae) group studied for one year. Some data are also presented from groups studied in other years. Adult males in the study groups gave more grooming than they received, while the opposite was true for females (e.g. Fig. 1). The two polyandrous males in the main study group were very rarely aggressive to each other, rarely tried to disrupt each others' copulations, groomed each other, and occasionally shared food, suggesting that their relationship was more affiliative than agonistic. Data on grooming (Fig. 2), spatial relationships, and the initiation of copulations suggest that the males of this group, may have been somewhat more responsible than the female for the maintenance of male-female relationships. Both males and females performed all forms of parental care except lactation. In the main study group each of the males groomed the offspring and remained in close proximity to them more than did the female (Figs.3 and 4). These data are compared with existing data on social relationships in bird species that exhibit cooperative polyandry.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46887/1/265_2004_Article_BF00299639.pd