The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single‐nucleotide polymorphisms in a large case‐control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA‐DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79‐0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04‐1.31, P = .008) and with high‐grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70‐0.87, P = 7.1 × 10−6; rs2844511: OR 1.13, 95% CI 1.01‐1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75‐0.91, P = 6.9 × 10−5; rs2844511: OR 1.14, 95% CI 1.04‐1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low‐grade dysplasia (OR 1.26, 95% CI 1.04‐1.54, P = .019). In case‐only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA‐DQA1, suggesting extensive co‐regulation. All three genes were upregulated in HPV16‐positive samples. In stratified analyses, rs9272117 was associated with HLA‐DQA1 levels, specifically in HPV‐positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA‐DQA1. Altogether, our results support 6p21.32‐33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA‐DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.
Decreasing rates of ovulation, hormonal changes, and increasing bone loss pre-date menopause by several years. Data suggest that, in addition to estradiol, progesterone may play a significant role in the interrelationship between the ovaries and the skeleton in women. Indeed, the differentiation of human osteoblasts from perimenopausal women has been shown to be dose-dependent on progesterone at physiological concentrations. Data from a pilot study in perimenopasual women also suggested that higher progesterone levels, as seen in the luteal phase of ovulatory cycles, may be associated with more bone formation and with slightly less bone resorption than anovulatory cycles in which progesterone levels are low (< 5.8 ng/ml). These data led to the initiation of a large, prospective, 2-year observational study in perimenopausal women (the PEKNO study). Interim data from the PEKNO study indicate that a decrease in ovulation correlated with an increase in the loss of bone mineral density (BMD). A meta-analysis estimated a BMD increase of 0.5% per year in women with normal ovulation, and a BMD decrease of 0.7% per year in young women with ovulatory disturbances (anovulation or short luteal phase). A meta-analysis in postmenopausal women demonstrated a 1.3% increase per year in BMD when receiving hormone replacement therapy with unopposed estrogens, and a further 0.4% increase in BMD in women receiving estrogens plus progestogens. The role of progesterone in bone metabolism in perimenopausal women who are estrogen-replete requires further study.
Purpose Malignant effusions challenge diagnostic accuracy due to cytomorphologic overlaps between various malignant primaries. Workup of this material to establish a correct diagnosis is time consuming and limited by the sparsity of material. In order to circumvent these drawbacks, the use of MALDI imaging MS (IMS) as a diagnostic platform has been explored. Experimental design Cytology cell blocks from malignant effusions (serous ovarian carcinoma and several non‐ovarian carcinomas including gastric adenocarcinoma) containing at least 30% neoplastic cells are selected for generation of cytology microarrays (CMA). CMA sections are transferred to conductive glass slides, subjected to on‐tissue tryptic digestion, and matrix application for MALDI–IMS analysis. Results Supervised classification analysis identifies serous ovarian carcinomas as the source of malignant effusions with a sensitivity of 85.7% when compared to samples from all other included primary sites. When compared to gastric adenocarcinoma, serous ovarian carcinoma samples can be delineated with a sensitivity of 97.3%. Conclusion and clinical relevance These preliminary results highlight that MALDI–IMS allows subtyping of malignant effusions to identify the precise origin of neoplastic cells. While achieving similar results compared to classical approaches such as immunocytology, more material is conserved that will be available for further tests.
Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta‐analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case‐control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.52, 95% CI 1.14‐2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68‐0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03‐2.36, P = .036) and with high‐grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70‐0.90, P = 1.9 × 10−4; rs2856437: OR 1.58, 95% CI 1.15‐2.17, P = .005). A combined analysis of high‐grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.57, 95% CI 1.18‐2.10, P = .002). No association was detected for rs2856437 with low‐grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV‐positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8‐AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non‐HLA cervical cancer susceptibility locus.
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