Gene therapy in gynecological cancer

Gynecological malignancies remain a major source of morbidity and mortality worldwide. In the USA alone, more than 77,000 women are diagnosed annually and over 28,000 die of some form of a gynecological malignancy. Many of these women will fail conventional therapy, leaving few remaining treatment options. Gene therapy presents one possible alternative treatment modality although, unfortunately, it is currently more theoretical than practical. Here, some of the basic science behind gene therapy is reviewed, different delivery systems used to transport the therapeutic gene are discussed, different methods of achieving a therapeutic effect are examined, some of the key trials in ovarian, endometrial, cervical and vulvar cancer research are highlighted and the future of gene therapy is explored.     

Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.     

Familial effects of prostate and other cancers on lifetime breast cancer risk

Summary Lifetime probabilities of developing breast cancer were calculated for first-degree female relatives of three groups of breast cancer patients: 114 with bilateral cancer, 186 unselected, and 88 males. The patients were classified according to whether they had a family history of prostate, endometrial, or ovarian cancer, or no family history of these cancers. In families of unselected female and male patients with no family history of prostate, endometrial, or ovarian cancer, the lifetime probability of developing breast cancer was 11.4%. The risk increased slightly to 13.5% when these other cancers may or may not have present (i.e., they were ignored, which is the usual method in computing risks) and increased further to 25.5% when prostate, endometrial, or ovarian cancer was present in the family. In families of patients with bilateral cancer the respective risks were 10.9%, 17.3%, and 34.4%. A family history of prostate cancer increased lifetime risk consistently in each of the groups, to 29.0% in the unselected and male groups and to 38.2% in the bilateral group. Endometrial cancer increased risk only in the bilateral group (to 41.8%) as did ovarian cancer (to 54.6%). Increased risk of breast cancer with a family history of endometrial or ovarian cancer appeared to be influenced by families with hereditary breast-ovarian cancer or the cancer family syndrome. The results indicate that prostate cancer, and endometrial and ovarian cancers in some families, can significantly increase breast cancer risk and should be taken into account when counseling women about their breast cancer risk.     

Positron emission tomography in gynecological malignancies

Positron emission tomography (PET) is a functional diagnostic imaging technique. F-18 fluoro-2-deoxy-d-glucose (FDG) is a commonly used radiopharmaceutical that is an analog of glucose. PET with FDG is now the standard of care in initial staging, monitoring the response to the therapy and management of various cancers. There is not sufficient data to support the use of PET in the initial diagnosis of cervical cancer; however, FDG-PET has a role in initial staging in the detection of distant metastases in patients with cervical cancer. PET has limited value in lesion localization in early stages of ovarian cancer, but plays a significant role in identifying recurrent tumors in patients with rising tumor markers. In this article, the clinical application of PET in gynecological malignancies is reviewed.     

A prospective study of postmenopausal hormone use and ovarian cancer risk

The relationship between postmenopausal hormone use (PMH) and ovarian cancer risk is unclear, particularly for specific hormone formulations, but recent studies suggest that there is a positive association. We conducted a prospective observational study with 82,905 postmenopausal women, including 389 ovarian cancers, in the Nurses' Health Study from 1976 to 2002. Compared with never users of PMH, both current and past users of > or =5 years had a significantly elevated risk of ovarian cancer (RR=1.41, 95% confidence interval (CI) 1.07-1.86 and relative risk (RR)=1.52, 95% CI 1.01-2.27, respectively). Examined by hormone type in continuous years, use of unopposed estrogen was associated with a significant increase in the risk of epithelial ovarian cancer (P for trend <0.001; RR for 5-year increment of use=1.25, 95% CI 1.12-1.38). Use of estrogen plus progestin (RR for 5-year increment of use=1.04, 95% CI 0.82-1.32) was not significantly associated with ovarian cancer risk. Generally, results were similar for serous tumours (RR for 5-year increment of unopposed estrogen use=1.23, 95% CI 1.07-1.40) and slightly stronger for endometrioid tumours (RR for 5-year increment of unopposed estrogen use=1.53, 95% CI 1.20-1.94). Recency of use was not significantly associated with ovarian cancer risk, but statistical power was limited here.     

Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.     

Variations in sex hormone metabolism genes, postmenopausal hormone therapy and risk of endometrial cancer

We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested case-control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (p(interaction) = 0.0027; p(interaction) = 0.010 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95% CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, p(interaction) = 0.024 and haplotype 3B, p(interaction) = 0.043). However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.     

Genetic polymorphisms and endometrial cancer risk

For most sporadic cancers, genetic susceptibility results from the additive effect of multiple genetic variants, each of which contributes a modest risk individually. The study of genetic single nucleotide polymorphisms (SNPs) may help explain the differences in individual cancer susceptibility and may assist in identifying novel markers of risk that can be utilized to create more effective and tailored cancer prevention strategies. Genetic polymorphisms in functionally critical genes have been suggested as risk factors for the development of a variety of cancers, including endometrial cancer. Candidate SNPs may be involved in DNA damage repair, steroid metabolism, carcinogen metabolism, cell-cycle control, apoptosis and steroid receptor activation pathways. In this review, recent findings of genetic association studies exploring genetic polymorphisms and their association with endometrial cancer are reported. In addition, the challenges of genetic association studies, such as power and bias, and the need for validation of promising findings are explored.     

Dietary glycaemic index, glycaemic load and endometrial and ovarian cancer risk: a systematic review and meta-analysis

Long-term consumption of a high glycaemic index (GI) or glycaemic load (GL) diet may lead to chronic hyperinsulinaemia, which is a potential risk factor for cancer. To date, many studies have examined the association between GI, GL and cancer risk, although results have been inconsistent, therefore our objective was to conduct a systematic review of the literature. Medline and Embase were systematically searched using terms for GI, GL and cancer to identify studies published before December 2007. Random effects meta-analyses were performed for endometrial cancer, combining maximally adjusted results that compared risk for those in the highest versus the lowest category of intake. Separate analysis examined risk by body mass index categories. Five studies examining GI and/or GL intake and endometrial cancer risk were identified. Pooled effect estimates for endometrial cancer showed an increased risk for high GL consumers (RR 1.20; 95% CI: 1.06-1.37), further elevated in obese women (RR 1.54; 95% CI: 1.18-2.03). No significant associations were observed for GI. Only two studies examined ovarian cancer and therefore no meta-analysis was performed, but results indicate positive associations for GL also. A high GL, but not a high GI, diet is positively associated with the risk of endometrial cancer, particularly among obese women.     

长链非编码RNA H19在妇科肿瘤中的研究进展

随着研究进展,长链非编码RNAs在疾病中的作用越来越受到重视,成为最新研究热点.其中H19是第一个被发现与癌症密切相关的lncRNA,在胚胎时期高表达,出生后表达减退,而在肿瘤中又重新出现,并积极参与到肿瘤发生发展的各个环节.尽管越来越多的证据支持H19是重要的癌基因之一,但其在肿瘤中的作用一直存在争议.本文综述H19在常见妇科肿瘤领域的研究进展,为妇科常见肿瘤的诊断、治疗及预后评估提供新的依据和方向.     

Novel breast cancer risk alleles and endometrial cancer risk

Genome-wide association studies have identified several novel risk alleles for breast cancer. We hypothesized that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between these 7 newly identified risk alleles for breast cancer and endometrial cancer risk using 692 invasive endometrial cancer cases and 1,723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In contrast to the breast cancer findings, we did not observe an increased risk of endometrial cancer. We observed an inverse association among rs2981582 (FGFR2) variant carriers [OR= 0.75 (95% CI: 0.60-0.95)]. We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk. We did not observe associations with the other single nucleotide polymorphisms (SNPs) and endometrial cancer risk. Replication studies investigating these polymorphisms and endometrial cancer risk are warranted. However, our findings do suggest the potential importance of biological differences between endometrial and breast cancer with respect to the genes identified in the scans. The molecular mechanisms underlying these differences remain to be defined.     

Primary breast cancer in patients with previous endometrial or ovarian cancer

The incidence of primary breast cancer is known to be increased in patients with previous endometrial or ovarian cancer, but the behavior of the breast cancer and the ultimate outlook for such patients is unknown. To provide data concerning these two questions, a group of 123 patients treated for breast cancer alone (Group I) served as a control for comparison with ten patients who had endometrial cancer (Group II) and six patients who had ovarian cancer (Group III) prior to diagnosis of breast cancer. The interval between the diagnosis of endometrial cancer and breast cancer averaged 4.6 yr, and between ovarian cancer and breast cancer, 5.4 yr. Age at diagnosis of breast cancer in Groups I, II, and III was 56, 66 (P = 0.05) and 56 yr, respectively. The incidence of patients with stage I, II, and III breast cancer was similar in Groups I, II, and III as was tumor size and number of metastatic nodes in each stage in each of the three groups. Average duration of follow-up after diagnosis of breast cancer was 3, 3.1, and 2.8 yr in Groups I, II, and III, respectively, with 70%, 60%, and 33% of patients living and free of either breast cancer, endometrial cancer, or ovarian cancer. Two of four deaths in Group II were due to endometrial cancer, and all four deaths in Group III were due to ovarian cancer. The remaining two deaths or recurrences in Group II were due to breast cancer. We conclude that 1) the behavior of breast cancer is similar in patients with or without previous endometrial or ovarian cancer; 2) breast cancer develops at an older age in patients with previous endometrial cancer than in patients with or without previous ovarian cancer and 3) death or recurrent cancer in patients with breast cancer and previous ovarian cancer is due to ovarian cancer, whereas, death or recurrent cancer in patients with breast cancer and previous endometrial cancer is due equally to breast cancer and endometrial cancer.     

Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk

Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case‐control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p‐trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20–1.00] and 0.26 (95% CI: 0.10–0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow‐up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. © 2009 UICC     

Anti‐Müllerian hormone and risk of ovarian cancer in nine cohorts

Animal and experimental data suggest that anti‐Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case‐control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme‐linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable‐adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable‐adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59–1.67) (P_trend: 0.91). The association did not differ by age at blood draw or oral contraceptive use (all P_{heterogeneity}: ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all P_{heterogeneity}: ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.     

角化生长因子及其受体在妇科肿瘤中的研究现状

在妇科肿瘤的诊断中,目前对这些疾病分子方面的检测尚无统一的、明确的标准,以宮颈癌为例,鳞状上皮细胞癌抗原的检测仍是目前研究该类疾病的主要内容之一,人们期望在众多所检测的因子中,能寻找到具有对疾病诊断、预后及治疗等方面更为有效的新兴检测指标.角化生长因子及其受体目前在多种肿瘤中被发现表达异常,与多种肿瘤的发生发展相关,本文就其在妇科肿瘤发生发展中的检测变化、现阶段研究进展加以着重综述,显示了其在不同肿瘤、疾病中作用的多形性,探索变化的规律性,以期对临床诊治疾病获益.     

Dietary acrylamide intake and the risk of endometrial or ovarian cancers in Japanese women

A meta‐analysis published in 2015 noted a marginally increased risk of endometrial and ovarian cancers in non‐smoking women with dietary acrylamide intake, but only a few studies were included, and they were limited to Western countries. The aim of this study was to investigate the association between dietary acrylamide intake and endometrial or ovarian cancer risk in the Japan Public Health Center‐based Prospective Study (JPHC Study). In this prospective cohort study, 47 185 participants aged 45‐74 years at the follow‐up starting point in the JPHC Study were enrolled. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI). In participants with endometrial and ovarian cancer, the average follow‐up periods were 15.5 and 15.6 years, respectively, and 161 and 122 cases of endometrial and ovarian cancer were diagnosed, respectively. Energy‐adjusted dietary acrylamide intake was negatively associated with endometrial cancer, but the association disappeared after adjusting for coffee consumption with an adjusted HR for the highest vs lowest tertile of 0.85 (95%CI: 0.54‐1.33). No association was observed, however, for ovarian cancer (adjusted HR, 0.77; 95%CI: 0.49‐1.23). Furthermore, after stratifying by smoking status, coffee consumption, alcohol consumption, body mass index, and menopause status, no association was observed. Dietary acrylamide intake was not associated with the risk of endometrial or ovarian cancer in Japanese women with a relatively lower dietary intake of acrylamide compared with Western populations.     

环状RNA在妇科恶性肿瘤中的研究进展

环状RNA(circular RNA,circRNA)是一类不具有5' 末端帽子和3' 末端poly(A)尾巴,并以共价键形成环状结构的RNA分子,广泛存在于真核生物细胞中。近年来,随着高通量测序技术和生物信息学的发展,研究学者在各类细胞中检测到了大量内源性circRNA的表达,并发现其具有miRNA海绵、调控基因表达及翻译等生物学功能。越来越多的研究证实circRNA在胶质瘤、结直肠癌、膀胱癌等恶性肿瘤有显著的差异表达,发挥着癌基因或抑癌基因的作用,有望成为恶性肿瘤的新型诊断标记物、分子治疗靶点和预后评估指标。本文就circRNA的形成机制、生物学特性、功能及其在妇科恶性肿瘤领域的最新研究进展作一详细综述。     

E-cadherin在妇科三大恶性肿瘤中表达的意义及研究进展

E-钙黏蛋白（E-cadherin）是一种主要存在于人和动物上皮的黏附分子,主要功能是维持正常上皮细胞形态和结构完整性。现已在多种肿瘤研究中发现,E-cadherin表达的下调,极易造成肿瘤细胞向外周组织发生浸润和远端转移,但与E-cadherin相关研究在妇科恶性肿瘤中进展缓慢,E-cadherin在子宫内膜癌、卵巢癌和宫颈癌病变过程的调控机制尚不完全清楚,而且肿瘤的发生和发展是多因素作用的过程,需要进一步加强研究,该文章就 E-cadherin在妇科三大妇科恶性肿瘤中表达的意义及研究进展进行综述。