Department of Women's Cancer, EGA Institute for Women's Health, Faculty of Population Health Sciences, University College London, London, UK.
Eurofins Genomics Europe Sequencing, Constance, Germany.
Lancet Oncol. 2019 Aug;20(8):1171-1182. doi: 10.1016/S1470-2045(19)30340-7. Epub 2019 Jul 9.
Various factors-including age, family history, inflammation, reproductive factors, and tubal ligation-modulate the risk of ovarian cancer. In this study, our aim was to establish whether women with, or at risk of developing, ovarian cancer have an imbalanced cervicovaginal microbiome.
We did a case-control study in two sets of women aged 18-87 years in the Czech Republic, Germany, Italy, Norway, and the UK. The ovarian cancer set comprised women with epithelial ovarian cancer and controls (both healthy controls and those diagnosed with benign gynaecological conditions). The BRCA set comprised women with a BRCA1 mutation but without ovarian cancer and controls who were wild type for BRCA1 and BRCA2 (both healthy controls and those with benign gynaecological conditions). Cervicovaginal samples were gathered from all participants with the ThinPrep system and then underwent 16S rRNA gene sequencing. For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH, in the cervicovaginal microbiota. We grouped samples into those in which lactobacilli accounted for at least 50% of the species present (community type L) and those in which lactobacilli accounted for less than 50% of the species present (community type O). We assessed the adjusted association between BRCA1 status and ovarian cancer status and cervicovaginal microbiota community type, using a logistic regression model with a bias reduction method.
Participants were recruited between Jan 2, 2016, and July 21, 2018. The ovarian cancer set (n=360) comprised 176 women with epithelial ovarian cancer, 115 healthy controls and 69 controls with benign gynaecological conditions. The BRCA set (n=220) included 109 women with BRCA1 mutations, 97 healthy controls wild type for BRCA1 and BRCA2 and 14 controls with a benign gynaecological condition wild type for BRCA1 and BRCA2. On the basis of two-dimensional density plots, receiver-operating characteristic curve analysis, and age thresholds used previously, we divided the cohort into those younger than 50 years and those aged 50 years or older. In the ovarian cancer set, women aged 50 years or older had a higher prevalence of community type O microbiota (81 [61%] of 133 ovarian cancer cases and 84 [59%] of 142 healthy controls) than those younger than 50 years (23 [53%] of 43 cases and 12 [29%] of 42 controls). In the ovarian cancer set, women younger than 50 years with ovarian cancer had a significantly higher prevalence of community type O microbiota than did age-matched controls under a logistic regression model with bias correction (odds ratio [OR] 2·80 [95% CI 1·17-6·94]; p=0·020). In the BRCA set, women with BRCA1 mutations younger than 50 years were also more likely to have community type O microbiota than age-matched controls (OR 2·79 [95% CI 1·25-6·68]; p=0·012), after adjustment for pregnancy (ever). This risk was increased further if more than one first-degree family member was affected by any cancer (OR 5·26 [95% CI 1·83-15·30]; p=0·0022). In both sets, we noted that the younger the participants, the stronger the association between community type O microbiota and ovarian cancer or BRCA1 mutation status (eg, OR for community type O for cases aged <40 years in the ovarian cancer set 7·00 [95% CI 1·27-51·44], p=0·025; OR for community type O for BRCA1 mutation carriers aged <35 years in the BRCA set 4·40 [1·14-24·36], p=0·031).
The presence of ovarian cancer, or factors known to affect risk for the disease (ie, age and BRCA1 germline mutations), were significantly associated with having a community type O cervicovaginal microbiota. Whether re-instatement of a community type L microbiome by using, for example, vaginal suppositories containing live lactobacilli, would alter the microbiomial composition higher up in the female genital tract and in the fallopian tubes (the site of origin of high-grade serous ovarian cancer), and whether such changes could translate into a reduced incidence of ovarian cancer, needs to be investigated.
EU Horizon 2020 Research and Innovation Programme, EU Horizon 2020 European Research Council Programme, and The Eve Appeal.
包括年龄、家族史、炎症、生殖因素和输卵管结扎在内的各种因素都会影响卵巢癌的发病风险。本研究旨在确定患有或有发展为卵巢癌风险的女性的宫颈阴道微生物组是否存在失衡。
我们在捷克共和国、德国、意大利、挪威和英国进行了一项病例对照研究，研究对象为年龄在 18-87 岁的两组女性。卵巢癌组包括上皮性卵巢癌患者和对照组（健康对照组和良性妇科疾病对照组）。BRCA 组包括携带 BRCA1 突变但无卵巢癌的女性和 BRCA1 和 BRCA2 野生型的对照组（健康对照组和良性妇科疾病对照组）。所有参与者均使用 ThinPrep 系统采集宫颈阴道样本，然后进行 16S rRNA 基因测序。对于每个样本，我们计算了产乳酸细菌物种（即乳酸脆杆菌、惰性乳酸杆菌、加氏乳酸杆菌和詹氏乳酸杆菌）的比例，这些细菌对于产生保护性的阴道低 pH 值至关重要。我们将样本分为产乳酸细菌占存在物种至少 50%的样本（社区类型 L）和产乳酸细菌占存在物种少于 50%的样本（社区类型 O）。我们使用具有偏差减少方法的逻辑回归模型，评估 BRCA1 状态和卵巢癌状态与宫颈阴道微生物群落类型之间的调整关联。
参与者于 2016 年 1 月 2 日至 2018 年 7 月 21 日期间被招募。卵巢癌组（n=360）包括 176 名上皮性卵巢癌患者、115 名健康对照组和 69 名良性妇科疾病对照组。BRCA 组（n=220）包括 109 名携带 BRCA1 突变的女性、97 名 BRCA1 和 BRCA2 野生型的健康对照组和 14 名 BRCA1 和 BRCA2 野生型的良性妇科疾病对照组。基于二维密度图、接收者操作特征曲线分析和以前使用的年龄阈值，我们将队列分为年龄小于 50 岁和年龄大于等于 50 岁两组。在卵巢癌组中，年龄大于等于 50 岁的女性中社区类型 O 微生物群的患病率更高（133 例卵巢癌病例中有 81 例[61%]和 142 名健康对照组中有 84 例[59%]），而年龄小于 50 岁的女性中社区类型 O 微生物群的患病率较低（43 例病例中有 23 例[53%]和 42 名健康对照组中有 12 例[29%]）。在卵巢癌组中，年龄小于 50 岁且患有卵巢癌的女性与年龄匹配的对照组相比，在具有偏差校正的逻辑回归模型中，社区类型 O 微生物群的患病率显著更高（比值比[OR]2·80[95%CI 1·17-6·94]；p=0·020）。在 BRCA 组中，年龄小于 50 岁且携带 BRCA1 突变的女性与年龄匹配的对照组相比，也更有可能存在社区类型 O 微生物群（OR 2·79[95%CI 1·25-6·68]；p=0·012），调整妊娠（是否）因素后，这种风险进一步增加。如果一个以上的一级亲属患有任何癌症（OR 5·26[95%CI 1·83-15·30]；p=0·0022），这种风险会更高。在两组中，我们注意到，参与者越年轻，社区类型 O 微生物群与卵巢癌或 BRCA1 突变状态之间的关联就越强（例如，在卵巢癌组中，年龄小于 40 岁的病例中社区类型 O 的比值比为 7·00[95%CI 1·27-51·44]，p=0·025；在 BRCA 组中，年龄小于 35 岁的 BRCA1 突变携带者中社区类型 O 的比值比为 4·40[1·14-24·36]，p=0·031）。
卵巢癌的存在或已知影响疾病风险的因素（即年龄和 BRCA1 种系突变）与存在社区类型 O 宫颈阴道微生物群显著相关。是否可以通过使用含有活乳酸杆菌的阴道栓剂来恢复社区类型 L 微生物群，从而改变女性生殖道更高部位和输卵管（高级别浆液性卵巢癌的起源部位）中的微生物组成，以及这种变化是否可以转化为卵巢癌发病率的降低，仍需进一步研究。
欧盟地平线 2020 研究和创新计划、欧盟地平线 2020 欧洲研究理事会计划以及 Eve 呼吁。
