Mima Kosuke, Nishihara Reiko, Qian Zhi Rong, Cao Yin, Sukawa Yasutaka, Nowak Jonathan A, Yang Juhong, Dou Ruoxu, Masugi Yohei, Song Mingyang, Kostic Aleksandar D, Giannakis Marios, Bullman Susan, Milner Danny A, Baba Hideo, Giovannucci Edward L, Garraway Levi A, Freeman Gordon J, Dranoff Glenn, Garrett Wendy S, Huttenhower Curtis, Meyerson Matthew, Meyerhardt Jeffrey A, Chan Andrew T, Fuchs Charles S, Ogino Shuji
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Gut. 2016 Dec;65(12):1973-1980. doi: 10.1136/gutjnl-2015-310101. Epub 2015 Aug 26.
Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of F. nucleatum in colorectal carcinoma might be associated with worse clinical outcome.
We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, and measured F. nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation).
Compared with F. nucleatum-negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in F. nucleatum-low cases and F. nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of F. nucleatum was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with F. nucleatum only in univariate analyses (p<0.001) but not in multivariate analysis that adjusted for MSI status.
The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.
越来越多的证据表明肠道微生物群与结直肠癌发生有关。具核梭杆菌可能促进结直肠癌生长，并抑制针对结直肠癌的T细胞介导的免疫反应。因此，我们推测结直肠癌中具核梭杆菌的数量可能与更差的临床结局相关。
我们使用了护士健康研究和卫生专业人员随访研究中1069例直肠癌和结肠癌病例的分子病理流行病学数据库，并测量了癌组织中的具核梭杆菌DNA。采用Cox比例风险模型计算风险比（HR），控制潜在混杂因素，包括微卫星不稳定性（MSI，错配修复缺陷）、CpG岛甲基化表型（CIMP）、KRAS、BRAF和PIK3CA突变以及LINE-1低甲基化（低水平甲基化）。
与具核梭杆菌阴性病例相比，具核梭杆菌低含量病例和具核梭杆菌高含量病例的结直肠癌特异性死亡的多变量HR（95%CI）分别为1.25（0.82至1.92）和1.58（1.04至2.39），（趋势p=0.020）。具核梭杆菌的数量与MSI高相关（多变量优势比（OR），5.22；95%CI 2.86至9.55），独立于CIMP和BRAF突变状态，而CIMP和BRAF突变仅在单变量分析中与具核梭杆菌相关（p<0.001），但在调整MSI状态的多变量分析中不相关。
结直肠癌组织中具核梭杆菌DNA的数量与较短生存期相关，并可能潜在地作为一种预后生物标志物。我们的数据可能对通过饮食、益生菌和抗生素靶向胃肠道微生物群制定癌症预防和治疗策略有启示。
