Hypothesis: Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer.
Hypothesis: Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer.
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DOI：
10.7150/jca.12352
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发表时间：
2015
影响因子：
3.9
通讯作者：
Lazarova D
中科院分区：
文献类型：
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作者：
Bordonaro M;Lazarova D
肿瘤的发展需要多种突变的积累（突变阈值）。我们假设肥胖至少在一定程度上通过降低突变阈值而增加了微卫星稳定型结肠癌（MSS）的风险。因此，我们假设，与BMI正常的患者相比，肥胖患者需要更少的突变，尤其是驱动突变。此外，我们认为肥胖患者所需突变数量的减少可能是由于几个因素，包括伴随肥胖的高水平细胞因子。细胞因子激活的ERK、AKT和JAK/STAT信号可以与cc启动突变协同促进肠道肿瘤的发展。因此，诱导这些特定途径的驱动突变可能不是肥胖症肿瘤发展的“必需”；肥胖导致的细胞信号的改变可以替代肿瘤进展中的一些驱动突变。这一假设得到了癌症基因组图谱（TCGA）数据的初步分析的支持。因此，我们观察到，与正常体重的患者相比，肥胖的MSS CC患者的癌症基因组表现出更少的体细胞突变，相应的，驱动基因的突变数量也更少（P = 0.026）。最引人注目的观察结果是，在高体重指数（BMI）患者中检测到的KRAS突变数量较低。考虑到所有可能的混杂因素，这些有趣的观察结果需要在患者数量增加的情况下进一步验证。如果这一假设得到证实，未来的研究还应该解决肥胖MSS CC患者中观察到的较低突变阈值的几种可能解释。
Neoplastic progression requires accumulation of several mutations (mutation threshold). We hypothesize that obesity raises the risk of microsatellite stable (MSS) colon cancer (CC) at least in part by decreasing the mutation threshold. Thus, we posit that obese patients require fewer mutations, particularly driver mutations, compared to their normal BMI counterparts. Further, we suggest that the reduced number of required mutations in obese patients could be due to several factors, including the high levels of cytokines that accompany obesity. Cytokine-activated ERK, AKT, and JAK/STAT signaling could synergize with CC-initiating mutations to promote intestinal neoplastic development. Therefore, driver mutations that induce these specific pathways may not be “required” for neoplastic development in obesity; alteration in cell signaling consequent to obesity can substitute for some driver mutations in neoplastic progression. This hypothesis is supported by preliminary analyses of data from The Cancer Genome Atlas (TCGA). Thus, we observed that, compared to normal weight patients, cancer genomes of obese MSS CC patients exhibit fewer somatic mutations, and correspondingly lower numbers of mutations in driver genes (P = 0.026).The most striking observation was the lower number of KRAS mutations detected in patients with high body-mass index (BMI). These intriguing observations require further validation with increased number of patients, taking into account all possible confounding factors. If the hypothesis is confirmed, future studies should also address several possible explanations for the observed lower mutation threshold in obese MSS CC patients.