Cancer incidence varies by tissue due to differences in environmental risk factor exposure, gene variant inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia. Conversely, high folic acid (FA) intake has been associated with higher CRC risk. However, the mutagenic potential of FA intake in different tissues has not been characterized. Here we quantified mutations in folate-susceptible somatic tissues, namely bone marrow and colon, from the same MutaMouse mice and determined the FA-induced mutation profiles of both tissues using next generation sequencing. FA-induced mutagenesis was tissue- and dose-specific: FA deficiency increased mutant frequency (MF) in bone marrow while FA supplementation increased MF in colon. Analyses of mutation profiles suggested that FA interacted with mutagenic mechanisms that are unique to each tissue. These data illuminate potential mechanisms underpinning differences in susceptibility to FA-related cancers.

中文翻译：

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叶酸缺乏和补充的致突变性是组织特异性的，并导致不同的突变情况

由于环境危险因素暴露，基因变异遗传以及组织中干细胞分裂的终生数量的差异，癌症的发病率因组织而异。叶酸缺乏与大肠癌（CRC）和急性淋巴细胞性白血病的风险增加相关。相反，高叶酸（FA）摄入与更高的CRC风险相关。但是，FA在不同组织中摄入的诱变潜力尚未得到表征。在这里，我们量化了来自同一只MutaMouse小鼠的叶酸敏感性体细胞组织（即骨髓和结肠）中的突变，并使用下一代测序确定了FA诱导的两种组织的突变谱。FA诱导的诱变具有组织和剂量特异性：FA缺乏会增加骨髓中的突变频率（MF），而FA补充会增加结肠中的MF。突变图谱分析表明，FA与每种组织独特的诱变机制相互作用。这些数据阐明了潜在的机制，可支持对FA相关癌症的敏感性差异。