DEVELOPMENT OF BIOLOGICAL MARKERS FOR INDIVIDUAL CANCER RISK AND CANCER PREVENTION ON THE BASIS OF A PROSPECTIVE COHORT STUDY

我们在一般人群（共3，625名年龄超过40岁的个体）中进行了一项前瞻性队列研究，使用各种生物标志物沿着生活方式问卷，调查了人类致癌作用中涉及的宿主-环境相互作用。对队列成员进行了为期11年的随访调查，共发现了192例癌症病例，揭示了外周血淋巴细胞（PBL）的NK（自然杀伤）活性与癌症发病率呈负相关，该活性在基线时通过同位素释放试验以K562为靶细胞进行评估。按三分位数对PBL的NK活性进行分类，年龄校正的癌症发病相对风险（所有地点）为0.62（95%CI，0.38-1.03）和0.72（0.45-1.16），以NK活性低者为参照; NK活性中等和高的女性分别为0.56（0.31-1.01）和0.52（0.28-0.95），NK活性中等和高的男女分别为0.59（0.40-0.87）和0.63（0.43-0.92）。尽管NK活性与生活方式因素有关，但即使调整这些因素后，结果几乎没有变化。我们的前瞻性队列研究结果随后进行了进一步研究，以比较PBL的两种不同细胞毒性（穿孔素/颗粒酶依赖性和Fas配体依赖性），沿着NK细胞的测量，NK细胞上KIR（嗜热细胞抑制受体）和KAR（嗜热细胞活化受体）的表达，以及细胞因子的产生。我们发现PBL甚至对高度表达MHC I类的靶细胞显示出强的FasL非依赖性NK活性，并且该NK活性与我们使用K562作为靶细胞的队列研究中测量的NK活性良好相关。

We investigated host-environmental interaction involved in human carcinogenesis in terms of a prospective cohort study among a general population (a total of 3,625 individuals aged over 40 years), using various biological markers along with a questionnaire on lifestyle. An eleven-year follow-up survey on cohort members found a total of 192 cancer cases, revealing that NK (natural killer) activity of peripheral blood lymphocytes (PBL), which was assessed at baseline by isotope-release assay using K562 as target cells, showed a negative association with cancer incidence. Categorizing the NK activity of PBL by tertiles, age-adjusted relative risk of cancer incidence (all sites) is 0.62 (95%CI, 0.38-1.03) and O.72 (0.45-1.16) for men with medium and high NK activity, respectively, taking the risk of those with low NK activity as reference ; 0.56 (0.31-1.01) and 0.52 (0.28-0.95) for women with medium and high NK activity, respectively ; 0.59 (0.40-0.87) and 0.63 (0.43-0.92) for both sexes with medium and high NK activity, respectively. Although NK activity was found to be associated with selected lifestyle factors, the results almost unchanged even after adjusting for these factors.The findings in our prospective cohort study were followed by a further study to compare the two different cytotoxicities of PBL (perforin/granzyme-dependent and Fas ligand-dependent) among 105 healthy individuals, along with measurement of NK cells, expression of KIR (killer-cell inhibitory receptor) and KAR (killer-cell activating receptor) on NK cells, and production of cytokines. We found that PBL showed a strong FasL-independent NK activity even towards the target cells which highly express MHC class I, and that this NK activity was well correlated to that measured in our cohort study using K562 as target cells..