Hsing Ann W, Sakoda Lori C, Chen Jinbo, Chokkalingam Anand P, Sesterhenn Isabel, Gao Yu-Tang, Xu Jianfeng, Zheng S Lilly
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Carcinogenesis. 2007 Dec;28(12):2530-6. doi: 10.1093/carcin/bgm196. Epub 2007 Sep 3.
Data from epidemiologic and twin studies suggest an important role of genetic susceptibility in prostate cancer. Variants of the macrophage scavenger receptor 1 (MSR1) gene have been linked to both hereditary and sporadic prostate cancer, although the evidence is inconclusive. Most studies have been conducted on Caucasians. The role of MSR1 in prostate cancer development among Asians, for whom rates of prostate cancer are low but rising rapidly, is unclear. To evaluate further the relationship between MSR1 variants and prostate cancer risk, we sequenced all the 11 MSR1 exons, exon-intron junctions, promoter regions, as well as 5' and 3' untranslated regions (UTRs) in 86 individuals from Shanghai, China. We identified a total of 21 sequence variants, including three novel variants that have not been reported previously. To balance genotyping cost and the capacity to capture sufficient genetic variation, we genotyped four haplotype-tagging variants (P275A, INDEL7, P346P and 3' UTR 70006), which capture 85% of the genetic variation in MSR1 in this population. These four variants, plus two other variants (PRO3 and INDEL1) that have been linked to prostate cancer risk in the previous studies, were typed for all study subjects, which included 130 prostate cancer cases, 130 patients with benign prostatic hyperplasia and 150 controls randomly selected from the population. Three of the six variants were associated with prostate cancer. Men with a P346P (a novel variant) G allele (AG + GG) had a significantly reduced risk of total prostate cancer [odds ratio = 0.47, 95% confidence interval (CI) 0.23-0.96], whereas those with a P275A G allele had a 37% reduced risk of prostate cancer (95% CI 0.39-1.02), with more pronounced reduction in risk seen for localized cancer cases (odds ratio = 0.25, 95% CI 0.12-0.52; P = 0.001). In addition, men with the INDEL7 variant had a 67% reduced risk of localized cancer (95% CI 0.16-0.68). Based on the four tagging variants, we inferred four major haplotypes that accounted for >90% of the haplotype variation in this population. The haplotype frequencies were significantly different between localized prostate cancer cases and controls, with a global P value of 0.004, and the haplotype containing the minor alleles of the P275A and INDEL7 variants was associated with a significantly reduced risk of localized prostate cancer (odds ratio = 0.28, 95% CI 0.13-0.59), relative to the most common haplotype. These results, although modest and confined mainly to localized prostate cancer, suggest that MSR1 polymorphisms may play a role in prostate cancer etiology in Chinese men. The role of MSR1 warrants further investigation in larger studies and other populations.
流行病学和双胞胎研究的数据表明，遗传易感性在前列腺癌中起着重要作用。巨噬细胞清道夫受体1（MSR1）基因的变体已被证明与遗传性和散发性前列腺癌都有关联，尽管证据并不确凿。大多数研究是针对高加索人进行的。对于前列腺癌发病率较低但正在迅速上升的亚洲人来说，MSR1在前列腺癌发展中的作用尚不清楚。为了进一步评估MSR1变体与前列腺癌风险之间的关系，我们对来自中国上海的86名个体的MSR1的所有11个外显子、外显子 - 内含子接头、启动子区域以及5'和3'非翻译区（UTR）进行了测序。我们总共鉴定出21个序列变体，包括3个以前未报道过的新变体。为了平衡基因分型成本和捕获足够遗传变异的能力，我们对4个单倍型标签变体（P275A、INDEL7、P346P和3'UTR 70006）进行了基因分型，这些变体捕获了该人群中MSR1 85%的遗传变异。这4个变体，加上另外2个在先前研究中已被证明与前列腺癌风险相关的变体（PRO3和INDEL1），对所有研究对象进行了分型，研究对象包括130例前列腺癌患者、130例良性前列腺增生患者和150名从人群中随机选择的对照。6个变体中的3个与前列腺癌相关。携带P346P（一个新变体）G等位基因（AG + GG）的男性患前列腺癌的总体风险显著降低[比值比 = 0.47，95%置信区间（CI）0.23 - 0.96]，而携带P275A G等位基因的男性患前列腺癌的风险降低了37%（95%CI 0.39 - 1.02），在局限性癌症病例中风险降低更为明显（比值比 = 0.25，95%CI 0.12 - 0.52；P = 0.001）。此外，携带INDEL7变体的男性患局限性癌症的风险降低了67%（95%CI 0.16 - 0.68）。基于这4个标签变体，我们推断出4种主要单倍型，它们占该人群单倍型变异的90%以上。局限性前列腺癌病例和对照之间的单倍型频率存在显著差异，全局P值为0.004，相对于最常见的单倍型，包含P275A和INDEL7变体次要等位基因的单倍型与局限性前列腺癌风险显著降低相关（比值比 = 0.28，95%CI 0.13 - 0.59）。这些结果虽然有限，且主要局限于局限性前列腺癌，但表明MSR1多态性可能在中国男性前列腺癌病因中起作用。MSR1的作用值得在更大规模的研究和其他人群中进一步研究。
