A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum.
A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum.
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DOI：
10.1677/erc-10-0248
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发表时间：
2011-02
影响因子：
3.9
通讯作者：
Hoh J
中科院分区：
文献类型：
--
作者：
Walsh KM;Choi M;Oberg K;Kulke MH;Yao JC;Wu C;Jurkiewicz M;Hsu LI;Hooshmand SM;Hassan M;Janson ET;Cunningham JL;Vosburgh E;Sackler RS;Lifton RP;Dewan AT;Hoh J
中肠类癌的遗传学研究主要集中在肿瘤细胞的基因组变化上。我们研究了体质遗传多态性在回肠类癌易感个体中的作用。从乌普萨拉大学医院、丹娜-法伯癌症研究所和MD安德森癌症中心这三个机构共收集了239例病例和110例对照，并使用微阵列分析了>300 000个单核苷酸多态性进行基因分型。在Bonferroni校正水平（<1.62×10−7）下，KIF 16 B中与rs 2208059的关联接近统计学显著性（Mantel-Haenszel比值比=2.42，P=4.16×10 − 7）。使用两种计算算法，在多个病例中鉴定出四种拷贝数变异（CNVs），这些变异在研究对照中不存在，在~1500个基于人群的对照中明显不常见。在这四个在血液来源的DNA中鉴定的CNV中，Chr 18 q22.1中的40 kb杂合性缺失对应于基于我们对先前发表的细胞遗传学研究的荟萃分析的回肠类癌细胞中经常显示杂合性缺失（洛）的区域（69.7%洛，95%置信区间=60.0-77.9%）。我们用实时定量PCR分析了我们研究样本中chr 18上的组成性40 kb缺失; 14/226例（6.19%）和2/97例对照（2.06%）携带CNV，尽管每个缺失的确切边界尚未确定。由于样本量小，我们的研究结果保证了一个独立的队列进行复制研究。由于这种疾病的罕见性，我们相信这些结果将为未来对这种严重疾病的研究提供宝贵的资源，使其他人能够在有针对性的研究中有效地利用他们的样本。
Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10−7) at a Bonferroni-corrected level (<1.62×10−7). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ~1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0–77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.