9p24.2处等位基因缺失的微卫星改变表明结直肠癌转移的侵袭性较低。
Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis.
作者信息
Koi Minoru, Garcia Melissa, Choi Chan, Kim Hyeong-Rok, Koike Junichi, Hemmi Hiromichi, Nagasaka Takeshi, Okugawa Yoshinaga, Toiyama Yuji, Kitajima Takahito, Imaoka Hiroki, Kusunoki Masato, Chen Yin-Hsiu, Mukherjee Bhramar, Boland C Richard, Carethers John M
机构信息
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
出版信息
Gastroenterology. 2016 Apr;150(4):944-55. doi: 10.1053/j.gastro.2015.12.032. Epub 2016 Jan 2.
BACKGROUND & AIMS: Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival.
METHODS
We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L.
RESULTS
LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P = .01).
CONCLUSIONS
E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.
背景与目的
目前对结直肠癌（CRC）患者根治性治疗后导致复发和/或转移的分子事件了解甚少。II期或III期原发性CRC患者，若在选定的四核苷酸重复序列处微卫星改变升高且微卫星不稳定性水平较低（E/L），则治疗后疾病复发的可能性更大。缺氧和/或炎症不仅会促进转移，还会通过导致癌细胞核中MSH3缺乏，诱导选定四核苷酸重复序列处的微卫星改变升高。我们旨在确定与原发性结直肠肿瘤肝转移相关的基因改变，并确定其对生存的影响。
方法
我们从韩国和日本的医院获取了4组原发性结直肠肿瘤及其匹配的肝转移灶。检测了141个位点具有大重复序列的基因内微卫星，以查找可能因MSH3缺乏导致的移码突变和/或杂合性缺失（LOH）。对高度改变的位点进行检测，以确定其与肝转移中E/L的相关性。我们分析了156例II期或III期原发性结直肠肿瘤患者的数据，以确定预后情况以及改变的位点是否与E/L相关。
结果
9号染色体p24.2区域（9p24.2-LOH）多个位点的LOH与肝转移中的E/L相关（比值比=10.5；95%置信区间：2.69-40.80；P=.0007）。我们发现原发性结直肠肿瘤及其匹配的转移灶在E/L频率、9p24.2-LOH、KRAS或BRAF突变，或E/L与9p24.2-LOH的组合方面无显著差异。与无E/L和9p24.2-LOH的患者相比，伴有E/L和9p24.2-LOH的II期或III期结直肠肿瘤患者在CRC复发后的生存率有所提高（风险比=0.25；95%CI：0.12-0.50；P=.0001）。E/L伴9p24.2-LOH似乎是III期CRC患者总生存的独立预后因素（风险比=0.06；95%CI：0.01-0.57；P=.01）。
结论
E/L伴9p24-LOH似乎是III期原发性结直肠肿瘤侵袭性较低转移的生物标志物。
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