Yang P, Cunningham J M, Halling K C, Lesnick T G, Burgart L J, Wiegert E M, Christensen E R, Lindor N M, Katzmann J A, Thibodeau S N
Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Department of Medical Genetics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.
Mol Genet Metab. 2000 Dec;71(4):639-45. doi: 10.1006/mgme.2000.3089.
Microsatellite instability (MSI) is a genomic alteration observed in 15-30% of colorectal cancer (CRC). Two MSI phenotypes have been defined for CRC: MSI-H is characterized by MSI at > or =30% of the examined loci and MSI-L by MSI at 1-30% of the loci. An absence of MSI at any examined loci has been defined as a microsatellite stable (MSS) phenotype. Current data suggest the majority of MSI tumors are the result of defective DNA mismatch repair (MMR). In this study, we have determined the alpha(1)-antitrypsin deficiency carrier (alpha(1)ATD-ht) status of 161 CRC patients whose MSI phenotype and protein expression states had previously been determined. Cases were selected to enrich a larger number of MSI-H cases. Among 51 CRC patients with MSI-H tumors, the alpha(1)ATD-ht rate was 21.6%; among 110 patients with MSI-L/MSS tumors, the rate was 9.1% (MSI-H vs MSI-L/MSS, P = 0.02); and among the 191 population-based controls the alpha(1)ATD-ht rate was 9.4% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among alpha(1)ATD-ht was 3.1 after adjusting for age, gender, and smoking history. The risk of having MSI-H CRC among current and past smokers was 6.6 and 2.7, respectively. Patients who were alpha(1)ATD-ht and smoked had a 20-fold increased risk of developing an MSI-H CRC compared to nonsmokers who were homozygous normal at the alpha(1)ATD locus. Our findings suggest an etiologic link between alpha(1)ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and alpha(1)ATD allele in the development of MSI-H CRC.
微卫星不稳定性（MSI）是在15%至30%的结直肠癌（CRC）中观察到的一种基因组改变。已为CRC定义了两种MSI表型：MSI-H的特征是在所检测位点的≥30%处存在MSI，MSI-L的特征是在1%至30%的位点存在MSI。在任何检测位点均不存在MSI被定义为微卫星稳定（MSS）表型。目前的数据表明，大多数MSI肿瘤是DNA错配修复（MMR）缺陷的结果。在本研究中，我们确定了161例CRC患者的α1抗胰蛋白酶缺陷携带者（α1ATD-ht）状态，这些患者的MSI表型和蛋白表达状态此前已被确定。病例选择旨在富集更多的MSI-H病例。在51例患有MSI-H肿瘤的CRC患者中，α1ATD-ht率为21.6%；在110例患有MSI-L/MSS肿瘤的患者中，该率为9.1%（MSI-H与MSI-L/MSS相比，P = 0.02）；在191例基于人群的对照中，α1ATD-ht率为9.4%（MSI-H与对照相比，P = 0.02）。在调整年龄、性别和吸烟史后，α1ATD-ht人群中患MSI-H CRC的估计相对风险为3.1。目前吸烟者和既往吸烟者患MSI-H CRC的风险分别为6.6和2.7。与α1ATD位点纯合正常的非吸烟者相比，α1ATD-ht且吸烟的患者发生MSI-H CRC的风险增加了20倍。我们的研究结果表明α1ATD等位基因与MMR缺陷的CRC发生之间存在病因学联系，以及吸烟与α1ATD等位基因在MSI-H CRC发生中存在协同作用。
