Luo Liping, Shen Gong-Qing, Stiffler Karen A, Wang Qing K, Pretlow Thomas G, Pretlow Theresa P
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Carcinogenesis. 2006 Jun;27(6):1153-9. doi: 10.1093/carcin/bgi354. Epub 2006 Feb 12.
Aberrant crypt foci (ACF), the earliest neoplastic lesions of the colon, have genetic and epigenetic alterations. Loss of heterozygosity (LOH) of tumor suppressor gene loci is seen in most colon cancers, but it is not known how early in tumorigenesis this takes place. Nine microsatellite markers close to specific genes, that is, APC (5q21), PTPRJ (11p11), p53 (17p13) and DCC (18q21), were analyzed in 32 ACF and samples of normal crypts from the same 28 patients. Six losses of heterozygosity were found in 5 of 32 ACF: 4 losses of heterozygosity were at 11p11, the location of the gene for protein tyrosine phosphatase receptor type J (PTPRJ) and of a second independent region of deletion; the others were at 5q21 and 18q21. Microsatellite instability (MSI) with markers for a single locus was found in 4 of 32 ACF. All the observed allelic alterations (LOH and MSI) were in 8 of 32 ACF. The finding of LOH in ACF with normal expressions of adenomatous polyposis coli (APC) and beta-catenin proteins suggests that LOH can occur very early in colon neoplasia and perhaps even before APC mutations. The finding of 3 of 4 of the losses of heterozygosity at 11p11 for PTPRJ and half of all the losses of heterozygosity in this study at PTPRJ suggest that this gene plays a role early in colon neoplasia.
异常隐窝灶（ACF）是结肠最早的肿瘤性病变，具有基因和表观遗传改变。大多数结肠癌中可见肿瘤抑制基因位点的杂合性缺失（LOH），但尚不清楚这种情况在肿瘤发生的早期阶段何时发生。对来自28名患者的32个ACF和正常隐窝样本分析了9个靠近特定基因的微卫星标记，即APC（5q21）、PTPRJ（11p11）、p53（17p13）和DCC（18q21）。在32个ACF中的5个中发现了6处杂合性缺失：4处杂合性缺失位于11p11，即蛋白酪氨酸磷酸酶受体J型（PTPRJ）基因的位置以及第二个独立的缺失区域；其他的分别位于5q21和18q21。在32个ACF中的4个中发现了单个位点标记的微卫星不稳定性（MSI）。所有观察到的等位基因改变（LOH和MSI）均出现在32个ACF中的8个中。在腺瘤性息肉病大肠杆菌（APC）和β-连环蛋白蛋白表达正常的ACF中发现LOH，这表明LOH可能在结肠肿瘤形成的早期甚至在APC突变之前就已发生。在本研究中，PTPRJ的11p11处4处杂合性缺失中的3处以及所有杂合性缺失的一半出现在PTPRJ，这一发现表明该基因在结肠肿瘤形成的早期起作用。
