Department of Surgery, University of California, San Diego, CA, USA.
J Gastrointest Surg. 2010 Oct;14(10):1521-8. doi: 10.1007/s11605-010-1340-6. Epub 2010 Sep 16.
Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers.
We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration.
Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001).
EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development.
在选定的四核苷酸重复序列中出现的微卫星不稳定性升高（EMAST）是在 60%的散发性结肠癌中发现的遗传特征，可能与 DNA 错配修复（MMR）蛋白 hMSH3 的异质性表达有关。与微卫星不稳定高（MSI-H）不同，后者 hMLH1 的甲基化先发生，然后是多个易感基因突变，EMAST 可能与炎症有关，随后 MMR 功能放松，其生物学后果尚不清楚。我们在直肠腺癌的基于人群的队列中评估了 EMAST 和 MSI 的患病率，因为之前尚未在直肠腺癌中确定 EMAST。
我们使用五个四核苷酸微卫星标记物和国家癌症研究所推荐的 MSI（单核苷酸和二核苷酸）标记物分析了 147 例散发性直肠腺癌病例。如果在比较同一患者的正常和癌症样本时发现至少两个位点存在移码重复，则认为 EMAST 和 MSI 测定为阳性。我们将 EMAST 数据与种族、性别和肿瘤分期相关联，并检查了淋巴细胞浸润的样本。
在这组直肠腺癌患者中（平均年龄 62.2±10.3 岁，36%为女性，24%为非裔美国人），3/147（2%）显示 MSI（3 名男性，2 名非裔美国人），49/147（33%）显示 EMAST。非裔美国人的直肠肿瘤比高加索人更有可能出现 EMAST（18/37，49% vs. 27/104，26%，p=0.014），并且与晚期疾病相关（18/29，62% EMAST vs. 18/53，非 EMAST 37%，p=0.02）。EMAST 与性别无关。与无肿瘤周围浸润的直肠肿瘤相比，有肿瘤周围浸润的直肠肿瘤中 EMAST 更为常见（30/49，60% EMAST vs. 24/98，25%非 EMAST，p=0.0001）。
直肠腺癌中 EMAST 很常见，MSI 很少见。EMAST 与非裔美国人有关，可能更常见于转移性疾病。EMAST 的病因和后果正在研究中，但它与免疫细胞浸润的关联表明炎症可能在其发展中起作用。
