Zauber Peter, Denehy Thad R, Taylor Robert R, Ongcapin Emelie H, Marotta Stephen, Sabbath-Solitare Marlene
Departments of *Medicine, †Obstetrics and Gynecology, and ‡Pathology, Saint Barnabas Medical Center, Livingston, NJ.
Int J Gynecol Cancer. 2015 Jun;25(5):863-8. doi: 10.1097/IGC.0000000000000421.
Endometrial cancer (EC) results from the accumulation of numerous genetic abnormalities contributing to the progression from hyperplasia to EC. Information on these various genetic changes has been primarily derived from studying groups of either hyperplasias or cancers.We evaluated both hyperplastic and EC tissue obtained from the same surgical specimens for KRAS mutations, microsatellite instability (MSI), and mismatch repair gene methylation, and results were correlated between the paired hyperplastic tissue and EC. The aim was to determine if molecular alterations appearing in ECs might also be present in the premalignant (hyperplastic) region of the tumor.
One hundred ninety-seven cases of EC with associated hyperplasia were evaluated. DNA samples were studied using primer sets for KRAS gene codons 12/13 and for MSI utilizing the Bethesda panel. Methylation testing was performed on specimens that were microsatellite unstable using the MRC Holland SALSA MS-MLPA methylation-specific DNA detection kit.
Forty-one (20.8%) of 197 cancers demonstrated a KRAS mutation, with 35 (85.4%) of 41 accompanying hyperplasias also containing a KRAS mutation. Forty-five cancers (22.8%) were microsatellite unstable, with 38 (84.4%) of 45 accompanying hyperplasias also demonstrating instability. Of the 45 microsatellite unstable cancers, 28 (62.2%) demonstrated methylation in both the cancer and the accompanying hyperplasia, whereas 9 pairs (20%) showed no methylation for either the cancer or hyperplasia.
Approximately 95% of endometrial specimens demonstrated identical molecular findings regarding KRAS mutation and microsatellite stability in the paired cancer and hyperplastic tissue. The same methylation pattern was found in 82.2% of the studied paired samples. Our findings strongly suggest that the molecular changes of KRAS mutation, MSI, and methylation occur early in the neoplastic process. We propose that endometrial biopsies revealing only hyperplasia should be studied for these molecular alterations as an indicator of possible early carcinogenesis.
子宫内膜癌（EC）是由众多遗传异常累积导致的，这些异常促使其从增生发展为EC。关于这些各种遗传变化的信息主要来自对增生组织或癌症组织群体的研究。我们评估了从同一手术标本中获取的增生组织和EC组织的KRAS突变、微卫星不稳定性（MSI）及错配修复基因甲基化情况，并将配对的增生组织和EC的结果进行关联分析。目的是确定出现在EC中的分子改变是否也可能存在于肿瘤的癌前（增生）区域。
对197例伴有增生的EC病例进行评估。使用针对KRAS基因密码子12/13的引物组以及利用贝塞斯达检测板对DNA样本进行MSI研究。对微卫星不稳定的标本使用MRC Holland SALSA MS-MLPA甲基化特异性DNA检测试剂盒进行甲基化检测。
197例癌症中有41例（20.8%）显示KRAS突变，41例中有伴有增生的35例（85.4%）也含有KRAS突变。45例癌症（22.8%）微卫星不稳定，45例中有伴有增生的38例（84.4%）也显示不稳定。在45例微卫星不稳定的癌症中，28例（62.2%）在癌症和伴有增生的组织中均显示甲基化，而9对（20%）在癌症或增生组织中均未显示甲基化。
大约95%的子宫内膜标本在配对的癌症组织和增生组织中显示出关于KRAS突变和微卫星稳定性的相同分子结果。在82.2%的研究配对样本中发现了相同的甲基化模式。我们的研究结果强烈表明KRAS突变、MSI和甲基化的分子变化在肿瘤形成过程中早期就会发生。我们建议对仅显示增生的子宫内膜活检组织进行这些分子改变的研究，作为可能早期致癌的指标。
