*Pathology and Clinical Laboratories, National Cancer Center Hospital †Molecular Pathology Division, National Cancer Center Research Institute ‡Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
Am J Surg Pathol. 2014 Mar;38(3):370-6. doi: 10.1097/PAS.0000000000000093.
To clarify the significance of GNAS mutations in cervical tumorigenesis, we performed mutational analyses in a total of 154 lesions and in 22 normal tissues of the uterine cervix. Activating GNAS mutations were found in 8 of the 19 lobular endocervical glandular hyperplasias (LEGH; 42%) and 4 of the 79 endocervical-type mucinous adenocarcinomas (5%) but were never seen in the normal endocervical tissue, minimal deviation adenocarcinomas, endometrioid adenocarcinomas, or squamous cell carcinomas. We further examined the presence of human papillomavirus (HPV) DNA and p16 expression to probe the relationship between GNAS mutations and HPV infection in LEGHs and carcinomas. All the GNAS-mutated LEGHs were negative for HPV DNA and p16 expression, whereas all the GNAS-mutated adenocarcinomas were positive for HPV DNA and/or p16 expression, implicating GNAS mutations in the development of LEGH and a minor subset of HPV-related cervical adenocarcinomas. Additional mutational analyses of LEGH identified KRAS and STK11 mutations in 1 and 2 cases, respectively. The GNAS, KRAS, and STK11 mutations were mutually exclusive; thus, a total of 11 LEGHs (58%) had 1 of these genetic alterations. Although LEGH has been regarded as a metaplastic lesion, the frequent presence of genetic alterations suggests a neoplastic nature.
为了阐明 GNAS 突变在宫颈肿瘤发生中的意义，我们对总共 154 个病变和 22 个宫颈正常组织进行了突变分析。在 19 例小叶状宫颈内腺体增生（LEGH；42%）和 79 例宫颈型黏液性腺癌（5%）中的 4 例中发现了激活的 GNAS 突变，但在正常宫颈内组织、微小偏离性腺癌、子宫内膜样腺癌或鳞状细胞癌中从未见过。我们进一步检查了人乳头瘤病毒（HPV）DNA 和 p16 表达的存在，以探讨 LEGH 和腺癌中 GNAS 突变与 HPV 感染之间的关系。所有 GNAS 突变的 LEGH 均为 HPV DNA 和 p16 表达阴性，而所有 GNAS 突变的腺癌均为 HPV DNA 和/或 p16 表达阳性，提示 GNAS 突变参与了 LEGH 和一小部分 HPV 相关的宫颈腺癌的发生。对 LEGH 的进一步突变分析分别在 1 例和 2 例中发现了 KRAS 和 STK11 突变。GNAS、KRAS 和 STK11 突变是相互排斥的；因此，总共 11 例 LEGH（58%）有其中一种遗传改变。尽管 LEGH 被认为是一种化生病变，但频繁存在的遗传改变提示其具有肿瘤性质。
