Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.M.) Department of Pathology (F.D., L.M.S., E.G., N.L.) Department of Pathology, Division of Women's and Perinatal Pathology (J.M., C.P.C., M.R.N., B.E.H.), Brigham and Women's Hospital Dana-Farber Cancer Institute (E.G., L.M.), Boston, Massachusetts Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK (W.G.M.) Department of Pathology, Stanford University School of Medicine, Stanford, California (B.E.H.).
Int J Gynecol Pathol. 2019 Nov;38(6):543-551. doi: 10.1097/PGP.0000000000000545.
Female adnexal tumor of probable Wolffian origin (FATWO) is a rare gynecologic neoplasm of low-malignant potential presumed to be derived from mesonephric remnants in the upper female genital tract. Similarly, mesonephric remnants in the lower female genital tract are thought to be the origin for mesonephric carcinoma. Although the molecular alterations in mesonephric carcinoma have been recently reported, the pathogenesis of and molecular alterations in FATWO are not well understood. The aims of this study were to examine the molecular alterations in FATWO and to establish whether these neoplasms are molecularly similar to mesonephric carcinoma. Eight FATWOs underwent massively parallel sequencing to detect single nucleotide variations, copy number variations, and structural variants by surveying exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes. Good quality DNA was isolated from 7 of 8 cases. Novel KMT2D variants (1 frameshift, 3 missense) were identified in 4 of 7 cases (57%), but were variants of uncertain biologic significance. STK11 mutations (both frameshift) were identified in 2 of 7 cases (29%); one of these was in a patient with a known history of Peutz-Jeghers syndrome. A mutation in the chromatin remodeling gene ARID1B was identified in 1 of 7 cases (14%). No cases harbored KRAS, NRAS, TP53, PIK3CA, PTEN, or DICER1 mutations. There were relatively low numbers of copy number variations, and no recurrent copy number variations were identified. One case demonstrated moderate copy gain of CCND1. No structural variants were identified. In summary, FATWO is characterized molecularly by the absence of KRAS/NRAS mutations (characteristic of mesonephric carcinoma), absence of DICER1 mutations (characteristic of Sertoli-Leydig cell tumor) and frequent KMT2D mutations of unknown biologic significance. FATWOs exhibit a limited number of molecular aberrations that are significantly different from those reported in tumors in the differential diagnosis, and our results question the relationship of mesonephric carcinoma with FATWO. Disease-defining molecular alterations for FATWO have yet to be discovered.
女性附件的可能沃夫氏来源的肿瘤（FATWO）是一种罕见的妇科低度恶性肿瘤，据推测来源于女性上生殖道的中肾残迹。同样，女性下生殖道的中肾残迹被认为是中肾管癌的起源。尽管中肾管癌的分子改变最近已经被报道，但 FATWO 的发病机制和分子改变还没有被很好地理解。本研究的目的是研究 FATWO 的分子改变，并确定这些肿瘤在分子上是否与中肾管癌相似。8 例 FATWO 进行了大规模平行测序，通过检测 300 个癌症基因和 35 个基因的 113 个内含子的外显子 DNA 序列，检测单核苷酸变异、拷贝数变异和结构变异。7 例中有 6 例成功提取到了高质量的 DNA。在 7 例中有 4 例（57%）检测到 KMT2D 新的变异（1 个移码，3 个错义），但这些变异的生物学意义尚不确定。STK11 突变（均为移码）在 7 例中有 2 例（29%），其中 1 例发生在已知有 Peutz-Jeghers 综合征病史的患者中。在 7 例中有 1 例（14%）检测到染色质重塑基因 ARID1B 的突变。没有病例存在 KRAS、NRAS、TP53、PIK3CA、PTEN 或 DICER1 突变。拷贝数变异数量相对较少，也没有发现重复的拷贝数变异。1 例病例表现为 CCND1 的中度拷贝数增益。没有结构变异。总之，FATWO 的分子特征是缺乏 KRAS/NRAS 突变（中肾管癌的特征）、缺乏 DICER1 突变（Sertoli-Leydig 细胞瘤的特征）和频繁出现意义不明的 KMT2D 突变。FATWO 表现出有限数量的分子异常，与鉴别诊断中的肿瘤报告的分子异常显著不同，我们的结果对中肾管癌与 FATWO 的关系提出了质疑。FATWO 的疾病定义性分子改变尚未被发现。
