Supplementary Material for: CLEAR CELL CARCINOMA ARISING IN LOW-GRADE MULLERIAN ADENOSARCOMA: FIRST REPORTED CASE WITH INSIGHT INTO MOLECULAR PROFILE

Uterine adenosarcoma is a rare biphasic neoplasm composed of a malignant, usually low-grade stromal component and benign epithelial component, usually endometrioid. Pathogenesis is unknown; some cases are undoubtably associated with tamoxifen use. Endometrial clear cell carcinoma (CCC) is an aggressive subtype of endometrial cancer, accounting for less than 10% of all uterine carcinomas. The etiology is unknown but can rarely be associated with Lynch syndrome and tamoxifen administration. The development of a composite neoplasm consisting of adenocarcinoma in adenosarcoma is extremely rare. Endometrioid carcinoma typically represents the epithelial component of the composite tumor. Here we present the very first case of composite tumor, namely adenosarcoma with clear cell carcinoma in which next-generation sequencing was performed. Patient was an 85-years-old woman treated with tamoxifen for five years. To better understand the pathobiology of two tumors, a targeted genomic analysis of both components was performed. We found seven identical somatic variants in the samples of both tumors, indicating that the tumors have a high probability of having the same origin. Dual amplification of CDK4 and MDM2 was the most likely primary cause of tumor formation, but also one driver variant in the DHX15 gene that was present in both tumor components, suggesting that DHX15 may play an important role in the initiation and development of sarcoma and carcinoma. The patient is followed by regular clinical controls and is alive without signs of disease recurrence 18 months after surgery.

子宫腺肉瘤（uterine adenosarcoma）是一种罕见的双相性肿瘤，由恶性（通常为低级别）间质成分与良性上皮成分组成，后者多为子宫内膜样表型。其发病机制尚不明确，部分病例明确与他莫昔芬（tamoxifen）使用相关。子宫内膜透明细胞癌（endometrial clear cell carcinoma, CCC）是一种侵袭性子宫内膜癌亚型，占所有子宫癌的比例不足10%。其病因尚未明确，但极少数病例可与林奇综合征（Lynch syndrome）及他莫昔芬用药相关。腺肉瘤合并腺癌的复合性肿瘤极为罕见，其中子宫内膜样腺癌通常作为复合性肿瘤的上皮成分。本文报告首例腺肉瘤合并透明细胞癌的复合性肿瘤病例，并对其实施了下一代测序（next-generation sequencing）检测。患者为一名85岁女性，有5年他莫昔芬用药史。为进一步明确这两种肿瘤的病理生物学特性，我们对两种肿瘤成分均进行了靶向基因组分析。结果在两种肿瘤的样本中发现7个完全一致的体细胞变异，提示二者极有可能具有共同起源。CDK4与MDM2的双重扩增极可能是肿瘤发生的主要诱因，同时两种肿瘤成分均携带DHX15基因的驱动变异，提示DHX15可能在肉瘤与癌的发生发展中发挥重要作用。患者术后接受定期临床随访，术后18个月时仍存活，无疾病复发迹象。