Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis
Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis
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DOI：
10.1111/cas.14507
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发表时间：
2020-06-26
期刊：
影响因子：
5.7
通讯作者：
Enomoto, Takayuki
中科院分区：
文献类型：
--
作者：
Suda, Kazuaki;Diaz, Luis Antonio Cruz;Enomoto, Takayuki
卵巢透明细胞癌被认为是由子宫内膜异位症引起的。此外，脱落子宫内膜的逆行性月经被认为是子宫内膜异位症的起源。然而，很少有证据支持细胞连续性从子宫内膜透明细胞癌通过子宫内膜异位症在基因组水平。在这里，我们进行了多区域全外显子组测序，以澄清子宫内膜，卵巢子宫内膜异位症和卵巢透明细胞癌之间的克隆关系，在一个56岁的病人。在子宫内膜、癌旁和远处的子宫内膜样病变以及癌组织中，存在许多共同的体细胞突变，包括ARID1A、ATM、CDH4、NRA和PIK3CA等癌相关基因突变。从子宫内膜到远处子宫内膜异位症、邻近子宫内膜异位症和子宫内膜癌，共有突变的突变等位基因频率增加。虽然ARID1A的剪接位点突变在四个上皮样本中是共享的，但ARID1A的移码插入在相邻的子宫内膜异位症和癌样本中是共享的，这表明双等位基因突变引发了恶性转化。体细胞拷贝数的改变，包括PIK3CA和ATM的杂合性丢失事件，仅在相邻的子宫内膜异位症和癌中发现，这表明突变等位基因特异性失衡是另一个驱动恶性转化的关键因素。通过重建克隆进化树的基础上的体细胞突变，我们表明，上皮样品来自一个单一的祖先克隆。虽然该研究仅限于单个患者，但该说明性病例的结果可能提示卵巢子宫内膜异位症和透明细胞癌的上皮细胞是子宫内膜上皮细胞的后代。
Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole-exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56-year-old patient. Many somatic mutations including cancer-associated gene mutations inARID1A,ATM,CDH4,NRASandPIK3CAwere shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation ofARID1Awas shared among the four epithelium samples, a frameshift insertion inARID1Awas shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events atPIK3CAandATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele-specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.