Summary The fundamental morphology of the endometrial glands is not sufficiently understood by 2D observation because these glands have complicated winding and branching patterns. To construct a large picture of the endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and layer analyses revealed that the endometrial glands form a plexus network in the stratum basalis and expand horizontally along the muscular layer, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of tissue affected by adenomyosis, a representative “endometrium-related disease,” and observed its 3D morphological features, including the direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, further understanding of the morphology of the human endometrium based on 3D analysis will lead to the identification of the pathogenesis of endometrium-related diseases.
We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.
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 in ARID1A, ATM, CDH4, NRAS and PIK3CA were 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 of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, 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.
Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.
Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.
It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that “rhizome structures”, in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.
Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as “endometriosis-associated ovarian cancer” (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.
ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-offunction mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations. The AT-rich interaction domain 1A (ARID1A) gene is located on chromosome 1p36.11 and encodes ARID1A, a key component of the SWI/SNF complex 1. The SWI/SNF complex plays an important role in chromatin remodeling and is associated with numerous biological functions, such as differentiation and proliferation 2. Therefore, aberrations in the SWI/SNF complex subunits have the potential to cause cancer. In particular, ARID1A, which is well known as a tumor suppressor gene, is frequently mutated in a wide variety of cancers 3,4. COSMIC data demonstrated that more than half of ARID1A mutations are loss-of-function mutations, including frameshift indels mutations, and nonsense mutations, that lead to a loss of ARID1A protein expression in cancer cells 5. ARID1A mutation is considered one of the most important driver events in endometriosis-associated ovarian cancer 6-8. According to previous studies, including ours 6,7,9-13 , 46-70% of clear cell carcinomas and 30-46% of endometrioid carcinomas harbor ARID1A mutations, and immunohistochemical analysis has demonstrated that ARID1A loss-of-function mutations are strongly correlated with the loss of ARID1A protein expression in
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