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Copy number alteration in chromosome 1, 2, 8, and 9 DNA copy number changes are represented as pseudo-color gradients corresponding to the copy number increase (red boxes) and decrease (blue boxes) as compared to pooled normal samples. LOHs are represented as pseudo-color with LOH in blue and non-LOH in yellow. Star indicates tumor with DNA copy number tracing plotted at the left panel. Candidate tumor suppressor genes residing within the deleted or LOH regions are indicated by arrows.
Source publication
Advanced ovarian clear cell carcinoma (CCC) is one of the most aggressive ovarian malignancies, in part because it tends to be resistant to platinum-based chemotherapy. At present, little is known about the molecular genetic alterations in CCCs except that there are frequent activating mutations in PIK3CA. The purpose of this study is to comprehens...
Contexts in source publication
Context 1
... addition to amplification in the chr20q13.2 locus, low levels of chromosomal gain encompassing large chromosomal regions were observed in chr8q (Fig. 3) as well as chr17q (Fig. 4 and Fig. S1). However, these regions are relatively large and containing numerous genes that preclude the identification of a candidate driver oncogene(s) at this ...
Context 2
... the advantages of high density SNP array is its exquisitely sensitive resolution which allows for the detection of discrete sub-chromosomal deletion. By using affinity-purified tumor cells, we were able to detect discrete homozygous deletions that have not been previously described. These include deletions at chr2q12.1, chr8p21.3, and chr9p21.3 (Fig. 3), each of which was identified in one of the 12 fresh samples analyzed. One additional case with copy neutral LOH was identified in the chr2q12.1 and chr9p21.3 respectively, but not in the chr8p21.3 locus. The deletion at chr2q12.1 encompasses 104,649,000 to 109,476,000 bp and harbors at least 25 known genes. There is no known tumor ...
Context 3
... were no subchromosomal deletions observed in chr1; however, we found 2 cases harboring copy neutral LOH at chr1p36.22 (Fig. 3). Our previous report has demonstrated frequent hemizygous deletions and LOH in this region in low-grade ovarian serous tumors ...
Context 4
... in CCCs. OVMANA, a CCC cell line that harbored ZNF217 amplification and over-expression, and OV207, a CCC line with ZNF217 overexpression were selected for functional studies (Fig 5). The relative ZNF217 mRNA levels decrease to 45% in OVMANA and 35% in OV207 as compared to control (luciferase) siRNA after treatment of both ZNF217 siRNAs (Fig. S3), and significantly suppressed cell growth in both CCC cell lines (Fig. 5A&B). We then used OV207 as a representative cell line to determine if the reduced cell number is due to a decrease in cellular proliferation and/or an increase in apoptosis. We found that ZNF217 siRNA treatment resulted in a significantly higher caspase 3/7 ...
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Citations
... The scarce information about genome-wide patterns of aberrations in OCCCs was obtained from studies focusing on individual cohorts with different geographical and ethnic origins [20][21][22][23][24]. Remarkably, two of the most frequent copy number (CN) alterations found in OCCCs, i.e., amplification of chromosomes 8q and 20q13.2 ...
Background
Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries.
Methods
Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations.
Results
The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes.
Conclusions
Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.
... In addition to MET, AKT2, and ZNF217, which are listed above, it was reported that amplification of chromosome 8 (8p11.21-q11.23 and 8q22.1-q24.13) was detected in 52% of OCCCs (Uehara et al., 2015), as well as copy number loss (loss of heterozygosity or homozygous deletion) at the loci of CDKN2A/2B (Cyclin-Dependent Kinase Inhibitor 2A/2B) (9p21.3) in 17% of OCCCs (Kuo et al., 2010). Other CNVs identified include amplification of chromosome 8q (64%), 17q (46%) and 20q (54%), and deletion of 9q (21%), 13q (28%), 18q (21%), and 19p (41%) by WES (Murakami et al., 2017). ...
Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer with unique molecular characteristics, specific biological and clinical behavior, poor prognosis and high resistance to chemotherapy. Pushed by the development of genome-wide technologies, our knowledge about the molecular features of OCCC has been considerably advanced. Numerous studies are emerging as groundbreaking, and many of them are promising treatment strategies. In this article, we reviewed studies about the genomics and epigenetics of OCCC, including gene mutation, copy number variations, DNA methylation and histone modifications.
... Expression of ZNF217: battles within transcriptional or post-transcriptional layer ZNF217 aberrant gene amplification, located in chromosome 20q13.2 region, was frequently detected in various precancerous lesions and cancers, including breast [6][7][8][9][10][11][12], ovarian [13][14][15][16], gastric [17,18], prostate [19], esophagus [18,20], pancreatic [21], and colorectal carcinomas [22][23][24][25], glioblastoma [26,27], hepatoma [28], lung cancer [29], lymphoma [30], Barrett's esophagus [31][32][33], head and neck squamous cell carcinoma [34] and melanoma [35]. ZNF217 aberrant gene amplification and mRNA levels are associated with high cancer risk and poor therapeutic sensitivity [36][37][38][39][40][41][42][43]. ...
The aberrant expression of the zinc finger protein 217 (ZNF217) promotes multiple malignant phenotypes, such as replicative immortality, maintenance of proliferation, malignant heterogeneity, metastasis, and cell death resistance, via diverse mechanisms, including transcriptional activation, mRNA N6-methyladenosine (m6A) regulation, and protein interactions. The induction of these cellular processes by ZNF217 leads to therapeutic resistance and patients' poor outcomes. However, few ZNF217 related clinical applications or trials, have been reported. Moreover, looming observations about ZNF217 roles in m6A regulation and cancer immune response triggered significant attention while lacking critical evidence. Thus, in this review, we revisit the literature about ZNF217 and emphasize its importance as a prognostic biomarker for early prevention and as a therapeutic target.
... including the ZNF217 (Zinc finger protein 217) locus, is frequently amplified in~36% of CCC cases [50]. Amplifications of the MET (chr7q31) and AKT2 (chr19q13.2) oncogenes have been identified in 31% and 24% of ovarian CCC, respectively, and deletions of the CDKN2A/2B (cyclin-dependent kinase inhibitor 2A/2B) tumor suppressor genes have been detected in 17% of cases [50][51][52]. We confirmed the protein levels of activated signals in ovarian CCC. ...
Simple Summary
Ovarian clear cell carcinoma (CCC) exhibits unique characteristics, including slow growth, glycogen accumulation in the cytoplasm, and poor prognosis for stress resistance. Several molecular targeting agents have failed to treat ovarian CCC. Recent reports have identified metabolic alterations through HNF1B, which is highly expressed in ovarian CCC. The Warburg effect, GSH synthesis, and mitochondrial regulation occur in CCC. The metabolic behaviors of ovarian CCC resemble the evolution of life to survive in stressful environments. Understanding the fundamental biology of ovarian CCC might help in the development of novel therapeutic strategies.
Abstract
Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments.
... Copy number alterations are also important genomic events related to cancer [37]. It has been reported that the frequency of copy number alterations is much lower in CCC than in HGSC [38] and that the ratio of whole-arm copy number alterations is significantly higher in CCC [39]. Amplification of chromosome 8 is detected in 52% of CCCs [39], especially ZNF217 copy number gain in CCCs, which is also frequently detected (in 20-36%) of CCCs [39][40][41]. ...
... Furthermore, MET (chr7q31) (31%) and AKT2 (chr19q13.2) (24%) are amplified in 31% and 24% of CCCs, respectively [42]. Copy number loss at CDKN2A/2B (9p21.3) is also often found [38]. Although these copy number alterations are potential molecular targets, a new treatment strategy based on copy number alterations has not been developed for CCC [43]. ...
Simple Summary
Driver gene mutations have been identified in not only various types of endometriosis which are considered the origin of endometriosis-associated ovarian cancer but also the normal endometrium which is considered the origin of endometriosis. We focused on genomic linkage from normal endometrium to ovarian endometriosis and endometriosis-associated ovarian cancer (EAOC) and summarized the current knowledge of the commonality and differentiation of genomic features in the uterine endometrium, endometriosis, and EAOC. In addition, we have proposed molecular mechanism of ovarian carcinogenesis from the normal endometrium via endometriosis based on genomic alterations. This review is expected to contribute to research for the prevention of endometriosis and EAOC.
Abstract
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.
... Currently, copy number variants (CNV) of CCC were revealed, which included deletion of cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) 20) , amplifications of zinc finger protein 217 (ZNF217) 20) , protein phosphatase, Mg 2+ / Mn 2+ dependent 1D (PPM1D) 21) , AKT Serine/Threonine kinase 2 (AKT2) 22) , and MET Proto-Oncogene, Receptor Tyrosine Kinase (MET) 22) . In our cell line, amplification of the 17q23.2 ...
... Currently, copy number variants (CNV) of CCC were revealed, which included deletion of cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) 20) , amplifications of zinc finger protein 217 (ZNF217) 20) , protein phosphatase, Mg 2+ / Mn 2+ dependent 1D (PPM1D) 21) , AKT Serine/Threonine kinase 2 (AKT2) 22) , and MET Proto-Oncogene, Receptor Tyrosine Kinase (MET) 22) . In our cell line, amplification of the 17q23.2 ...
Clear cell carcinoma (CCC) is a rare subtype of ovarian cancer resistant to standard platinum chemotherapy, which leads to a poor prognosis for patients with CCC. Kinases are targets for anticancer drugs; few studies have profiled kinase activity to identify kinase inhibitors as novel anticancer drugs. In this study, we aimed to identify novel anticancer drugs for the treatment of CCC with comprehensive kinase activity assay and drug screening. Using ascites from a 51-year old patient, we established and characterized the NCC-cOV1-C1 cell line. We screened the antiproliferative effects of 152 small anticancer compounds and conducted comprehensive kinase activity assays with the PamStation12 platform. The NCC-cOV1-C1 cells harbor copy number variation of HFN1β amplification, and exhibit constant growth, spheroid formation, and invasion capability. NCC-cOV1-C1 cells responded remarkably to idarubicin HCl and vorinostat. The kinase activity assay revealed that SRC and EGFR were highly activated in NCC-cOV1-C1 cells; the SRC inhibitor dasatinib and the EGFR inhibitor lapatinib exhibited antiproliferative effects and down-regulation of downstream signaling. The NCC-cOV1-C1 cell line will be a useful tool for basic and preclinical study of CCC, and the clinical utility of idarubicin HCl, vorinostat, dasatinib, lapatinib is worthy of further investigation.
... Previous studies have highlighted that EOC subtypes differ with respect to genomic stability: HGSC exhibit a high level of genomic instability due to mutated DNA repair pathways which results in a large proportion of their genome undergoing copy number variation, whereas the OCCC and endometrioid subtypes are generally much more stable and show far less copy number alteration [43,58]. We assessed the level of genomic variation in eleven OCCC cell lines and found that they exhibited a wide-range of copy number variation (ranging from 0.88% to 73.5%, (Supplementary Table S2) with three cell lines (KOC-7c, TOV-21G, and 105C) possessing remarkably unaltered genomes (0.88%, 7.46%, 8.12% of genome altered, respectively)) which puts them into the CIN-low arm of OCCC defined by Uehara and co-workers [59]. ...
Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.
... Another study showed there is an association between the selected DDR defects (mainly including ARID1A) and a high TMB in more than 20 % of 17,486 tumor samples [43]. Moreover, some studies found that cancers with high ARID1A deficiency rates typically lack copy number alterations (CNAs) [17,45]. CNAs are positively associated with high TMB, and the increased in somatic CNAs has been identified as immunosuppressive factor, and are associated with adverse response to ICB treatment [46]. ...
The AT-rich interaction domain 1A (ARID1A) are frequently mutates across a broad spectrum of cancers. The majority of ARID1A mutations are inactivating mutations and lead to loss expression of the ARID1A protein. To date, clinical applicable targeted cancer therapy based on ARID1A mutational status has not been described. With increasing number of studies reported that the ARID1A deficiency may be a novel predictive biomarker for immune checkpoint blockade (ICB) treatment. ARID1A deficiency would compromise mismatch repair pathway and increase the number of tumor-infiltrating lymphocytes, tumor mutation burden and expression of programmed cell death ligand 1 (PD-L1) in some cancers, which would suggested cooperate with ICB treatment. In this review, we summarize the relationship between ARID1A deficiency and ICB treatment including potential mechanisms, potential therapeutic combination, and the biomarker value of ARID1A deficiency.
... Moreover, in another study, APOBEC3B overexpression was shown to associate with improved clinical outcome in clear cell carcinoma and to have a potential role in predicting response to platinumbased chemotherapy. 64 Copy-Number Alterations The total number of copy-number alterations in clear cell carcinoma is similar to that in low-grade serous carcinoma, 65 and much lower than in high-grade serous carcinoma. 65 66 Conversely, the ratio of whole-arm copy-number alterations in clear cell carcinoma was significantly higher than in serous carcinoma. ...
... which includes a potential oncogene, zinc finger protein 217 (ZNF217), at a frequency of 20%-36%. 65 68 69 ZNF217 was amplified significantly more frequently in Japanese (62%) than in Korean (7%) or German (25%) clear cell carcinoma, 67 and high-level amplification of ZNF217 was identified in C-APOBEC (33%) and C-AGE (57%) tumors. 43 Moreover, ZNF217 amplification in clear cell carcinoma correlated significantly with shorter progression-free survival (HR 2.6, 95% CI 1.1 to 6.1, p=0.339) and overall survival (HR 3.5, 95% CI 1.1 to 10.6, p=0.031). ...
Clear cell carcinoma of the ovary has distinct biology and clinical behavior. There are significant geographical and racial differences in the incidence of clear cell carcinoma compared with other epithelial ovarian tumors. Patients with clear cell carcinoma are younger, tend to present at an early stage, and their tumors are commonly associated with endometriosis, which is widely accepted as a direct precursor of clear cell carcinoma and has been identified pathologically in approximately 50% of clear cell carcinoma cases. The most frequent and important specific gene alterations in clear cell carcinoma are mutations of AT-rich interaction domain 1A (ARID1A) (~50% of cases) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (~50% cases). More broadly, subgroups of clear cell carcinoma have been identified based on C-APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and C-AGE (age-related) mutational signatures. Gene expression profiling shows upregulation of hepatocyte nuclear factor 1-beta (HNF1β) and oxidative stress-related genes, and has identified epithelial-like and mesenchymal-like tumor subgroups. Although the benefit of platinum-based chemotherapy is not clearly defined it remains the mainstay of first-line therapy. Patients with early-stage disease have a favorable clinical outcome but the prognosis of patients with advanced-stage or recurrent disease is poor. Alternative treatment strategies are required to improve patient outcome and the development of targeted therapies based on molecular characteristics is a promising approach. Improved specificity of the histological definition of this tumor type is helping these efforts but, due to the rarity of clear cell carcinoma, international collaboration will be essential to design appropriately powered, large-scale clinical trials.
... OCCC-specific somatic mutations are clustered in AT-rich interactive domain 1A (SWI-like) (ARID1A), phosphatidylinositol-4, 5bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), protein phosphatase 2 scaffold subunit alpha (PPP2R1A) and K-ras (KRAS) [8][9][10][11][12]. Somatic copy number amplification of the ZNF217 gene in OCCC was also previously reported [13]. ...
Little is known about the genetic alterations characteristic of ovarian clear cell carcinoma (OCCC). Our aim was to identify targetable genomic alterations in this type of cancer. Forty-two OCCC formalin-fixed, paraffin-embedded (FFPE) tissue samples were analyzed by whole-exome sequencing (WES), and 74 FFPE tissue samples underwent targeted sequencing (TS) to confirm the relevant driver mutations. Cell proliferation was assessed by cell counting kit-8 (CCK8) assays. In the 42 samples, ARID1A (64.3%) and PIK3CA (28.5%) were frequently mutated, as were PPP2R1A (11.9%), PTEN (7.1%) and KRAS (4.8%), which have been reported in previous OCCC studies. We also detected mutations in MUC4 (28.6%), MAGEE1 (19%), and ARID3A (16.7%); associations with these genes have not been previously reported. The functional protein-activated pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 83% of OCCCs and with chromatin remodeling in 71% of OCCCs. Patients with alterations in MAGEE1 (64% in the targeted sequencing cohort) had worse clinical outcomes (log-rank p < 0.05). A functional study revealed that two MAGEE1 mutants, one lacking two MAGE domains and the other containing two MAGE domains, significantly decreased the proliferative capacity of OCCC cells. We successfully identified novel genetic alterations in OCCC using whole-exome sequencing and targeted sequencing of OCCC patient samples and potential therapeutic targets for the treatment of this malignancy.
