To comprehensively compare the survival outcomes of clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC), the study cohort included ccRCC and pRCC patients in 2004-2017 from the Surveillance, Epidemiology, and End Results (SEER) database, which comprises 18 registries. Primary outcomes including overall mortality (OM) and cancer-specific mortality (CSM) were evaluated. Subgroup analyses were conducted for different ages, race, and disease stages. A total of 112,270 cases were eligible for the current analysis, including 92,209 cases of ccRCC and 20,061 cases of pRCC. Univariate analyses suggested that pRCC has a more favorable outcome than ccRCC in terms of CSM (HR: 0.72, 95% CI: 0.68-0.75, p < 0.001) and OM (HR: 0.90, 95% CI: 0.88-0.93, p < 0.001). Multivariate-adjusted HRs suggested that pRCC has worse survival outcomes than ccRCC (adjusted HR: 1.08 for CSM and 1.05 for OM, both p < 0.05). Subgroup analyses showed that pRCC had a significantly poorer prognosis than ccRCC among patients ≤45 years old (HRCSM : 1.59, 95% CI: 1.31-1.93, p < 0.001; HROM : 1.63, 95% CI: 1.40-1.90, p < 0.001). Among patients with distant metastasis, those with pRCC had a higher risk of CSM and OM than those with ccRCC (HRCSM : 1.28, 95% CI: 1.19-1.39, p < 0.001; HROM : 1.30, 95% CI: 1.21-1.40, p < 0.001). Propensity score analyses for patients ≤45 years old and those with metastasis showed similar results. The lack of information on pRCC subtypes in the SEER database was a limitation. In conclusion, pRCC has poorer survival outcomes than ccRCC among patients younger than 45 years old and patients with distant metastasis.

Primary clear cell adenocarcinoma of the lung (CCAL) is a rare form of lung cancer with poorly understood clinical features. We sought to investigate the clinicopathological characteristics and independent prognostic factors of primary CCAL.

Clear cell adenocarcinoma of the lung (CCAL) is a rare diagnosis with poorly understood clinicopathological characteristics and disease progression.

Clear cell adenocarcinoma of the cervix (CCAC) is a special type of HPV-independent cervical cancer. It has a low incidence rate, can be difficult to diagnose early, has a poor prognosis. Its peak incidence is in adolescence, which poses a great threat to women's health. Therefore, it is very important to explore the pathogenesis of cervical clear cell adenocarcinoma to guide subsequent treatment and prevention. This study analyzed 3 juvenile patients with CCAC diagnosed at the First Affiliated Hospital of Zhengzhou University. Using next-generation sequencing methods, we analyzed the pathogenesis of the patients and their close relatives by analyzing the genetic alterations of patients. CMTM5 was identified as the only shared mutated gene. Using published literature and comparative analyses of related disease-causing genes, 6 of the 19 genes (ALKBH7, MYCBP, MZF1, RNF207, RRS1, and TUSC2) were screened as genes with mutations in patients and had higher mutation rates in reproductive cancers. Pathway analysis showed that downregulated genes in non-HPV cervical cancer were mainly related to the immune system response, suggesting that non-HPV cervical cancer differs from HPV-infected cervical cancer in that the immune response is weaker, which is consistent with the weak correlation with viral infection.

There has been little progress in the use of patient-derived xenografts (PDX) to guide individual therapeutic strategies. In part, this can be attributed to the operational challenges of effecting successful engraftment and testing multiple candidate drugs in a clinically workable timeframe. It also remains unclear whether the ancestral tumor will evolve along similar evolutionary trajectories in its human and rodent hosts in response to similar selective pressures (i.e., drugs). Herein, we combine a metastatic clear cell adenocarcinoma PDX with a timely 3 mouse x 1 drug experimental design, followed by a co-clinical trial to longitudinally guide a patient's care. Using this approach, we accurately predict response to first- and second-line therapies in so far as tumor response in mice correlated with the patient's clinical response to first-line therapy (gemcitabine/nivolumab), development of resistance and response to second-line therapy (paclitaxel/neratinib) before these events were observed in the patient. Treatment resistance to first-line therapy in the PDX is coincident with biologically relevant changes in gene and gene set expression, including upregulation of phase I/II drug metabolism (CYP2C18, UGT2A, and ATP2A1) and DNA interstrand cross-link repair (i.e., XPA, FANCE, FANCG, and FANCL) genes. A total of 5.3% of our engrafted PDX collection is established within 2 weeks of implantation, suggesting our experimental designs can be broadened to other cancers. These findings could have significant implications for PDX-based avatars of aggressive human cancers.

This study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA).

This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets.

When compared with other epithelial ovarian cancers, the clinical characteristics of ovarian clear cell adenocarcinoma (CCC) include 1) a higher incidence among Japanese, 2) an association with endometriosis, 3) poor prognosis in advanced stages, and 4) a higher incidence of thrombosis as a complication. We used high resolution comparative genomic hybridization (CGH) to identify somatic copy number alterations (SCNAs) associated with each of these clinical characteristics of CCC. The Human Genome CGH 244A Oligo Microarray was used to examine 144 samples obtained from 120 Japanese, 15 Korean, and nine German patients with CCC. The entire 8q chromosome (minimum corrected p-value: q = 0.0001) and chromosome 20q13.2 including the ZNF217 locus (q = 0.0078) were amplified significantly more in Japanese than in Korean or German samples. This copy number amplification of the ZNF217 gene was confirmed by quantitative real-time polymerase chain reaction (Q-PCR). ZNF217 RNA levels were also higher in Japanese tumor samples than in non-Japanese samples (P = 0.027). Moreover, endometriosis was associated with amplification of EGFR gene (q = 0.047), which was again confirmed by Q-PCR and correlated with EGFR RNA expression. However, no SCNAs were significantly associated with prognosis or thrombosis. These results indicated that there may be an association between CCC and ZNF217 amplification among Japanese patients as well as between endometriosis and EGFR gene amplifications.

Primary clear-cell adenocarcinoma of the urethra, a rare tumor that histomorphologically resembles clear-cell carcinoma of the female genital tract, occurs predominantly in women and is associated with a relatively poor prognosis. The histogenesis of this rare urethral neoplasm has not been completely resolved, but it is thought to arise from either müllerian rests or metaplastic urothelium. Herein, we present comprehensive surgical pathological and cytopathological findings from a patient with primary urethral clear-cell adenocarcinoma and describe next-generation sequencing results for this patient's unique tumor-the first such reported characterization of molecular aberrations in urethral clear-cell adenocarcinoma at the transcriptomic and genomic levels. Transcriptome analysis revealed novel gene fusion candidates, including ANKRD28-FNDC3B. Whole-exome analysis demonstrated focal copy number loss at the SMAD4 and ARID2 loci and 38 somatic mutations, including a truncating mutation in ATM and a novel nonsynonymous mutation in ALK.

Clear cell adenocarcinoma (CCA) is a rare variant of urinary bladder carcinoma with a glycogen-rich phenotype and unknown prognosis. Using the National Cancer Institute's surveillance, epidemiology, and end results (SEER) program database, we documented recent trends in incidence, mortality, demographical characteristics, and survival on this rare subtype of urinary bladder cancer. The overall age-adjusted incidence and mortality of CCA was 0.087 (95% confidence interval (CI): 0.069-0.107) and 0.064 (95% CI: 0.049-0.081) respectively per million population. In comparison to non-CCAs, CCAs were more commonly associated with younger age (<60 years old, p = 0.005), female (p < 0.001), black ethnicity (p = 0.001), grade III (p < 0.001), and higher AJCC 6th staging (p < 0.001). In addition, CCA patients more frequently received complete cystectomy (p < 0.001) and beam radiation (p < 0.001) than non-CCA patients. Our study showed a poorer prognosis of CCAs compared to all other carcinomas of the urinary bladder (p < 0.001), accounted for by higher tumor staging of CCA cases. This study adds to the growing evidence that glycogen-rich cancers may have unique characteristics affecting tumor aggressiveness and patient prognosis. Additional mechanistic studies are needed to assess whether it's the excess glycogen that contributes to the higher stage at diagnosis.

The association between iron ions and endometriosis-associated ovarian cancer (EAOC) has been previously investigated to elucidate EAOC carcinogenesis; however, the dynamics of iron deposition in the endometrial epithelium and endometrial stroma of ovarian endometrioma (OE) remains unknown. The present study aimed to determine the expression of iron transporters on the cell surface and the distribution of tumor-associated macrophages (TAMs) englobed with iron in the endometrial stroma. The current retrospective study investigated 20 OE and 18 ovarian clear cell adenocarcinoma (CCC) samples, using Perls Prussian blue staining and immunohistochemistry of iron transporters, including divalent metal transporter 1 (DMT1), transferrin receptor (TfR) and ferroportin (FPN). Additionally, samples were stained for CD68, CD11c, CD163 and CD206, and double-immunostained for iron and CD163 to define the distribution of macrophages. Iron transporters were identified on the endometrial epithelium of OE and CCC tumor cells, and TAMs were englobed with iron in the endometrial stroma of OE and CCC. Histological findings revealed DMT1 upregulation in OE and CCC, whereas lower TfR and FPN expression was observed in OE than in CCC. M2 macrophages were englobed with iron ions in the deep layers of the OE and CCC stroma. The endometrial epithelium located in the endometrial stroma of one patient with OE and the endometrial epithelium adjacent to CCC in two patients with CCC stained positive for the tumor proliferation marker Ki67. Epithelium infiltrating the stroma of OE may become the origin of cancer under the influence of M2 macrophages englobed with iron. These findings provide new perspectives on the malignant transformation of OE into EAOC and its possibility as a precancerous index.

Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive.

Ovarian clear cell adenocarcinoma (Ov-CCA) has a higher prevalence in the Japanese ancestry than other populations. The ancestral disparities in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations and may provide an opportunity to identify the novel genes associated with Ov-CCA tumorigenesis. Using 94 previously reported genes as the phenotypic trait, we conducted multistep expression quantitative trait loci (eQTL) analysis with the HapMap3 project datasets. Four single-nucleotide polymorphisms (SNPs) (rs4873815, rs12976454, rs11136002, and rs13259097) that had different allele frequencies in the Japanese ancestry and seven genes associated in cis (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified. In silico functional annotation analysis and in vitro promoter assay validated the regulatory effect of rs4873815-TT on ZNF707 and rs11136002-TT on TNFRSF10B. Furthermore, ZNF707 was highly expressed in Ov-CCA and had a negative prognostic value in disease recurrence in our sample cohort. This prognostic power was consistently observed in The Cancer Genome Atlas (TCGA) clear cell renal cell carcinoma dataset, suggesting that ZNF707 may have prognostic value in clear cell histology regardless of tissue origin. In conclusion, rs4873815-TT/ZNF707 may have clinical significance in the prognosis and tumorigenesis of Ov-CCA, which may be more relevant to clear cell histology. Besides, this study may underpin the evidence that cis-eQTL analysis based on ancestral disparities can facilitate the discovery of causal genetic alterations in complex diseases, such as cancer.

Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++)-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1 α /VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1 α protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 α and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1 α signaling in CCA. Furthermore, stathmin knockdown inhibited hypoxia-induced HIF-1 α and VEGF expression and S6K phosphorylation. The silencing of stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1 α /VEGF signaling pathway. By contrast, stathmin overexpression upregulated hypoxia-induced HIF-1 α and VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1 α and VEGF expression. These results illustrate that regulation of HIF-1 α through the PI3K/Akt/mTOR pathway is controlled by stathmin in CCA. Our findings point to a new mechanism of stathmin regulation during ovarian cancer.

Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.

The retrospective study aimed to analyze the clinical characteristics, primary treatment, and prognosis of cervical clear cell adenocarcinoma in a tertiary referral center. The medical data of cervical clear cell adenocarcinoma patients treated in our institution between 1993 and 2020 were reviewed. Their clinical characteristics and information on treatment and follow-up were collected. Seventy-four cases were included. Six early-stage patients successfully preserved their fertility. Forty-five patients underwent a radical hysterectomy. Patients with pathological risk factors all received adjuvant treatment including chemotherapy, radiotherapy, and chemoradiation. Fifteen patients without risk factors underwent surveillance and five patients received adjuvant chemotherapy for poorly differentiated disease. Twenty cases had radiation for primary treatment. Six of them underwent surgery after chemoradiotherapy, and five had pathological residual disease, including three who had pathological risk factors. The median follow-up interval was 36 months, with a 3-year OS and PFS rate of 82.4% and 81.4%, respectively. No recurrence or death was observed in patients with fertility-sparing treatment. FIGO stage was prognostic factors of PFS (P = .001) and OS(P = .006) and lymph node status was that of PFS (P = .023). FIGO stage and lymph node status were prognostic factors for survival. Fertility-sparing treatment is a safe option for young patients in early stage. Early-stage patients without risk factors may benefit from postoperative surveillance. Occult tumor after chemoradiotherapy is common, and surgical resection is recommended when operable residual disease is detected.

Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA) at younger age. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. The complete epidemiologic curve of CCA has not been reported, yet.

Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex that plays crucial roles in various cellular processes. However, no systematic studies on the expression and functions of CRBN in solid tumors have been conducted to date. Here, we analyzed CRBN expression and its clinical value using several bioinformatic databases. CRBN mRNA expression was downregulated in various cancer types compared to normal cells. Survival analysis demonstrated that overall survival was significantly positively correlated with CRBN expression in some cancer types including lung adenocarcinoma (LUAD), kidney renal clear cell carcinoma (KIRC), and skin cutaneous melanoma (SKCM). CRBN expression was downregulated regardless of clinicopathological characteristics in LUAD and KIRC. Analysis of genes that are commonly correlated with CRBN expression among KIRC, LUAD, and SKCM samples elucidated the potential CRBN-associated mechanisms of cancer progression. Overall, this study revealed the prognostic value of CRBN and its potential associated mechanisms, which may facilitate the development of anti-cancer therapeutic agents.

DS-7423, a novel, small-molecule dual inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), is currently in phase I clinical trials for solid tumors. Although DS-7423 potently inhibits PI3Kα (IC50 = 15.6 nM) and mTOR (IC50 = 34.9 nM), it also inhibits other isoforms of class I PI3K (IC50 values: PI3Kβ = 1,143 nM; PI3Kγ = 249 nM; PI3Kδ = 262 nM). The PI3K/mTOR pathway is frequently activated in ovarian clear cell adenocarcinomas (OCCA) through various mutations that activate PI3K-AKT signaling. Here, we describe the anti-tumor effect of DS-7423 on a panel of nine OCCA cell lines. IC50 values for DS-7423 were <75 nM in all the lines, regardless of the mutational status of PIK3CA. In mouse xenograft models, DS-7423 suppressed the tumor growth of OCCA in a dose-dependent manner. Flow cytometry analysis revealed a decrease in S-phase cell populations in all the cell lines and an increase in sub-G1 cell populations following treatment with DS-7423 in six of the nine OCCA cell lines tested. DS-7423-mediated apoptosis was induced more effectively in the six cell lines without TP53 mutations than in the three cell lines with TP53 mutations. Concomitantly with the decreased phosphorylation level of MDM2 (mouse double minute 2 homolog), the level of phosphorylation of TP53 at Ser46 was increased by DS-7423 in the six cell lines with wild-type TP53, with induction of genes that mediate TP53-dependent apoptosis, including p53AIP1 and PUMA at 39 nM or higher doses. Our data suggest that the dual PI3K/mTOR inhibitor DS-7423 may constitute a promising molecular targeted therapy for OCCA, and that its antitumor effect might be partly obtained by induction of TP53-dependent apoptosis in TP53 wild-type OCCAs.