Clear cell carcinomas of the ovary and kidney: clarity through genomics

Ji, Jennifer X.; Wang, Yi Kan; Cochrane, Dawn R.; Huntsman, David G.

doi:10.1002/path.5037

Cited by 42 publications

(37 citation statements)

References 173 publications

(193 reference statements)

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“…Indeed, CCC has a specific immune‐related molecular profile and epidemiologic associations with ethnicity and endometriosis . Intriguingly, CCC is a major histologic subtype of renal cell carcinoma, with remarkable multifaceted mutational similarities between endometrial and renal CCC . It is reported that loss‐of‐function mutations of PBRM1 , a subunit of the switch‐sucrose nonfermentable (SWI/SNF) chromatin‐remodeling complex, was associated with clinical benefit for ICI in clear‐cell renal carcinoma; this is supported by other reports showing that lower expression of PBRM1 and ARID2 was correlated with higher cytotoxic activity contributed by CD8 T cells in human cancers and that Pbrm1 ‐deficient murine tumor cells were more sensitive to T‐cell‐mediated cytotoxicity .…”

Section: Discussionmentioning

confidence: 69%

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

et al. 2020

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Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed.Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE.There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR. K E Y W O R D Scombined positive score, objective response rate, ovarian cancer, PD-L1, pembrolizumab | 1325 NISHIO et al.

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Section: Discussionmentioning

confidence: 69%

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

et al. 2020

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“…As already stated, OCCC is the second most common ovarian cancer after serous carcinoma and represent 26% of ovarian cancer in Southeast Asia [3]. However, fewer molecular targets have been identified for OCCC compared with HGSOC.…”

Section: Discussionmentioning

confidence: 99%

“…Although the carcinogenic mechanism and chemoresistance of OCCC are still unclear, several genetic changes have been extensively studied. Compared with HGSOC, OCCC is usually negative for p53 mutations, and the frequency of breast cancer 1 or 2 (BRCA1/2) mutations is low (6.3%) [3,4]. Higher frequencies of AT-rich active domain 1A (ARID1A) and phosphatidylinositol-4,5-diphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations (36%) have also been observed in OCCC patients [5,6].…”

Section: Introductionmentioning

confidence: 99%

Distinct gene expression profiles associated with clinical outcomes in patients with ovarian clear cell carcinoma and high-grade serous ovarian carcinoma

et al. 2020

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Background: Ovarian clear cell carcinoma (OCCC) is the second most common ovarian cancer after serous carcinoma in Southeast Asia. OCCC has a more unfavourable clinical outcome due to a poor response to platinumbased chemotherapy compared with serous carcinoma. The identification of biomarkers related to the prognosis of OCCC is critically important for an improved understanding of the biology that drives OCCC progression and leads to poor outcomes. To detect differences in gene expression profiles between OCCC and high-grade serous ovarian carcinoma (HGSOC), twelve patients with OCCC and twelve patients with HGSOC were recruited in whom the pathological diagnosis was confirmed on surgically resected specimens. Results: Compared with HGSOC, OCCC has 609 differentially expression genes, and 199 are significantly different (P < 0.05). These genes are involved in the cell cycle, apoptosis, DNA damage repair, the PI3K pathway and so on. There were 164 differentially expressed genes in the PI3K pathway. There were 35 overexpressed genes in OCCC, while there were 12 overexpressed genes in HGSOC. Among these differentially expressed genes, we found that the MET gene and the CCNE1 gene were overexpressed in OCCC and associated with a worse prognosis. Conclusions:In conclusion, there are many differentially expressed genes in OCCC and HGSOC, which indicates that the two kinds of tumours differ greatly in tumourigenesis and provides a theoretical basis for targeted therapy in the future. Further studies need to be performed to clarify the association of the differentially expressed genes with the unfavourable prognosis in OCCC.

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“…As we identified four SNPs and seven associated genes based on the difference of Ov-CCA prevalence by Japanese ancestry, the potential role of seven identified genes in Ov-CCA prognostication or tumorigenesis may be limited to Japanese ancestry. Given that ccRCC has a similar molecular profile to Ov-CCA [28], we performed expression and survival analyses to verify the clinical significance of seven associated genes with the TCGA-ccRCC dataset composed of various ancestries. In addition, further validation was conducted in a minority ancestry with our Korean EOC cohort.…”

Section: Discussionmentioning

confidence: 99%

“…gov/tcga/tcgaHome2.jsp). As there were no Ov-CCA cases in the TCGA database, a clear cell renal cell carcinoma (TCGA-ccRCC) dataset, reported to have similar molecular profiles to that of Ov-CCA, was included in the survival analysis as an alternative [28]. In addition, the HGSOC dataset was included as a control.…”

Section: Analysis Of the Clinical Significance Of The Seven Identifiementioning

confidence: 99%

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis

Kim

Chung

Hwang

et al. 2020

JCM

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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.

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Clear cell carcinomas of the ovary and kidney: clarity through genomics

Cited by 42 publications

References 173 publications

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

Distinct gene expression profiles associated with clinical outcomes in patients with ovarian clear cell carcinoma and high-grade serous ovarian carcinoma

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis

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