ArticlePloS one2016
Immunohistochemistry Successfully Uncovers Intratumoral Heterogeneity and Widespread Co-Losses of Chromatin Regulators in Clear Cell Renal Cell Carcinoma.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer.Scientific reports · 2018Pooled it
- Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.Scientific reports · 2025Article
- The convergence of tumor suppressors on the type I interferon pathway in clear cell renal cell carcinoma and its therapeutic implications.American journal of physiology. Cell physiology · 2022Review
- BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma.Cancer letters · 2022Article
- Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway.Oncology letters · 2021Article
- The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by Targeting the Mitochondria.Molecular cancer therapeutics · 2021Article
- The Heterogeneity Metabolism of Renal Cell Carcinomas.Advances in experimental medicine and biology · 2021Article
- Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma.Diagnostics (Basel, Switzerland) · 2020Article
- Solid-type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex.Cancer science · 2020Article
- PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.Nature communications · 2019Article
- Immunohistochemical validation of COL3A1, GPR158 and PITHD1 as prognostic biomarkers in early-stage ovarian carcinomas.BMC cancer · 2019Article
- von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME.Cell death & disease · 2019Article
- Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.Neoplasia (New York, N.Y.) · 2019Article
- Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations.Urologic oncology · 2019Article
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- EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.Journal of Cancer · 2018Article
- Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing. It is not known whether immunohistochemistry (IHC) can be used as a tool to study ITH. To address this question, we examined the protein expression of PBRM1, and PBRM1-related proteins such as ARID1A, SETD2, BRG1, and BRM. Altogether, 160 ccRCC (40 per stage) were used to generate a tissue microarray (TMA), with four foci from each tumor included. Loss of expression was defined as 0-5% of tumor cells with positive nuclear staining in an individual focus. We found that 49/160 (31%), 81/160 (51%), 23/160 (14%), 24/160 (15%), and 61/160 (38%) of ccRCC showed loss of expression of PBRM1, ARID1A, SETD2, BRG1, and BRM, respectively, and that IHC could successfully detect a high prevalence of ITH. Phylogenetic trees were constructed that reflected the ITH. Striking co-losses among proteins were also observed. For instance, ARID1A loss almost always accompanied PBRM1 loss, whereas BRM loss accompanied loss of BRG1, PBRM1 or ARID1A. SETD2 loss frequently occurred with loss of one or more of the other four proteins. Finally, in order to learn the impact of combined losses, we compared the tumor growth after cells acquired losses of ARID1A, PBRM1, or both in a xenograft model. The results suggest that ARID1A loss has a greater tumor-promoting effect than PBRM1 loss, indicating that xenograft analysis is a useful tool to investigate how these losses impact on tumor behavior, either alone or in combination.
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