Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma

Our plain-English summary of Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma, by Y. Togo, Y. Yoshikawa, T. Suzuki, et al (International Journal of Oncology, 2016).

The study

• Authors: Y. Togo, Y. Yoshikawa, T. Suzuki, Y. Nakano, A. Kanematsu, M. Zozumi, M. Nojima, S. Hirota, S. Yamamoto, T. Hashimoto-Tamaoki
• Journal: International Journal of Oncology
• Published: 2016;48(4):1571-80
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Somatic mutations of the BRCA1 associated protein-1 (BAP1) gene, which maps to 3p21, have been found in several tumors including malignant mesothelioma, uveal melanoma, and renal cell carcinoma (RCC). The role of BAP1 inactivation in tumor development remains unclear. It has been reported that Vhl knock-out mice did not develop RCC, but Vhl knock-out mice with single allele loss of Bap1 in nephron progenitor cells developed RCC, indicating that Bap1 inactivation may be essential in murine renal tumorigenesis. To clarify the role of BAP1 in human RCC development, we performed mutation analyses, including copy number detection of BAP1 and assessment of allelic imbalance using microsatellite polymorphisms on 3p, in 45 RCC samples derived from 45 patients without VHL or BAP1 germline mutation. Additionally, we analyzed the sequences of the VHL, PBRM1, and SETD2 genes, and examined promoter methylation of VHL. Using immunostaining, we also checked for expression of BAP1 protein, which is normally located in the nuclei. None of the RCCs had biallelic deletion of BAP1, but five (11.1%) showed a biallelic mutation (four with a sequence-level mutation with monoallelic loss and one with a biallelic sequence-level mutation); these cells were negative for nuclear BAP1 staining. These patients had worse recurrence-free survival than the patients without a biallelic mutation (p=0.046). However, there were no significant differences in worse outcome by multivariate analysis combined with age, T stage, histological subtype, infiltration and vascular invasion. In 35 RCCs (77.8%), monoallelic loss of BAP1 was accompanied by VHL biallelic mutation or VHL promoter hypermethylation. In five RCCs (11.1%), we detected 3p loss-of-heterozygosity, but the copy number of BAP1 was normal. Surprisingly, nuclear staining of BAP1 was negative in 10 out of 31 tumors (32.3%) with hemizygous normal BAP1, suggesting that haploinsufficiency may relate to RCC development.

In plain English

This was a laboratory study of genes on the short arm of chromosome 3 (3p) in kidney tumors. It did not study asbestos exposure. The authors analyzed 45 renal cell carcinoma samples from 45 patients who had their kidney removed at the Hospital of Hyogo College of Medicine in Japan. Of these tumors, 42 were clear cell and three were chromophobe renal cell carcinoma. The authors tested the VHL, BAP1, PBRM1 and SETD2 genes and stained the tumors for BAP1 protein. VHL mutations were found in 36 of 45 tumors (80%). One copy of BAP1 was lost in 35 of 45 tumors (77.8%). BAP1 mutations were found in five of the 45 tumors (11.1%), all of them clear cell tumors, and in each of these both copies of BAP1 were inactivated. Ten of 31 clear cell tumors (32.3%) that still had one normal BAP1 copy were classified as negative for nuclear BAP1 staining, meaning most of their tumor-cell nuclei did not stain for the protein. Patients whose tumors had both BAP1 copies inactivated had worse recurrence-free survival (p=0.046). This was not significant once age, tumor stage and other factors were taken into account, which the authors said was probably due to the small sample size. The authors suggested that losing one working copy of BAP1 might be related to kidney cancer development.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory genetic and protein-staining analysis of tumor samples, with recurrence-free survival comparison
• Who was studied: 45 renal cell carcinoma samples from 45 patients who had radical nephrectomy at the Hospital of Hyogo College of Medicine, Japan; 42 clear cell RCC and three chromophobe RCC; study dates not given
• Main results:
  • VHL mutation was found in 36 of 45 RCC tumors (80%)
  • Loss of heterozygosity on 3p was found in 41 of 45 tumors (91%). Monoallelic loss of all BAP1 exons was found in 35 of 45 tumors (77.8%). No tumor had biallelic loss of BAP1.
  • Somatic BAP1 mutation was found in five clear cell RCC tumors with LOH. The 11.1% frequency corresponds to 5 of all 45 RCC tumors.
  • PBRM1 mutations were found in 21 of 45 tumors (46.7%) and SETD2 mutations in 7 of 45 (15.6%)
  • BAP1 nuclear staining was negative in 10 of 31 clear cell RCC tumors (32.3%) that had one normal BAP1 copy. A tumor was scored negative when the majority of its tumor-cell nuclei stained negatively.
  • In clear cell RCC, biallelic loss-of-function BAP1 mutation was associated with recurrence-free survival (p=0.046), but not in multivariate analysis with age, T stage, histological subtype, infiltration and vascular invasion
  • SETD2 mutations were significantly associated with recurrence-free survival (p=0.007); PBRM1 mutations were not (p=0.761)
  • Negative BAP1 nuclear staining in clear cell RCC was not associated with tumor recurrence (p=0.143)
• The authors' conclusion: The authors concluded that, because about 30% of clear cell RCC tumors with one normal BAP1 copy showed negative nuclear BAP1 staining, haploinsufficiency (loss of one working copy) might be related to RCC development. They also said that genomic analysis of BAP1 is useful in interpreting RCC prognosis.
• Limitations the authors state:
  • The authors attributed the lack of a multivariate association between BAP1 mutation and recurrence probably to small sample size
  • BAP1 gene expression level could not be tested because the samples contained a substantial proportion of non-tumor cells
  • Overall survival was not analyzed

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Somatic Mutation, BAP1, Mesothelioma, Carcinogenesis, Germline Mutation, Recurrence-Free Survival, Multivariate Analysis.

Related studies

• Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus — C. Walker, Y.T. Ahn, et al. (1996)
• Carbonic anhydrase IX is expressed in mesothelioma and metastatic clear cell renal cell carcinoma of the lung — M.L. Ramsey, B.J. Yuh, et al. (2012)
• Renal cell carcinoma — P.A. Godley, M.A. Escobar (1998)
• The epidemiology of renal cell carcinoma — L. Lipworth, R.E. Tarone, et al. (2006)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter urothelial and renal cancer study — B. Pesch, J. Haerting, et al. (2000)

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