Genomic characterization of clear cell renal cell carcinoma using targeted gene sequencing

Lin,Po-Hung; Huang,Chao-Yuan; Yu,Kai-Jie; Kan,Hung-Cheng; Liu,Chung-Yi; Chuang,Cheng-Keng; Lu,Yu-Chuan; Chang,Ying-Hsu; Shao,I-Hung; Pang,See-Tong

doi:10.3892/ol.2021.12430

Genomic characterization of clear cell renal cell carcinoma using targeted gene sequencing

Authors:
- Po-Hung Lin
- Chao-Yuan Huang
- Kai-Jie Yu
- Hung-Cheng Kan
- Chung-Yi Liu
- Cheng-Keng Chuang
- Yu-Chuan Lu
- Ying-Hsu Chang
- I-Hung Shao
- See-Tong Pang
View Affiliations

Affiliations: Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan, R.O.C., Department of Urology, National Taiwan University Hospital, Taipei 10022, Taiwan, R.O.C.
Published online on: January 4, 2021 https://doi.org/10.3892/ol.2021.12430
Article Number: 169
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Kidney cancer is one of the most lethal cancer types worldwide. The most common subtype of kidney cancer is clear cell renal cell carcinoma (ccRCC), and the somatic mutations of ccRCC have been identified through the development of large databases. The present study aimed to validate the status of the associated gene mutations in a Taiwanese cohort. Targeted sequencing was used to validate the mutation status of genes related to ccRCC in Taiwanese patients who had nephrectomy for kidney cancer. The top eight mutated genes in the Catalogue Of Somatic Mutations In Cancer (COSMIC) were selected. These genes were VHL, protein polybromo‑1 (PBRM1), histone‑lysine N‑methyltransferase SETD2, BRCA1‑associated protein‑1 (BAP1), lysine‑specific demethylase 5C (KDM5C), TP53, MTOR and PTEN. The association between the gene mutation status of VHL, PBRM1, SETD2 and BAP1 was validated with clinicopathological parameters as well as overall survival time. Tumor cells from 96 patients with ccRCC were target sequenced. The order of mutation rate of the eight aforementioned genes was similar to that reported within COSMIC. The present Taiwanese cohort exhibited lower PBRM1 and BAP1 mutation rates compared with average, with increased mutation rates for SETD2 and KDM5C. BAP1 mutation was associated with the tumor and cancerous stage. None of these four genes were positively associated with the overall survival of patients. The PBRM1 and SETD2 mutations were mutually exclusive to BAP1 mutation. Overall, the present study provided data confirming gene alteration in Taiwanese patients with ccRCC and showed some differences when compared with Western countries. Further comprehensive genomic and epigenomic studies, as well as downstream validation, are necessary to evaluate the impact of these differences.

View Figures

View References

1	Siegel RL, Miller K and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2018. View Article : Google Scholar
2	2016 Taiwan Cancer Registry. simplehttps://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=269&pid=10227April 4–2020
3	Shuch B, Amin A, Armstrong AJ, Eble JN, Ficarra V, Lopez-Beltran A, Martignoni G, Rini BI and Kutikov A: Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity. Eur Urol. 67:85–97. 2015. View Article : Google Scholar : PubMed/NCBI
4	COSMIC Cancer Browser. simplehttps://cancer.sanger.ac.uk/cosmic/browse/tissue?wgs=off&sn=kidney&ss=NS&hn=carcinoma&sh=clear_cell_renal_cell_carcinoma&in=t&src=tissue&all_data=nFebruary 15–2020
5	Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 356:115–124. 2007. View Article : Google Scholar : PubMed/NCBI
6	Kim WY and Kaelin WG: Role of VHL gene mutation in human cancer. J Clin Oncol. 15:4991–5004. 2004. View Article : Google Scholar
7	Xing T and He H: Epigenomics of clear cell renal cell carcinoma: Mechanisms and potential use in molecular pathology. Chin J Cancer Res. 28:80–91. 2016.PubMed/NCBI
8	Cancer Genome Atlas Research Network, . Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 499:43–49. 2013. View Article : Google Scholar : PubMed/NCBI
9	Edge SB and Compton CC: The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
10	Xu C, Ranjbar MR, Wu Z, DiCarlo J and Wang Y: Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller. BMC Genomics. 18:52017. View Article : Google Scholar : PubMed/NCBI
11	Li H and Durbin R: Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI
12	McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M and DePristo MA: The genome analysis toolkit: A mapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–1303. 2010. View Article : Google Scholar : PubMed/NCBI
13	Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel S, Meyerson M, Lander ES and Getz G: Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 31:213–219. 2013. View Article : Google Scholar : PubMed/NCBI
14	McLaren W, Pritchard B, Rios D, Chen Y, Flicek P and Cunningham F: Deriving the consequences of genomic variants with the ensembl API and SNP effect predictor. Bioinformatics. 26:2069–2070. 2010. View Article : Google Scholar : PubMed/NCBI
15	Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, Gore JL, Sun M, Wood C and Russo P: Epidemiology of renal cell carcinoma. Eur Urol. 75:74–84. 2019. View Article : Google Scholar : PubMed/NCBI
16	Brugarolas J: Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol. 32:1968–1976. 2014. View Article : Google Scholar : PubMed/NCBI
17	Kaelin WG Jr: The von hippel-lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 13:680s–684s. 2007. View Article : Google Scholar : PubMed/NCBI
18	Posadas EM, Limvorasak S and Figlin RA: Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 13:496–511. 2017. View Article : Google Scholar : PubMed/NCBI
19	Kondo K, Yao M, Yoshida M, Kishida T, Shuin T, Miura T, Moriyama M, Kobayashi K, Sakai N, Kaneko S, et al: Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters. Genes Chromosomes Cancer. 34:58–68. 2002. View Article : Google Scholar : PubMed/NCBI
20	Hodges C, Kirkland JG and Crabtree GR: The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb Perspect Med. 6(pii): a0269302016. View Article : Google Scholar : PubMed/NCBI
21	Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, et al: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 469:539–542. 2011. View Article : Google Scholar : PubMed/NCBI
22	Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU, Xie Y, Aras O, Han S, Oyama T, Takeda S, et al: The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep. 18:2893–2906. 2017. View Article : Google Scholar : PubMed/NCBI
23	Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F, Bachrati CZ, Helleday T, Legube G, La Thangue NB, Porter AC and Humphrey TC: SETD2-Dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7:2006–2018. 2014. View Article : Google Scholar : PubMed/NCBI
24	Chiang YC, Park IY, Terzo EA, Tripathi DN, Mason FM, Fahey CC, Karki M, Shuster CB, Sohn BH, Chowdhury P, et al: SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma. Cancer Res. 78:3135–3146. 2018. View Article : Google Scholar : PubMed/NCBI
25	Kanu N, Gronroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, et al: SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene. 34:5699–5708. 2015. View Article : Google Scholar : PubMed/NCBI
26	Carbone M, Yang H, Pass HI, Krausz T, Testa JR and Gaudino G: BAP1 and cancer. Nat Rev Cancer. 13:153–159. 2013. View Article : Google Scholar : PubMed/NCBI
27	Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, et al: BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 44:751–759. 2012. View Article : Google Scholar : PubMed/NCBI
28	Huang A, Garraway LA, Ashworth A and Weber B: Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 19:23–38. 2020. View Article : Google Scholar : PubMed/NCBI
29	Kim HS, Kim JH, Jang HJ, Han B and Zang DY: Clinicopathologic significance of VHL gene alteration in clear-cell renal cell carcinoma: An updated meta-analysis and review. Int J Mol Sci. 19:E25292018. View Article : Google Scholar : PubMed/NCBI
30	Salinas-Sanchez AS, Serrano-Oviedo L, Nam-Cha SY, Roche-Losada O, Sánchez-Prieto R and Giménez-Bachs JM: Prognostic value of the VHL, HIF-1α, and VEGF signaling pathway and associated MAPK (ERK1/2 and ERK5) pathways in clear-cell renal cell carcinoma. A long-term study. Clin Genitourin Cancer. 15:e923–e33. 2017. View Article : Google Scholar : PubMed/NCBI
31	da Costa WH, Rezende M, Carneiro FC, Rocha RM, da Cunha IW, Carraro DM, Guimaraes GC and de Cassio Zequi S: Polybromo-1 (PBRM1), a SWI/SNF complex subunit is a prognostic marker in clear cell renal cell carcinoma. BJU Int. 113:E157–E163. 2014. View Article : Google Scholar : PubMed/NCBI
32	Pawlowski R, Muhl SM, Sulser T, Krek W, Moch H and Schraml P: Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int J Cancer. 132:E11–E117. 2013. View Article : Google Scholar : PubMed/NCBI
33	Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A, Bastian P, Seitz C, Shariat SF, Bensalah K, et al: BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma. J Urol. 191:603–610. 2014. View Article : Google Scholar : PubMed/NCBI
34	Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, Liu H, Takeda S, Voss MH, Tickoo SK, et al: Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: A report by MSKCC and the KIRC TCGA research network. Clin Cancer Res. 19:3259–3267. 2013. View Article : Google Scholar : PubMed/NCBI
35	Kim SH, Park WS, Park EY, Park B, Joo J, Joung JY, Seo HK, Lee KH and Chung J: The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry. PLoS One. 12:e01796102017. View Article : Google Scholar : PubMed/NCBI
36	Manley BJ, Zabor EC, Casuscelli J, Tennenbaum DM, Redzematovic A, Becerra MF, Benfante N, Sato Y, Morikawa T, Kume H, et al: Integration of recurrent somatic mutations with clinical outcomes: A pooled analysis of 1049 patients with clear cell renal cell carcinoma. Eur Urol Focus. 3:421–427. 2017. View Article : Google Scholar : PubMed/NCBI
37	Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik ED, Bowlby R, Gibb EA, Akbani R, Beroukhim R, et al: The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23:313–326. 2018. View Article : Google Scholar : PubMed/NCBI
38	Corces MR, Granja JM, Shams S, Louie BH, Seoane JA, Zhou W, Silva TC, Groeneveld C, Wong CK, Cho SW, et al: The chromatin accessibility landscape of primary human cancers. Science. 362:eaav18982018. View Article : Google Scholar : PubMed/NCBI
39	Data published by the Taiwanese National Health Insurance Administration. simplehttps://www.nhi.gov.tw/Content_List.aspx?n=7157A9A3E2A3B110&topn=3FC7D09599D25979April 4–2020