Relevance of Arm Somatic Copy Number Alterations for Oncologic Outcomes and Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2020 Jan 14

PMID 31930047

Citations 5

Authors

Ying Xiong

Yu Qi

Qi Bai

Yu Xia

Li Liu

Jianming Guo

Affiliations

Soon will be listed here.

Abstract

Background: Prognostic value of arm somatic copy number alterations (SCNAs) in clear cell renal cell carcinoma (ccRCC) have not been systematically evaluated in a large cohort. Its association with tumor microenvironment remained unknown.

Methods: We retrospectively correlated arm SCNAs with OS and recurrence free survival (RFS) in a cohort of 524 ccRCC patients. The prognostic landscape of arm SCNA was depicted by bubble heatmap. Associations between arm SCNAs and tumor microenvironment were evaluated by CIBERSORT and Gene Set Enrichment Analysis (GSEA).

Results: We found that amplifications of 1p, 3p and loss of 4p, 4q, 5p, 5q, 11p, 11q, 11q, 13q, 19p were independent adverse risk factor for OS, while amplification of 1q and deletions of 4p, 4q, 9p, 9q associated with worse RFS. Loss of 4q were independent adverse risk factor for OS (P=0.012, HR =1.614) and RFS (P=0.001, HR =2.005). It could identify a subset of early stage ccRCC patients with high risk of death and recurrence. CXCL9, CXCL10, CXCL11 mRNA level and CD8+ T cell infiltration were downregulated in ccRCC with 4q deletion. Patients with high arm SCNA level had shorter OS (P=0.005) and RFS (P=0.001). Markers, immune cells and pathways referring to immune suppression were elevated in tumors with high arm SCNA level.

Conclusions: In conclusion, loss of 4q was an independent adverse risk factor for OS and RFS in ccRCC patients and contributed to cytotoxic cell exclusion via downregulation of CXCL9, CXCL10 and CXCL11. Patients with higher arm SCNAs had worse survival and a more immunosuppressive tumor microenvironment.

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References

Ito T, Pei J, Dulaimi E, Menges C, Abbosh P, Smaldone M . Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features. J Urol. 2015; 195(4 Pt 1):852-8. PMC: 4871784. DOI: 10.1016/j.juro.2015.10.180. View

Chen M, Ye Y, Yang H, Tamboli P, Matin S, Tannir N . Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays. Int J Cancer. 2009; 125(10):2342-8. PMC: 2768265. DOI: 10.1002/ijc.24642. View

Fu H, Zhu Y, Wang Y, Liu Z, Zhang J, Wang Z . Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma. Ann Surg Oncol. 2016; 24(5):1435-1442. DOI: 10.1245/s10434-016-5702-5. View

Cohen H, McGovern F . Renal-cell carcinoma. N Engl J Med. 2005; 353(23):2477-90. DOI: 10.1056/NEJMra043172. View

La Rochelle J, Klatte T, Dastane A, Rao N, Seligson D, Said J . Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer. 2010; 116(20):4696-702. DOI: 10.1002/cncr.25279. View

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

Gentles A, Newman A, Liu C, Bratman S, Feng W, Kim D . The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015; 21(8):938-945. PMC: 4852857. DOI: 10.1038/nm.3909. View

Fridman W, Zitvogel L, Sautes-Fridman C, Kroemer G . The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017; 14(12):717-734. DOI: 10.1038/nrclinonc.2017.101. View

Elfving P, Mandahl N, Lundgren R, Limon J, Ferno M, Olsson H . Prognostic implications of cytogenetic findings in kidney cancer. Br J Urol. 1997; 80(5):698-706. DOI: 10.1046/j.1464-410x.1997.00439.x. View

10.

Palucka A, Coussens L . The Basis of Oncoimmunology. Cell. 2016; 164(6):1233-1247. PMC: 4788788. DOI: 10.1016/j.cell.2016.01.049. View

11.

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

12.

Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf A . Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013; 39(4):782-95. DOI: 10.1016/j.immuni.2013.10.003. View

13.

Moch H, Presti Jr J, Sauter G, Buchholz N, Jordan P, Mihatsch M . Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res. 1996; 56(1):27-30. View

14.

Klatte T, Rao P, de Martino M, LaRochelle J, Shuch B, Zomorodian N . Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol. 2009; 27(5):746-53. DOI: 10.1200/JCO.2007.15.8345. View

15.

Speiser D, Ho P, Verdeil G . Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016; 16(10):599-611. DOI: 10.1038/nri.2016.80. View

16.

Motzer R, Ravaud A, Patard J, Pandha H, George D, Patel A . Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol. 2017; 73(1):62-68. PMC: 6684251. DOI: 10.1016/j.eururo.2017.09.008. View

17.

Cahill D, Kinzler K, Vogelstein B, Lengauer C . Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999; 9(12):M57-60. View

18.

Moore L, Jaeger E, Nickerson M, Brennan P, de Vries S, Roy R . Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation. Oncogenesis. 2013; 1:e14. PMC: 3412648. DOI: 10.1038/oncsis.2012.14. View

19.

Gunawan B, Huber W, Holtrup M, von Heydebreck A, Efferth T, Poustka A . Prognostic impacts of cytogenetic findings in clear cell renal cell carcinoma: gain of 5q31-qter predicts a distinct clinical phenotype with favorable prognosis. Cancer Res. 2001; 61(21):7731-8. View

20.

Friedlander M, Hedley D, TAYLOR I . Clinical and biological significance of aneuploidy in human tumours. J Clin Pathol. 1984; 37(9):961-74. PMC: 498910. DOI: 10.1136/jcp.37.9.961. View