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Observational Study
. 2017 Jan 24:7:41371.
doi: 10.1038/srep41371.

Functional PTGS2 polymorphism-based models as novel predictive markers in metastatic renal cell carcinoma patients receiving first-line sunitinib

Arancha Cebrián  1 , Teresa Gómez Del Pulgar  1 , María José Méndez-Vidal  2 , María Luisa Gonzálvez  3 , Nuria Lainez  4 , Daniel Castellano  5 , Iciar García-Carbonero  6 , Emilio Esteban  7 , Maria Isabel Sáez  8 , Rosa Villatoro  9 , Cristina Suárez  10 , Alfredo Carrato  11 , Javier Munárriz-Ferrándiz  12 , Laura Basterrechea  13 , Mirta García-Alonso  14 , José Luis González-Larriba  15 , Begoña Perez-Valderrama  16 , Josefina Cruz-Jurado  17 , Aránzazu González Del Alba  18 , Fernando Moreno  19 , Gaspar Reynés  20 , María Rodríguez-Remírez  1 , Valentina Boni  21 , Ignacio Mahillo-Fernández  1 , Yolanda Martin  22 , Andrea Viqueira  23 , Jesús García-Foncillas  1
Affiliations
Observational Study

Functional PTGS2 polymorphism-based models as novel predictive markers in metastatic renal cell carcinoma patients receiving first-line sunitinib

Arancha Cebrián et al. Sci Rep. .

Abstract

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management.

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Figures

Figure 1
Figure 1
Association of single nucleotide polymorphism rs2243250 (IL4) (A) and rs5275 (PTGS2) (B) with cancer-specific survival in metastatic renal cell carcinoma patients treated with sunitinib. Correlation between PTGS2 mRNA expression levels according to rs5275 genotypes (C). Gene expression was determined in patients carrying T allele (TT/TC) or homozygous for C allele. There is a significant difference between the T carriers and CC genotype (P = 0.013).
Figure 2
Figure 2
Kaplan-Meier curves for each of the proposed two-SNPs models. (A) Progression-free survival for patients grouped by adverse genotypes in rs5275 (PTGS2) and rs7651265 (PIK3CA). (B) Cancer-specific survival for patients stratified according to combination of deleterious genotypes in rs5275 (PTGS2) and rs2243250 (IL4).
See this image and copyright information in PMC

References

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