Thymidine phosphorylase gene variant, platelet counts and survival in gastrointestinal cancer patients treated by fluoropyrimidines

Liu Huang, Fengju Chen, Yangyang Chen, Xiaomei Yang, Sanpeng Xu, Shuwang Ge, Shengling Fu, Tengfei Chao, Qianqian Yu, Xin Liao, Guangyuan Hu, Peng Zhang, Xianglin Yuan, Liu Huang, Fengju Chen, Yangyang Chen, Xiaomei Yang, Sanpeng Xu, Shuwang Ge, Shengling Fu, Tengfei Chao, Qianqian Yu, Xin Liao, Guangyuan Hu, Peng Zhang, Xianglin Yuan

Abstract

The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF ≥ 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients.

Figures

Figure 1
Figure 1
(A; B; C; D): OS in patients according to Age, Thrombocytopenia, Thrombocytosis, and Smoke status; (E; F; G; H): Prognostic value of platelet counts in patients with different rs11479 genotypes (log-rank test).
Figure 2. Immunohistochemical staining for thymidine phosphorylase…
Figure 2. Immunohistochemical staining for thymidine phosphorylase (TP)in cancer tissues (original magnification × 100).
TP = 0, Stromal cells TP-positive but TP-negative tumor cells (a);TP = 1, more than 5% but less than 50% of the cancer cells were TP-positive (b); TP = 2, more than 50% of the cancer cells were TP-positive (c).

References

    1. Miyadera K. et al. Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res. 55, 1687–1690 (1995).
    1. Bronckaers A., Gago F., Balzarini J. & Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med. Res. Rev. 29, 903–953 (2009).
    1. Sasaki K., Kawai K., Tsuno N. H., Sunami E. & Kitayama J. Impact of Preoperative Thrombocytosis on the Survival of Patients with Primary Colorectal Cancer. World J. Surg., 10.1007/s00268-011-1329-7 (2011).
    1. Ishizuka M., Nagata H., Takagi K., Iwasaki Y. & Kubota K. Preoperative thrombocytosis is associated with survival after surgery for colorectal cancer. J. Surg. Oncol. 106, 887–891, 10.1002/jso.23163 (2012).
    1. Hwang S. G. et al. Impact of pretreatment thrombocytosis on blood-borne metastasis and prognosis of gastric cancer. Eur. J. Surg. Oncol. 38, 562–567, 10.1016/j.ejso.2012.04.009 (2012).
    1. Kohne C. H. et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann. Oncol. 13, 308–317 (2002).
    1. Nyasavajjala S. M. et al. Is there a role for pre-operative thrombocytosis in the management of colorectal cancer? Int J Surg 8, 436–438, 10.1016/j.ijsu.2010.05.005 (2010).
    1. Sobrero A., Guglielmi A., Grossi F., Puglisi F. & Aschele C. Mechanism of action of fluoropyrimidines: relevance to the new developments in colorectal cancer chemotherapy. Semin. Oncol. 27, 72–77 (2000).
    1. Longley D. B., Harkin D. P. & Johnston P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3, 330–338, 10.1038/nrc1074 (2003).
    1. Dolnick B. J., Angelino N. J., Dolnick R. & Sufrin J. R. A novel function for the rTS gene. Cancer Biol Ther 2, 364–369 (2003).
    1. Farina-Sarasqueta A., van Lijnschoten G., Rutten H. J. & van den Brule A. J. Value of gene polymorphisms as markers of 5-FU therapy response in stage III colon carcinoma: a pilot study. Cancer Chemother. Pharmacol. 66, 1167–1171, 10.1007/s00280-010-1403-0 (2010).
    1. Capitain O. et al. The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogenomics J 8, 256–267, 10.1038/sj.tpj.6500476 (2008).
    1. Ruzzo A. et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J. Clin. Oncol. 25, 1247–1254, 10.1200/jco.2006.08.1844 (2007).
    1. Jakobsen A., Nielsen J. N., Gyldenkerne N. & Lindeberg J. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J. Clin. Oncol. 23, 1365–1369, 10.1200/jco.2005.06.219 (2005).
    1. Martinez-Balibrea E. et al. UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy. Br. J. Cancer 103, 581–589, 10.1038/sj.bjc.6605776 (2010).
    1. Baranyai Z. et al. The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer. Thromb. Haemost. 111, 10.1160/th13-08-0632 (2013).
    1. Wan S. et al. Preoperative platelet count associates with survival and distant metastasis in surgically resected colorectal cancer patients. J Gastrointest Cancer 44, 293–304, 10.1007/s12029-013-9491-9 (2013).
    1. Giessen C. et al. Analysis for prognostic factors of 60-day mortality: evaluation of an irinotecan-based phase III trial performed in the first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 10, 317–324, 10.1016/j.clcc.2011.03.027 (2011).
    1. Son H. J. et al. Preoperative plasma hyperfibrinogenemia is predictive of poor prognosis in patients with nonmetastatic colon cancer. Ann. Surg. Oncol. 20, 2908–2913, 10.1245/s10434-013-2968-8 (2013).
    1. Shaw T., Smillie R. H. & MacPhee D. G. The role of blood platelets in nucleoside metabolism: assay, cellular location and significance of thymidine phosphorylase in human blood. Mutat. Res. 200, 99–116 (1988).
    1. Jennings B. A. et al. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. PloS one 8, e78053, 10.1371/journal.pone.0078053 (2013).
    1. Arienti C. et al. Role of conventional chemosensitivity test and tissue biomarker expression in predicting response to treatment of peritoneal carcinomatosis from colon cancer. Clin Colorectal Cancer 12, 122–127, 10.1016/j.clcc.2012.11.006 (2013).
    1. Marcuello E. et al. Single nucleotide polymorphism in the 5′ tandem repeat sequences of Thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int. J. Cancer 112, 733–737, 10.1002/ije.20487 (2004).
    1. Wang Y. C., Xue H. P., Wang Z. H. & Fang J. Y. An integrated analysis of the association between Ts gene polymorphisms and clinical outcome in gastric and colorectal cancer patients treated with 5-FU-based regimens. Mol. Biol. Rep. 40, 4637–4644, 10.1007/s11033-013-2557-8 (2013).
    1. Etienne-Grimaldi M. C. et al. Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan. Br. J. Clin. Pharmacol. 73, 776–785, 10.1111/j.1365-2125.2011.04141.x (2012).
    1. Gusella M. et al. Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer. Br. J. Cancer 100, 1549–1557, 10.1038/sj.bjc.6605052 (2009).
    1. Uchida K., Danenberg P. V., Danenberg K. D. & Grem J. L. Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 8, 386, 10.1186/1471-2407-8-386 (2008).
    1. Popat S., Matakidou A. & Houlston R. S. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J. Clin. Oncol. 22, 529–536 (2004).
    1. Salonga D. et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin. Cancer Res. 6, 1322–1327 (2000).
    1. Meropol N. J. et al. Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J. Clin. Oncol. 24, 4069–4077 (2006).
    1. Kodera Y. et al. Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: correlation with drug sensitivity against 5-fluorouracil. Cancer Lett. 252, 307–313, 10.1016/j.canlet.2007.01.006 (2007).
    1. Koopman M. et al. Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study. Eur. J. Cancer 45, 1999–2006, 10.1016/j.ejca.2009.04.017 (2009).
    1. Stoehlmacher J. et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br. J. Cancer 91, 344–354, 10.1038/sj.bjc.6601975 (2004).
    1. Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 13 Suppl 2, 19–21, 10.1634/theoncologist.13-S2-19 (2008).
    1. Luo H. Y. et al. Phase 2 study of capecitabine and irinotecan combination chemotherapy (modified XELIRI regimen) in patients with advanced gastric cancer. American journal of clinical oncology 34, 555–560, 10.1097/COC.0b013e3181f47ac1 (2011).
    1. van der Bol J. M. et al. Cigarette smoking and irinotecan treatment: Pharmacokinetic interaction and effects on neutropenia. Journal of Clinical Oncology 25, 2719–2726, 10.1200/jco.2006.09.6115 (2007).

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