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Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil

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Abstract

Purpose

Chemoradiotherapy using 5-fluorouracil has shown to be effective treatment for rectal cancer. Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. However, the predictive role of TS levels in early stage rectal cancer is not yet well understood. We analyzed the value of TS gene polymorphisms as a predictive marker in patients with stage II and III rectal cancer treated with preoperative concomitant radiotherapy and fluoropyrimidine-based chemotherapy.

Methods and materials

Between 1998 and 2007, blood samples were obtained from 51 patients with stage II/III rectal cancer. Forty patients were T2–3 (78%), 11 were T4 (22%), and 59% were N+. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR-restriction fragment length polymorphism and automated sequencing techniques.

Results

The *3/*3 thymidylate synthase genotype was associated with a higher response rate (pathological complete remission and microfoci residual tumor; 61 vs. 22% in *2/*2 and *2/*3; P = 0.013). In the multivariate analysis, the *3/*3 thymidylate synthase genotype was also an independent prognostic factor for better survival (P < 0.05).

Conclusions

The thymidylate synthase genotype might help to identify patients with stage II/III rectal cancer who could benefit from pre- and postoperative fluorouracil-based chemotherapy.

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References

  • Danenberg PV (1977) Thymidylate synthetase—a target enzyme in cancer chemotherapy. Biochim Biophys Acta 473:73–92

    CAS  PubMed  Google Scholar 

  • Dotor E, Cuatrecases M, Martinez-Iniesta M, Navarro M, Vilardell F, Guino E, Pareja L, Figueras A, Mollevi DG, Serrano T, de Oca J, Peinado MA, Moreno V, Germa JR, Capella G, Villanueva A (2006) Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 24:1603–1611

    Article  CAS  PubMed  Google Scholar 

  • Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23

    Article  CAS  PubMed  Google Scholar 

  • Gusella M, Bolzonella C, Crepaldi G, Ferrazzi E, Padrini R (2006) A novel G/C single-nucleotide polymorphism in the double 28-bp repeat thymidylate synthase allele. Pharmacogenomics J 6:421–424

    Article  CAS  PubMed  Google Scholar 

  • Horie N, Aiba H, Oguro K, Hojo H, Takeishi K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20:191–197

    Article  CAS  PubMed  Google Scholar 

  • Jakob C, Liersch T, Meyer W, Baretton GB, Hausler P, Schwabe W, Becker H, Aust DE (2005) Immunohistochemical analysis of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer (cUICC II/III): correlation with histopathologic tumor regression after 5-fluorouracil-based long-term neoadjuvant chemoradiotherapy. Am J Surg Pathol 29:1304–1309

    Article  PubMed  Google Scholar 

  • Jakob C, Liersch T, Meyer W, Baretton GB, Schwabe W, Hausler P, Kulle B, Becker H, Aust DE (2006) Prognostic value of histologic tumor regression, thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer UICC Stage II/III after neoadjuvant chemoradiotherapy. Am J Surg Pathol 30:1169–1174

    PubMed  Google Scholar 

  • Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE (2008) Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol 14:1060–1066

    Article  CAS  PubMed  Google Scholar 

  • Janjan NA, Khoo VS, Abbruzzese J, Pazdur R, Dubrow R, Cleary KR, Allen PK, Lynch PM, Glober G, Wolff R, Rich TA, Skibber J (1999) Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 44:1027–1038

    CAS  PubMed  Google Scholar 

  • Kawakami K, Watanabe G (2003) Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 63:6004–6007

    CAS  PubMed  Google Scholar 

  • Kawakami K, Omura K, Kanehira E, Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252

    CAS  PubMed  Google Scholar 

  • Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7:4096–4101

    CAS  PubMed  Google Scholar 

  • Liersch T, Langer C, Ghadimi BM, Kulle B, Aust DE, Baretton GB, Schwabe W, Hausler P, Becker H, Jakob C (2006) Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol 24:4062–4068

    Article  CAS  PubMed  Google Scholar 

  • Lindebjerg J, Spindler KL, Ploen J, Jakobsen A (2009) The prognostic value of lymph node metastases and tumor regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy. Colorectal Dis 11:264–269

    Article  CAS  PubMed  Google Scholar 

  • Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    Article  CAS  PubMed  Google Scholar 

  • Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73:2680–2686

    Article  CAS  PubMed  Google Scholar 

  • Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD (2003) A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63:2898–2904

    CAS  PubMed  Google Scholar 

  • Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352:476–487

    Article  CAS  PubMed  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  PubMed  Google Scholar 

  • Negri FV, Campanini N, Camisa R, Pucci F, Bui S, Ceccon G, Martinelli R, Fumagalli M, Losardo PL, Crafa P, Bordi C, Cascinu S, Ardizzoni A (2008) Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer 98:143–147

    Article  CAS  PubMed  Google Scholar 

  • Pare L, Marcuello E, Altes A, del Rio E, Sedano L, Barnadas A, Baiget M (2008) Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin? Pharmacogenomics J 8:315–320

    Article  CAS  PubMed  Google Scholar 

  • Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688–8696

    Article  PubMed  Google Scholar 

  • Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R, Group GermanRectalCancerStudy (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

    Article  CAS  PubMed  Google Scholar 

  • Spindler KL, Nielsen JN, Lindebjerg J, Jakobsen A (2007) Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 50:1363–1369

    Article  PubMed  Google Scholar 

  • Stoehlmacher J, Goekkurt E, Mogck U, Aust DE, Kramer M, Baretton GB, Liersch T, Ehninger G, Jakob C (2008) Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation. Cancer Lett 272:221–225

    Article  CAS  PubMed  Google Scholar 

  • Tepper JE, O’Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ (2002) Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control–final report of intergroup 0114. J Clin Oncol 20:1744–1750

    Article  CAS  PubMed  Google Scholar 

  • Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9:1381–1385

    CAS  PubMed  Google Scholar 

  • Villafranca E, Okruzhnov Y, Dominguez MA, Garcia-Foncillas J, Azinovic I, Martinez E, Illarramendi JJ, Arias F, Martinez Monge R, Salgado E, Angeletti S, Brugarolas A (2001) Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 19:1779–1786

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

DP is a fellowship recipient of the Instituto de Salud Carlos III (CM08/00065). This study was supported in part by Instituto de Salud Carlos III (FIS/080199). The authors thank Carolyn Newey for revising the English.

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Authors and Affiliations

  1. Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    David Páez, Agustí Barnadas & Eugenio Marcuello

  2. Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    Laia Paré, Juliana Salazar, Elisabeth del Rio & Montserrat Baiget

  3. Department of Hematology, Althaia Foundation, Av. Bases de Manresa 6-8, 08242, Manresa, Spain

    Albert Altés

  4. Department of Pathology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    Francesc Josep Sancho-Poch

  5. Department of Radiotherapy, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    Lourdes Petriz

  6. Department of Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    Jordi Garriga

  7. Department of Radiology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Pare Claret 167, 08025, Barcelona, Spain

    Josep Maria Monill

  8. U-705, CIBERER, Barcelona, Spain

    Juliana Salazar

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  1. David Páez
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  2. Laia Paré
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  3. Albert Altés
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  5. Lourdes Petriz
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  8. Juliana Salazar
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  9. Elisabeth del Rio
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  10. Agustí Barnadas
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Correspondence to David Páez.

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Páez, D., Paré, L., Altés, A. et al. Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil. J Cancer Res Clin Oncol 136, 1681–1689 (2010). https://doi.org/10.1007/s00432-010-0826-7

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  • DOI: https://doi.org/10.1007/s00432-010-0826-7

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