#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Gene Expression Profiling in Prediction of Tumor Response to Neoadjuvant Concomitant Chemoradiotherapy in Patients with Locally Advanced Rectal Carcinoma: Pilot Study


Authors: I. Garajová 1,5;  O. Slabý 2,5;  M. Svoboda 1,5;  P. Fabian 2;  J. Silák 3;  T. Šmerdová 2;  I. Kocák 1;  J. Růžičková 4;  J. Hoch 6;  R. Vyzula 1,5
Authors‘ workplace: Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno 1;  Oddělení onkologické a experimentální patologie, Masarykův onkologický ústav, Brno 2;  Oddělení chirurgické onkologie, Masarykův onkologický ústav, Brno 3;  Klinika radiační onkologie, Masarykův onkologický ústav, Brno 4;  Lékařská fakulta, Masarykova univerzita, Brno 5;  Chirurgická klinika 2. LF UK a FNM, Praha 6
Published in: Čas. Lék. čes. 2008; 147: 381-386
Category: Original Article

Overview

Background.
Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It can reduce tumor volume, thus increases a feasibility of sphincter-sparing surgery, shows less acute toxicity, improves local control rate. It is based on fluoropyrimidines (5-fluorouracil, capecitabine) with concurrent radiotherapy. The aim of the study was to evaluate the capability of gene expression method to identify nonresponders (NR) pretherapeutically.

Methods and Results.
17 patients with LARA, clinical stage II, III according to IUCC were enrolled into our pilot study. Response to therapy was determined clinically by transrectal ultrasonography and CT/MRI before and after therapy and histopathologically by TRG (tumor regression grade) according to Mandard. Patients with TRG 1–2 were included to responders group (R) and patients with TRG 4–5 composed NR group. Gene expression levels of 440 genes were obtained by low-density oligonucleotide microarrays. Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 8 genes (RB1, RBBP4, HYOU1, JUNB, MDM4, CANX, MMP2, TCF7L2) significantly upregulated in NR.

Conclusions.
Validation of identified changes on the mRNA level (Real-Time PCR) and on protein level (immunohistochemistry) is ongoing. We suggest that low-density oligonucleotide microarray technology could contribute to individualize the therapy of patients with LARA.

Key words:
neoadjuvant therapy, fluoropyrimidines, radiotherapy, rectal adenocarcinomas, gene expression profiling, DNA arrays.


Sources

1. Rimkus, C., Friederichs, J., Boulesteix, A. et al.: Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal carcinoma. Clinical Gastroenterology and Hepatology, 2008, 6, s. 53–61.

2. Kocáková, I., Růžičková, J., Kocák I. et al.: Role of concomitant chemoradiotherapy in the treatment algorithm for rectal carcinoma. Čas. Lék. čes., 2003, 142 (Suppl. 1), s. 32–35.

3. Sauer, R., Becker, H., Hohenberger, W. et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N. Eng. J. Med., 2004, 351, s. 1731–1740.

4. Kapiteijn, E., Marijnen, C., Nagtegaal, I. et al.: Preoperative radiotherapy combined with total mesorectal excision for resecable rectal cancer. N. Eng. J. Med., 2001, 345, s. 638–646.

5. Bosset, J., Collette, L., Calais, G. et al.: Chemotherapy with preoperative radiotherapy in rectal cancer. N. Eng. J. Med., 2006, 355, s. 1114–1123.

6. Gerard, J., Conroy, T., Bonnetain, F. et al.: Preoperative radiotherapy with or without concurrent fluorouracil with leucovorin in T3–4 rectal cancers: results of FFCD 9203. J. Clin. Oncol., 2006, 24, s. 4620–4625.

7. Yerushalmi, R., Idelevich, E., Dror, Y. et al.: Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continous infusion of 5-fluorouracil. J. Clin. Oncol., 2006, 93, s. 529–533.

8. Ortholan, C., Francois, E., Thomas, O. et al.: Role of radiotherapy with surgery for T3 and resecable T4 rectal cancer: evidence from randomized trials. Dis. Colon Rectum, 2006, 49, s. 302–310.

9. Kim, D., Kim, D., Kim, T. et al.: Is T classification still correlated with lymph node status after preoperative chemoradiotherapy for rectal cancer? Cancer, 2006, 106, s. 1694–700.

10. Theodoropoulos, G., Wise, W., Padmanabhan., A. et al.: T‑level downstaging and complete pathological response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis. Colon Rectum, 2002, 45, s. 895–903.

11. Kocáková, I., Svoboda M., K., Kubosova, K. et al.: Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine physphorylase mRNAs in rectal carcinoma. Neoplasma, 2007, 54, s. 447–453.

12. Merkerová, M., Kráčmarová, A., Bruchová, H. et al.: Využití biočipových technologií v onkologii. Klin. Onkol., 2006, 19 (Suppl. 2), s. 333–337.

13. Brdička, R., Bruchová, H. et al.: Vznik a rozmach čipových technológií. Klin. Onkol., 2006, 19 (Suppl. 2), s. 331–332.

14. Svoboda, M., Michálek, J. et al: Úvod do technologie DNA čipů. Lékař a technika, 2006, 35, s. 67–75.

15. Mandard, A., Dalibard, F., Mandard, J. et al.: Pathologic assessment of tumor regression after preoperative chemoradiotherapy of oesophageal carcinoma: Clinicopathologic correlations. Cancer, 1994, 73, s. 2680–2686.

16. Schroeder, A., Mueller, O., Stocker, S. et al.: The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol. Biol., 2006, 7, s. 3–13.

17. Dudoit, S., Gentleman, R., Quackenbush, J. et al.: Open source software for the analysis of microarray data. Biotechniques, 2003 (Suppl.), s. 45–51.

18. Kooperberg, C., Sipione, S., LeBlanc, M. et al.: Evaluating test statistics to select interesting genes in microarray experiments. Hum. Mol. Genet., 2002, 11, s. 2223–2232.

19. Slabý, O., Garajová, I., Svoboda, M. et al.: Pilotní studie identifikace prognostických markerů u pacientů s kolorektálním karcinomem analýzou profilů genové exprese. Klin. Onkol., 2006, 19 (Suppl. 2), s. 402–407.

20. Slabý, O., Garajová, I., Svoboda, M. et al.: Studium patogeneze kolorektálních karcinomů pomocí profilů genové exprese a možnosti jejich využití v diagnostické a prediktivní onkologii. Klin. Onkol., 2006, 19 (Suppl. 2), s. 382–388.

21. Clemo, N., Arhel, N., Barnes, J. et al.: The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival. Biochem. Soc. Trans., 2005, 33, s. 676–678.

22. Scuto, A., Zhang, H., Zhao, H. et al.: RbAp48 regulates cytoskeletal organization and morphology by increasing K–Ras activity and signaling through mitogen-activated protein kinase. Cancer Res., 2007, 67, s. 10317–10324.

23. Pacifico, F., Paolillo, M., Chiapetta, G. et al.: RbAp48 is a target of nuclear factor-kappaB activity in thyroid cancer. J. Clin. Endocrinol. Metab., 2007, 92, s. 1458–1466.

24. Wardman, P.: Chemical radiosenzitiers for use in radiotherapy. Clin. Oncol. (R. Coll. Radiol.), 2007, 19, s. 397–417.

25. Stojadinovic, A., Hooke, J., Shriver, C. et al.: HYOU1/Orp150 expression in breast cancer. Med. Sci. Monit., 2007, 13, s. 231–239.

26. Mathas, S., Hinz, M., Anagnostopoulos, I. et al.: Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-B. Embo J., 2002, 21, s. 4104–4113.

27. Gilkes, D., Chen, L., Chen, J. et al.: MDMX regulation of p53 response to ribosomal stress. Embo J., 2006, 25, s. 5614–5625.

28. Delom, F., Fessart, D., Chevet, E. et al.: Regulation of calnexin sub-cellular localization modulates endoplasmic reticulum stress-induced apoptosis in MCF-7 cells. Apoptosis, 2007, 12, s. 293–305.

29. Arenas-Huertero, F., Herrera-Goepfert, R., Delgado-Chavez, R. et al.: Matrix metalloproteinases expressed in squamous cell carcinoma of the oral cavity: correlation with clinicopathologic features and neo–adjuvant chemotherapy response. J. Exp. Clin. Cancer Res., 1999, 18, s. 279–284.

30. Angenete, E., Langenskiöld, M., Falk, P. et al.: Matrix metalloproteinases in rectal mucosa, tumour and plasma: response after preoperative irradiation. Int. J. Colorectal. Dis., 2007, 22, s. 667–674.

31. Hilska, M., Roberts, P., Collan, Y. et al.: Prognostic significance of matrix metalloproteinases-1,-2,-7 and -13 and tissue inhibitors of metalloproteinases-1,-2,-3 and -4 in colorectal cancer. Int. J. Cancer, 2007, 15, s. 714–723.

32. Burwinkel, B., Shanmugam, K., Hemminki, K. et al.: Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case control study. BMC Cancer, 2006, 6, s. 268–271.

33. Ghadimi, B., Grade, M., Difilippantonio, M. et al.: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J. Clin. Oncol., 2005, 23, s. 1826–1838.

34. Watanabe, T., Komuro, Y., Kiyomatsu, T. et al.: Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles. Cancer Res., 2006, 66, s. 3370–3374.

35. Kim, I., Lim, S., Kang, H. et al.: Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis. Colon Rectum, 2007, 50, s. 1342–1353.

36. Dworak, O., Keilholz, L., Hoffman, A. et al.: Pathological features of rectal cancer after preoperative radiochemotherapy. Int. J. Colorectal. Dis., 1997, 12, s. 19–23.

37. Response assessment of nonsurgical treatment for colorectal carcinoma. Japanese classification of colorectal carcinoma. Japanese Society for Cancer of the Colon and Rectum. 1st English ed.Tokyo, Kanehara & Co. Ltd, 1997, s. 77–82.

Labels
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain management
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#