K-ras mutational status and tumour-infiltrating lymphocytes in human colon cancer: state of the art and future perspectives
Authors:
P. Kocian 1; M. Šedivcová 3; J. Drgáč 4; K. Černá 3
; J. Hoch 1; R. Kodet 4; J. Bartůňková 2; R. Špíšek 2; A. Fialová 2
Authors place of work:
Chirurgická klinika 2. LF UK a FN v Motole
1; Ústav imunologie 2. LF UK a FN v Motole
2; Ústav patologie LF Plzeň
3; Ústav patologie a molekulární medicíny 2. LF UK a FN v Motole
4
Published in the journal:
Rozhl. Chir., 2012, roč. 91, č. 8, s. 427-432.
Category:
Original articles
Práce byla věnována prof. MUDr. Jiřímu Hochovi, CSc. při příležitosti jeho významného životního jubilea.
Summary
Introduction:
Nowadays, the prognosis of newly diagnosed colorectal cancer patients relies mostly on the tumour-node-metastasis (TNM) classification which is also a determining criterion for the indication of adjuvant oncological treatment. Currently, new prognostic and predictive biomarkers are sought after in order to more precisely define prognosis and better predict the benefits of adjuvant treatment in colorectal cancer. Besides several molecular biomarkers, such as mutations in the proto-oncogene K-ras, analyses of tumour-infiltrating lymphocytes have shown promising prognostic value. The aim of the study is to examine the correlations between K-ras mutational status and tumour-infiltrating immune cells in colon cancer patients with respect to colon cancer recurrence.
Material and methods:
Formalin-fixed paraffin-embedded specimens were obtained from 44 patients with surgically resected colon cancer (R0 resection) treated between 2004 and 2009. K-ras mutational status was detected using PCR amplification of exon 1 followed by direct sequencing and K-ras StripAssay. Tumour-infiltrating immune cells were detected by immunofluorescence staining using monoclonal antibodies against CD3, CD8, FoxP3, CD1a and DC-LAMP.
Results:
All 44 patients in our cohort underwent radical resection of colon cancer. In 16 patients the tumour relapsed (36.4%). K-ras mutations were found in 45.5% (n=20) of the primary carcinomas: 65% in codon 12 and 35% in codon 13. Although codon 13 K-ras mutations were associated with disease relapse, they were present in both disease-free and relapsed patients. However, disease-free and relapsed patients differed markedly in their patterns of tumour-infiltrating immune cells. There was a trend towards decreased density of tumour-infiltrating lymphocytes within the group of relapsed patients. In addition, relapsed patients with codon 13 mutations had markedly lower levels of tumour-infiltrating mature DC-LAMP+ dendritic cells and higher frequency of CD1a+ cells compared to disease-free patients.
Conclusion:
Colon cancer patients with low levels of tumour-infiltrating lymphocytes, a high CD1a+/DC-LAMP+ tumour-infiltrating DC ratio and a K-ras mutation in codon 13 are at a high risk of disease recurrence.
Keywords:
colorectal cancer– K-ras– tumour-infiltrating lymphocytes
Zdroje
1. Chau I, Cunningham D. Adjuvant therapy in colon cancer– what, when and how? Ann Oncol 2006;17(9):1347–59.
2. Chung KY, Saltz LB. Adjuvant therapy of colon cancer: current status and future directions. Cancer J 2007;13(3):192–7.
3. Van Cutsem E, Oliveira J. Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol 2009;20 Suppl4:49–50.
4. Bazan V et al. Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol 2002;13(9):1438–46.
5. Bos JL et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987;327(6120):293–7.
6. Boughdady IS et al. K-ras gene mutations in adenomas and carcinomas of the colon. Surg Oncol 1992;1(4):275–82.
7. Benvenuti S et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007;67(6):2643–8.
8. De Roock W et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19(3):508–15.
9. Di Fiore F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 2007;96(8):1166–9.
10. Lievre A et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26(3):374–9.
11. Andersen SN et al. K-ras mutations and prognosis in large-bowel carcinomas. Scand J Gastroenterol 1997;32(1):62–9.
12. Ince WL et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 2005;97(13): 981–9.
13. Tortola S et al. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol 1999;17(5):1375–81.
14. Galon J et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–4.
15. Chiba T et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004;91(9):1711–7.
16. Naito Y et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998;58(16):3491–4.
17. Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
18. Ropponen KM et al. Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;182(3): 318–24.
19. Forrester K et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 1987;327(6120): 298–303.
20. Pretlow TP et al. K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst 1993;85(24):2004–7.
21. Vogelstein B et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319(9):525–32.
22. Dunn GP et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3(11):991–8.
23. Dadabayev AR et al. Dendritic cells in colorectal cancer correlate with other tumor-infiltrating immune cells. Cancer Immunol Immunother 2004;53(11):978–86.
24. Dhodapkar MV et al. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001;193(2):233–8.
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