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Lana, Andrea (2016) CXCL12, CXCR4 and IL8 Genetic Polymorphysm in the Prognosis of Human Gastric Cancer. [Tesi di dottorato]

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Abstract (inglese)

Background: In the last few years gastric cancer’s prognosis hasn’t improved. At the present the two main prognostic factors are the TNM staging classification and surgery with radical intent.
Objective: To identify independent prognostic factors to improve the risk stratification of gastric cancer’s death and to select patients at high risk to be submitted to adjuvant treatment because the TNM classification presents uncertainty primarily in the intermediate stages and, although an apparently radical surgery, gastric cancer prognosis remains poor. The study is based on tumor microenvironment because the are many recent evidences that underline its fundamental role in tumor growth, angiogenesis and metastasis.
Materials and Methods: 333 patients affected with gastric cancer at different TNM stages (I- IV) of disease who underwent radical surgery from 1991. Before surgery a sample of peripheral blood was withdrawn from each patient. From each sample PBMC were used for DNA (germline) isolation for allelic discrimination assay. This study evaluated a set of polymorphisms of three different genes coding for CXCL12 and IL8 (cytokines) and CXCR4 (receptor) and the present work shows the partial results concerning the following three polymorphisms: rs1801157, rs2228014 e rs4073.
Results: Survival analysis reported no statistically significant results (p-value>0,05) in allelic, dominant and recessive genetic models. As regards the data anatomo-pathological, a statistically significant correlation between polymorphisms and grading and lymphatic and venous infiltration in the three genetic models was not found (p-value>0,05). Instead, a weakly association (p-value=0,049) between genotypes A/A and A/T of rs4073 of the gene encoding for IL8 and lymph node involvement was found in the dominant model. At the logistic regression with lymph node involvement as dependent variable: odds ratio=0,602, p-value=0,050, I.C.95%=0,363-0.999. At the multivariate analysis the polymorphism wasn’t found to be an independent factor of T parameter of TNM staging (odds ratio=0,663; I.C. 95%=0,361-1,215; p-value:0,184).
Conclusions: The results of this thesis suggest that there are interesting evidences in favour of the association between the allele T of rs4073 and the decreased risk of lymph node metastasis but that these can’t be considered conclusive. New studies are needed to analyze additional polymorphisms of the gene encoding for IL8 because these can explain the association between the protein and the lymph node involvement with a more consistent level of significance.

Abstract (italiano)

Presupposti dello studio: La prognosi del cancro gastrico non è migliorata in maniera significativa negli ultimi anni. Attualmente i due principali fattori prognostici sono rappresentati dallo stadio TNM alla diagnosi e dalla possibilità di ottenere un intervento chirurgico apparentemente radicale.
Scopo dello studio: Individuare nuovi fattori prognostici indipendenti che permettano di migliorare la stratificazione del rischio di decesso per carcinoma gastrico e selezionare quei soggetti che potrebbero beneficiare di una terapia adiuvante dal momento che la stadiazione TNM presenta un certo grado di incertezza soprattutto negli stadi intermedi e che, nonostante una chirurgia apparentemente radicale, la prognosi rimane insoddisfacente in una significativa percentuale di casi. Si è studiato il microambiente tumorale per le crescenti evidenze indicanti un ruolo fondamentale del microambiente tumorale nei processi di proliferazione, angiogenesi e metastatizzazione.
Materiali e metodi: Sono stati arruolati 333 soggetti sottoposti ad intervento chirurgico per carcinoma gastrico (stadi I- IV) a partire dal 1991. Ogni soggetto è stato sottoposto ad un prelievo di sangue venoso periferico nel pre-operatorio dalle cui PBMC è stato estratto il DNA (germline) per la discriminazione allelica. Lo studio ha esaminato un set di polimorfismi di tre diversi geni (codificanti per le citochine CXCL12 e IL8 e per il recettore CXCR4) e la presente tesi riporta dei risultati parziali che riguardano i seguenti tre polimorfismi: rs1801157, rs2228014 e rs4073.
Risultati: L’analisi di sopravvivenza non ha riportato risultati statisticamente significativi (p-value>0,05) nei modelli genetici allelico, dominante e recessivo. Per quanto riguarda i dati anatomo-patologici esaminati non è stata individuata una correlazione statisticamente significativa (p-value>0,05) tra i polimorfismi e grading, infiltrazione linfatica e venosa nei tre modelli genetici. È stata, invece, evidenziata un’associazione debolmente significativa (p-value=0,049) tra i genotipi A/A e A/T del polimorfismo rs4073 del gene codificante per IL8 e il coinvolgimento linfonodale nel modello dominante. Alla regressione logistica con variabile dipendente il coinvolgimento linfonodale: odds ratio=0,602, p-value=0,050, I.C.95%=0,363-0.999. All’analisi multivariata il polimorfismo non è risultato essere un fattore indipendente dal parametro T della stadiazione TNM (odds ratio=0,663; I.C. 95%=0,361-1,215; p-value:0,184).
Conclusioni: Questo lavoro suggerisce che vi siano delle evidenze interessanti a favore dell’associazione dell’allele T del polimorfismo rs4073 e la riduzione del rischio di metastasi linfonodali, ma che non possano essere ritenute conclusive. Sono pertanto necessari ulteriori studi allo scopo di analizzare ulteriori polimorfismi del gene per IL8 che potrebbero spiegare, con un livello di significatività più consistente, l’associazione tra la proteina e il coinvolgimento linfonodale.

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Tipo di EPrint:Tesi di dottorato
Relatore:Nitti, Donato
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:25 Gennaio 2016
Anno di Pubblicazione:25 Gennaio 2016
Parole chiave (italiano / inglese):CXCL12, CXCR4, IL8, cancro dello stomaco/gastric cancer, polimorfismi/polymorphisms,
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/18 Chirurgia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:9135
Depositato il:07 Ott 2016 13:01
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I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Ferro A, Peleteiro B, Malvezzi M, Bosetti C, Bertuccio P, Levi F, et al. Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype. Eur J Cancer. 2014;50:1330–44. Cerca con Google

2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. Cerca con Google

3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917 Cerca con Google

4. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81 Cerca con Google

5. http://www.registri-tumori.it/PDF/AIOM2014/I_numeri_del_cancro_2014.pdf Vai! Cerca con Google

6. Lauren P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49. Cerca con Google

7. Polkowski W, van Sandick JW, Offerhaus GJ, et al. Prognostic value of Laurén classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 1999;6:290-7 Cerca con Google

8. Lauren P. The two histological main types of gastric carcinoma: diffuse and so called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31-49 Cerca con Google

9. Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet 1999;36:873-80 Cerca con Google

10. Kaneko S, Yoshimura T. Time trend analysis of gastric cancer incidence in Japan by histological types, 1975-1989. Br J Cancer 2001;84:400-5 Cerca con Google

11. Parsonnet J, Vandersteen D, Goates J, et al. Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 1991;83:640-3 Cerca con Google

12. Lauwers GY, Carneiro F, Graham DY. Gastric carcinoma. In: Bowman FT, Carneiro F, Hruban RH, eds. Classification of Tumours of the Digestive System. WHO; 2010 Cerca con Google

13. Hughes C, Greywoode G, Chetty R. Gastric pseudo-signet ring cells: a potential diagnostic pitfall. Virchows Arch 2011;459:347-9 Cerca con Google

14. Chandrasoma PT, Der R, Ma Y, et al. Histology of the gastroesophageal junction: an autopsy study. Am J Surg Pathol 2000;24:402-9 Cerca con Google

15. Genta RM, Huberman RM, Graham DY. The gastric cardia in Helicobacter pylori infection. Hum Pathol 1994;25:915-9 Cerca con Google

16. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998;85:1457-9 Cerca con Google

17. Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging manuel. 7 th ed. New York: Springer, 2010. Cerca con Google

18. Huang Q, Shi J, Feng A, et al. Gastric cardiac carcinomas involving the esophagus are more adequately staged as gastric cancers by the 7th edition of the American Joint Commission on Cancer Staging System. Mod Pathol 2011;24:138-46. Cerca con Google

19. Hamilton R, Aatonen LA. Tumors of Digestive System.Lyon:IARC; 2000:39-52. Cerca con Google

20. Murakami T. Patholomorphological diagnosis. Definition and gross classification of early gastric cancer. Gann Monohr Cancer Res 1971;11:53-5 Cerca con Google

21. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. GastrointestEndosc 2003;58:S3-43 Cerca con Google

22. Everett SM, Axon AT. Early gastric cancer in Europe. Gut 1997;41:142-50 Cerca con Google

23. Yoshikawa K, Maruyama K. Characteristics of gastric cancer invading to the proper muscle layer--with special reference to mortality and cause of death. Jpn J ClinOncol 1985;15:499-503 Cerca con Google

24. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20 Cerca con Google

25. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectablegastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J ClinOncol 2011;29:1715-21 Cerca con Google

26. Hwang SW, Lee DH, Lee SH, et al. Preoperative staging of gastric cancer by endoscopic ultrasonography and multidetector-row computed tomography. J Gastroenterol Hepatol 2010;25:512-8 Cerca con Google

27. Lee YY, Derakhshan MH. Environmental and Lifestyle Risk Factors of Gastric Cancer. Arch Iran Med. 2013;16(6):358-365 Cerca con Google

28. Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol. 1995;19 Suppl 1:S37-43. Cerca con Google

29. Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev MedPharmacol Sci. 2010;14(4):302-8. Cerca con Google

30. Smith MG, Hold LG, Tahara E et al (2006) Cellular and molecular aspects of gastric cancer. World J Gastroenterol 12:2979–2990 Cerca con Google

31. Tahara E (2004) Genetic pathways of two types of gastric cancer. In: Buffler P, Rice J, Bann R, Bird M, Boffeta P (eds) Mechanisms of carcinogenesis: contributions of molecular epidemiology. IARC Scientific Publications No.157, Lyon, pp 327–349 Cerca con Google

32. Kitamura Y, Kometani K, Hashida H et al (2007) SMAD4-deficinet intestinal tumors recruit CCR1 myeloid cells that promote invasion. Nat Genet 39:467–475 Cerca con Google

33. Tahara E (2005) Growth factors and oncogenes in gastrointestinal cancers. In: Meyers RA (ed) Encyclopedia of molecular cell biology and molecular medicine, vol 6. 2nd edn. Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim, pp 1–31 Cerca con Google

34. Kitadai Y. Cancer-stromal cell interaction and tumor angiogenesis in gastric cancer. Cancer Microenviron. 2010 Dec;3(1):109-16. Cerca con Google

35. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986;46:467–473. Cerca con Google

36. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6. Cerca con Google

37. Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996;77:858–863. Cerca con Google

38. Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett. 2008;267:226–244. Cerca con Google

39. Kitadai Y, Haruma K, Sumii K, Yamamoto S, Ue T, Yokozaki H, Yasui W, Ohmoto Y, Kajiyama G, Fidler IJ, et al. Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol. 1998;152:93–100. Cerca con Google

40. Tanimoto H, Yoshida K, Yokozaki H, Yasui W, Nakayama H, Ito H, Ohama K, Tahara E. Expression of basic fibroblast growth factor in human gastric carcinomas. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61:263–267. Cerca con Google

41. Takahashi Y, Bucana CD, Akagi Y, Liu W, Cleary KR, Mai M, Ellis LM. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res. 1998;4:429–434. Cerca con Google

42. Lee YL, Kuo WH, Lin CW, Chen W, Cheng WE, Chen SC, Shih CM. Association of genetic polymorphisms of CXCL12/SDF1 gene and its receptor, CXCR4, to the susceptibility and prognosis of non-small cell lung cancer. Lung Cancer. 2011 Aug;73(2):147-52. Cerca con Google

43. Schimanski CC, Jordan M, Schlaegel F, Schmidtmann I, Lang H, Galle PR, Moehler M, Gockel I. SNP rs1801157 significantly correlates with distant metastasis in CXCL12 expressing esophagogastric cancer. Int J Oncol. 2011 Aug;39(2):515-20. Cerca con Google

44. Lee HJ, Jo DY. “The role of the CXCR4/CXCL12 axis and its clinical implications in gastric cancer”. Histol Histopathol. 2012 Sep;27(9):1155-61. Cerca con Google

45. Teng Y.-H., Liu T.-H., Tseng H.-C., et al. Contribution of genetic polymorphisms of stromal cell-derived factor-1 and its receptor, CXCR4, to the susceptibility and clinicopathologic development of oral cancer. Head and Neck. 2009;31(10):1282–1288. Cerca con Google

46. Xue H, Liu J, Lin B, Wang Z, Sun J, Huang G. A meta-analysis of interleukin-8 -251 promoter polymorphism associated with gastric cancer risk. PLoS One. 2012;7(1):e28083. Cerca con Google

47. Kamali-Sarvestani E, Aliparasti MR,Atefi S. Association of interleukin-8 (IL-8 or CXCL8) -251T/A and CXCR2 +1208C/T gene polymorphisms with breast cancer. Neoplasma. 2007;54(6):484-9. Cerca con Google

48. Liu S, Yin C, Chu N, Han L, Li C. IL-8-251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population. Scand J Rheumatol. 2013;42(2):150-8. Cerca con Google

49. Rosenkilde MM, Schwartz TW. “The chemokine system -- a major regulator of angiogenesis in health and disease”. APMIS. 2004 Jul-Aug;112(7-8):481-95. Cerca con Google

50. Tahara E1. “Abnormal growth factor/cytokine network in gastric cancer”. Cancer Microenviron. 2008 Dec;1(1):85-91. Cerca con Google

51. Hölscher AH, Drebber U, Mönig SP, Schulte C, Vallböhmer D and Bollschweiler E: Early gastric cancer: lymph node metastasis starts with deep mucosal infiltration. Ann Surg 250: 791-797, 2009. Cerca con Google

52. Strieter RM: Chemokines: not just leukocyte chemoattractants in the promotion of cancer. Nat Immunol 2: 285-286, 2001. Cerca con Google

53. Rempel SA, Dudas S, Ge S and Gutierrez JA: Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6: 102-111, 2000. Cerca con Google

54. Murphy PM: Chemokines and the molecular basis of cancer metastasis. N Engl J Med 345: 833-835, 2001 Cerca con Google

55. Shi J, Li YJ, Yan B, Wei PK. “Interleukin-8: A potent promoter of human lymphatic endothelial cell growth in gastric cancer”. Oncol Rep. 2015 Jun;33(6):2703-10. Cerca con Google

56. McCarron SI, Edwards S, Evans PR, et al: Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res 2002; 62: 3369-72. Cerca con Google

57. Landi S, Moreno V, Gioia-Patricola L, et al: Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha , NF-KB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res 2003;63:3560-6. Cerca con Google

58. Taguchi A, Ohmiya N, Shirai K, Mabuchi N, Itoh A, Hirooka Y, Niwa Y, Goto H: Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev. 2005 Nov;14(11 Pt 1):2487-93. Cerca con Google

59. Kaouther Snoussi, Wijden Mahfoudh, Noureddine Bouaouina, Slim Ben Ahmed, A. Noureddine Helal, and Lotfi Chouchane: Genetic variation in Il-8 associated with increased risk and poor prognosis of breast carcinoma. Hum Immunol. 2006 Jan-Feb; 67(-2):13-21. Cerca con Google

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