... : : 2418 (COX-2) (DPD)

... :. 2011-2012..: 2418 (COX-2) (DPD) 2012

...... ( 5343/32,.20 2.1268/82,. 50 8)

,

(650-570..)

1. 1.1 1.2 1.3, 2. 2.1 2.2 2.3 2.4 2.5-2.6-2.7 2.8 2.9 2.10 3. 3.1 3.2 3.3 4.

ii 5. 5.1 5.2 6. 7. 7.1 7.2 7.3 8. 8.1 8.2 8.3 8.4 8.5 (COX-2) 8.6 (DPD) 9. 10. 10.1 10.2 ( ) 10.3 10.4 10.5 RNA 10.6 (PCR) 11.

iii 12. A 12.1 12.2 12.3 12.4 mrna DPYD PTGS2 (40- CT) 12.5 COX-2 ( ) 12.6 (OS) (DFS) 12.7,, OS, DFS 12.8 13. 14. 15. 16. SUMMARY

iv

v 20,.,,,, 1 2.,,,,,,.,,,.... 1998, -,, /,,.,,, 13..,,.,.

vi -...,.,,..,,,..,,.... (HECOG),..,,,.,,,.,,,.

vii o 5-FU 5- Fluorouacil / 5 o ACF Abberant crypt foci/ o ACS American Cancer Society / o AJCC American Joint Committee on Cancer / o APC Adenomatous Polyposis Coli / o APR Abdominoperineal Resection / o ASCO American Society of Clinical Oncology / o ASCRS American Society of Colon and Rectal Surgeons / o CEA Carcinoembryonic antigen/ o COX Cyclooxygenase / o CRC Colorectal Cancer / o CRM Circumferential Resection Margins / o DALYs Disability Adjusted Life Years / o DFS Didease Free Survival / o DPD Dihydropyrimidine Dehydrogenase / o DRM Distal Resection Margin / o EGF Epidermal Growth Factor / o EGFR Epidermal Growth Factor Receptor / o EGTM European Group of Tumor Markers / o ESMO European Society for Medical Oncology / o EUS Endoscopic Ultrasonography / o FAP Familial Adenomatous Polyposis / o FGF Fibroblast Growth Factor / o FISH Fluorescence In Situ Hybridization / in situ

viii o FOBT Fecal Occult Blood Testing / o HNPCC Hereditary Nonpolyposis Colorectal Cancer / o HR Hazard Ratio / o IARC International Agency for Research on Cancer / o IHC Immunohistochemistry/ A (AIX) o IUAG International Union Against Cancer / o LAR Low Anterior Resection / o LOH Loss of Heterozygosity / o LV Leukovorin / o mac modified Astler-Coller / Astler-Coller o MAPK Mitogen Activated Protein Kinases / o MMPs Matrix Metalloproteinases/ o MMR Mismatch Repair / DNA o mrna Messanger ribonucleic acid/ o MSI/MIN Microsatellite Instability / o MSS Microsatellite stable/ o NCCN National Comprehensive Cancer Network / o NCI National Cancer Institute / o NSAIDs Non-Steroidal Anti-Inflammatory Drugs / ( ) o OECD Organization for Economic Co-operation and Development / ( ) o OS Overall Survival / o PCR: Polymerase Chain Reaction / o PDGF Platelet-derived Growth Factor / o PET Positron Emission Tomography / o PFS Progression-Free Survival / o PPARs Peroxisome Proliferator-Activated Receptors /

ix o RER Replication Error / o RR Relative Risk / o SE R Surveillance, Epidemiology and End Results /, (NCI) o SMAC Second Mitochondrial Activator of Caspases / o TEMs Transanal Endoscopic Microsurgery / o TGF- Transforming Growth Factor-beta / o TK Tyrosine Kinase / o TMA: Tissue Microarrays / o TNF-a Tumor Necrosis Factor-alpha / o TRAIL TNF-Related Apoptosis-Including Ligand / TNF o UICC Union for International Cancer Control / o VEGF Vascular Endothelial Growth Factor / o WCRF World Cancer Research Fund / o WHO World Health Organization / ( ) o World Cancer Declaration

x

3 1. 1.1 O,,,. 1-2 2008,, 12.7 7.6, 56% 64%. 3-4,,. 5-11 1.2. 12,,,,,. ( ), 2008 1.233.700 608.700, 9.7% 8% 5-6, 13., (10%), (16,5%) (13,6%), (7,6%), (22,5%), (11,3%) (11%),.,, (9,4%), (22,9%),

4 (8,6%), (13,7%) (12,8%). 2008 663.600 320.600.,, 570.100 288.100. 5-6,13 ( ) -.,,,.,., (,, ) (,, )., ( ),., (,, ),, 1, 5-6, 13-17., (7.8 100.000 ),, 8.4% 2008. 18 Globocan 2008 (...), (15.7 100.000),,, (9.3 100.000),., (11.0 100.000), (6.6 100.000),. 11,19-21

5 1.3,, 35% - 40%.,. (48,3%) (51,7%), ( 1.2:1), (57,5%) (42,5%) ( 1.7:1). 15-16, 22-23 5,3% ( 19 ) 4,97% ( 20 )..., 2,17% ( 12, 15 46) 2,03% ( 49). 40, 50 55 ( ). 90% 94% 50. 6, 12, 14, 16, 24-26...., 72., -. 20% 45% -.,,,,. 16, 27

6 2... ( ), 18, 28-29,. (60-85% ), 10-30%, 5% ( 1). 30 1.., (60 80 ). 31-32,,. (Familiar Adenomatous Polyposis, FAP) (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) Lynch. 31-32

7,, ( ), ( 50 ).. 31-32 2.1, (aberrant crypt foci (ACP), ), ( ),, ( ). (HNPCC), (FAP, APC) (sporadic cancer),,,. 33,,. (germline mutations) (somatic mutations). Fearon Vogelstein,.,, 31, 34-35. : -,.. 36-38 (oncogenes), -. -,,..,

8,,,..,, -. - G1. K-ras, myc, src, erbb2, 31, 37, 39-41 BRAF. (tumor suppressor genes) S ( DNA),.,.,,.. : APC ( ), p53, DCC (Deleted in colon cancer, 31, 37, 39-41 ), SMAD4, SMAD2. DNA (MMR: Missmatch Repair) DNA, G2. 37, 39-40 DNA. 1. (gatekeepers) (caretakers).,., (APC), ( ) -..

9,, -. 40-44 1.. 31 APC* MMR** HNPCC*** ( Lynch) myc ras src erbb2 p53 DCC APC MMR hmsh2 hmlh1 hpms1 hpms2 hmsh6 hmsh3 *APC: **MMR: DNA ***HNPCC:. DNA (MMR), (HNPCC).,.,.,, 4,,, 40, 42-44., TP53., TP53, ( )

10 DNA, DNA. DNA,., TP53,., TP53, 40-41, 45-46., APC, 1987 5 1991 5q21. APC 310 KDa. PC,,,., 80% 40, 47-48 PC. ( Lynch), 5,, DNA. hmsh2, hmsh6, hmlh1, hpms1 hpms2. hmlh1 hmsh2. 5,.,, 40, 48-51. /. (HNPCC) Amsterdam ( 2) Bethesda ( 3).

11 MLH1 MSH2 Amsterdam Bethesda. 52-54 2. Amsterdam 50,54-59 Amsterdam I (1990)*: Amsterdam II (1998)*: 1. 1. HNPCC,. HNPCC (..,,, ). 2. 2.. 3. 50.. 3.. 4. 4.. 50. 5.. * HNPCC 50, 52, 54-60 3. Bethesda (1997)* 1. Amsterdam. 2. HNPCC, - (,,, -,, ). 3. / - HNPCC /, 45 40. 4. 45. 5. 45. 6. (signet ring cell type), 45. 7. 40. * HNPCC,..,.

12 2.2 (DNA),., ( ) : (Loss of Heterozygosity Pathway) DNA (Mismatch Repair Deficiency Pathway). 47,53,61-67 (LOH),,, (CIN). 70%., Kras, APC p53,. 53, 61-67. DNA (MMR Deficiency Pathway), (mismatches) DNA. MMR 6 (MMR- Mismatch Repair genes): hmlh1, hmsh2, hmsh3, hmsh6, hpms1, hpms2. MMR, DNA,, (microsatellites). DNA (Microsatellite Instability, MSI). 10-15% (85-90%) 53-54, 61-69 (HNPCC).

13 (MSI)., MSI (MSI-H), 30-40%., MSI (MSI-L) 30-40%, MSI (Microsatellite Stable, MSS), ( ). MSI-L MSS., 54, 61-62, 65-66, 68-69 MSI., 15%, DNA MSI-H (High-Microsatellite Instability). (promoter) hmlh1, mrna hmlh1,., MMR. MSI-H 62, 64-68, 70-71. (MSI-H),.,, (Crohn s like). MSI,,,,,,,.,,

14,,,,,., MSI,. MSI 2 (COX-2),,,, COX-2. MSI-H (. / ). (, - ). 33,54,61-62,64-65,67-68,70-71 -.. /,, DNA.., APC, (aberrant crypt foci, ACF)., COX-2,. ACF, K-ras APC.,,,,,.,,,., DCC,. DCC 18q22

15.,,.,,,, (tumor progression). p16 p53,. p53 17p 70% Fearon Vogelstein,,. ( ) 47, 53, 61, 65-66, 72-82. (MSI). HNPCC MSI hmlh1 hmsh2. MSI (promoter) hmlh1, 33, 47, 53, 61, 65, 72-79, 81-84 hmlh1. H Volgestein Fearon 2. 2.. 85

16 2.3 : 1. 50. 40, 50 55, ( ). 90% 50. 12, 14, 16, 25, 27 2...,.,., 28, 86-89. 3.. ( ) ( 3-6%), ( ) ( 2-5%)., 50% 5-7. 90-93 4.. 15-20%. ( 50 ). 94-97 5. (, Crohn). 10 15-20

17 ( ). 0.5% 10 20 1% 20. 16, 30, 94-97 6.. : ),. 20-25 40. : i) (FAP): 1% -. (APCgene) 5q21-q22. 100%. ii) Gardner, iii) Turcot, iv) Peutz-Jehers. 16,30,96-98 ) (HNPCC Lynch I II). 2-5%. DNA (MMR) (MSI). 70-80%. - (,,, -,, 16, 30, 96-98 ). 4 (stratification). 99-107 4.. (Low Risk) <50 (Average Risk) >50 (Increased Risk) Crohn (High Risk) (FAP) (HNPCC)

18 2.4 50-80%,. ( ),,. 108-112 (10 12 /ml ),, (mutagens). -,, -,, 7-.., 95, 109-110, 112.,.. 16, 95, 109-110, 112-127,,..,,., 16, 95, 109-110, 112-124, 128-130.

19,,. (, 9), : 1) 2)., D. 16, 109-110, 112-124 (,, ), 109-110, 131-132. 2.5 -.,.,,,,,., 16, 29, 109-111, 115, 119-123. 60 86, (Body Mass Index,, Kg/m 2 ).. 15% 5Kg/m 2. 16, 29, 95, 109-112, 119-123, 133-134

20 2.6 - - 21 ( )., 2-3,. 16, 29, 109, 115, 119-124, 135-137, (24),,.,. 16, 29, 109, 119, 121, 123-124, 138 2.7., ( ), (feedback). (>10 ) 32, 112, 139-141.,,,, 32, 142. (100-550 ). 32, 112, 141,

21 (Pouch). 32 2.8,,. -, C, D,., (NSAIDs) -2 (COX-2), 16,28-29,95,115,123, 143-144. 2.9,,.,,,, 16,28-29, 115,123,143,145. 2.10, : ( ),, ( )

22,. 95 (World Cancer Research Fund, WCRF) (American Institute for Cancer Research, AICR) 16, 104, 110, 113, 146 : 1. (<20% ). 2.,,,,. 5. 3.. 4. (,,, ). 5.. 6.. 7.. 8. (,, ). 30 60 30. 9. (,, ). (American Society of Colon and Rectal Surgeons, ASCRS) 5. 147-149

23 5. (ASCRS). 149 I. : (65-75%).. II. : (20-30%)., 55. >55. (>1cm). -. : (6-8%)... 1. 2. : (FOBT) ( ),,,, (, ) 50 50 FOBT, 5 50 5-10 40 10, 50 10, 1 5 5-10 -1-5 - 3-5 - 12-14 ( ) 1-2 21-40 40 2 15 8 1-2 1-2 FOBT (Fecal Occult Blood Testing):

24 3. 3.1 ( ) 130, 5, 10-15,..,,,.. 7-9, 112, 150-151,. ( - - ),.,....,.. 10%, 112, 150-151. ( - - - ).

25 ( )... 112, 150-151., ( )....,,. 112, 150-151 ( ). 3.2 ( ) : 150-153 1. :., 2.,.,,. 2. :....

26 3. :.... 4. :. Blumer, frozen pelvis, Kruckenberg. 5. :.. 3.3 O : 1) 2) A 3) 4) 112, 150-151 5) :,. 6).

27 4..,,, (, Crohn) 112, 150-153. : ( ), ( ) ( ). ( ) ( ) ( )., ( ).. 112, 150-153 H (fecal occult blood testing, FOBT) ( 90%),,,.,. 112, 150-153..,. 112, 150-153.,

28,,,, Crohn.. 112, 150-153,.,,.,,.,. (CEA)., (..,,, ). CEA.,,. CEA 90%., CEA 112, 150-153 CA50, CA19-9, TPA AFP.,, (, )., ( 81-95%),. 153 DNA test ( ), (Virtual colonoscopy, CT colonography) ( RI Colonography).. ras-

29. 154-156

30 5. 5.1 : 151-152 1.. 2.. 3.. 4.. 5.. 5.2 : 1. : 95-98%.,,. >50%, (signet-ring)... 28, 112, 151, 157-158. / (grade),,.,, (),. >95% (Grade 1), 50-95% (Grade 2) <50% (Grade 3), <5% (Grade 4). 157-158

31 2. (NET, NEC):.. Lieberkuhn. 28, 112,157 3. :.,. 112, 157-158 PV. 28, 157-158 4. :. 5. :. 28, 157-158.

32 6.. : ), ), ) ). : ) ( c ),,, ) ( p ),, 30-31, 112, 150-151., ( ), C. E. Dukes (1932) stler Coller (1954). (American Joint Committee on Cancer, AJCC) (UICC) ( Tumor, Node, Metastasis ).,, ( ), ( ) 30-31, 112, 150-151 ( ). 31, 112, 151-152 Dukes (1932).. C. D.

33 31, 112, 151-152 Astler Coller (1954) :. 1: (Dukes A) 2:, (Dukes B). B3:. C1:,. C2:,. C3:. D:. (AJCC 7 ) 7 UICC/AJCC (2010),. 159 ( ) x 0 Tis in situ, T1 2 3 4a 4b

34 ( ) x 0 1 1 3 1a N1b 2-3 1c,,, 2 4 2a 4 6 2b 7 ( ) 0 1 1a,,,, 1b 7,,, C ( 4bN0), IV IVA IVB., 1a, N1b N2a N2b,,,., 4bN1,, IIIC, C.,,,,,,,. 159

35 6. A 159 Dukes MAC 0 Tis N0 M0 - - I T1 T2 N0 N0 M0 M0 A A A B1 IIA IIB IIC IIIA IIIB IIIC T3 T4a T4b T1 T2 T1 T3 T4a T2 T3 T1 T2 T4a T3 T4a T4b N0 N0 N0 N1 / N1c N2a N1 / N1c N2a N2b N2a N2b N1 N2 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 IVA 1a - - IV T 1b - - B B B C C C C C C C C B2 B2 B3 C1 C1 C2 C1/C2 C1 7 5 TNM. 7. TNM 5. 28 NM 5 5 Ca Ca I T1-2N0MO 74% 74% IIA T3N0M0 67% 65% IIB T4aN0M0 59% 52% IIC T4bN0M0 37% 32% IIIA T1 2N1/NIcM0 T1N2aM0 73% 74% IIIB T3 T4aN1/N1cM0 T2 T3N2aM0 T1 T2N2bM0 46% 45% IIIC T4aN2aM0 T3-T4aN2bM0 28% 33% T4bN1-2M0 IV 1 6% 6% (R) 112, 159,,. RX R0 R1 R2 C2 C2 C3

36 (Circumferential Resection Margins, CRM),. (mm). (CRM) 31, 159-164 TNM.

37 7. 7.1.. Morson,.,.,., (No 30-31, 58, 112, 165-166 Touch Technique).,,,.,,.,. - -,. -. 30-31, 38, 58, 112, 150-151, 165-166 : ) (LAR) -, >4, ) (APR),

38, ) Hartmann,,,,. ) 30-31, 38, 58, 112, 150-151, 165-167., (en block) 30-31, 38, 58, 150, 166-167. 7.2. ( II III TNM B C Duke), 40% II 70% 31, 38, 112, 167, 168-174 III ( 8). 8. 31 TNM DUKE 5- (%) I A, B1 85-95 II B2 60-80 III C 30-60 IV D <5,. (adjuvant) -.,. (adjuvant),.

39,, 31, 112, 168-174. DNA,. (Fluorouracil, 5-FU) (TS), DNA. (Capecitabine) (Per os). (Irinotecan) DNA, DNA,. (Oxaliplatin) DNA DNA. Cetuximab (Erbitux) (EGF) (EGFR),,.,,,,. Bevacizumab (Avastin) - (VEGF) (VEGFR).,, 31, 170. (Fluorouracil, 5-FU) (, Leucovorin, LV), (FOLFOX) (FOLFIRI). 5-FU (TS), 5-FU 30-31, 38, 168-174.

40 MOSAIC, 2.246 II (40%) III (60%) LV5FU2 (FOLFOX 4). 44 FOLFOX 4 3 (78.7% 73.3%), 23% (P=0.0008). III (70% 61%, P=0.002), II (85% 81%, ).,,.. (bolus) 5-FU., 5-FU (bolus) 31, 175 5-FU., 5-FU, 6 5-FU, III. 5-FU, 5-FU. FOLFOX 4 III, 30-31, 38, 150, 166, 168-175. III, II., II (5- : 75%)

41. - 31, 176. QUASAR-1 II. (3.238 91% II) 5-FU,. 22.2% 26.2%, 5-80.3% 77.4%.,,, 3% II., II, MOSAIC. 31,175,177, (ASCO) II.,,, 5%., : 4,,, (<12),.,, 31, 174, 178., II, 31, 38, 168-178.. (EGFR-cetuximab) (VEGF-bevacizumab),

42.,,.,.,. II, ( 18, ), 31, 169-174, 178.,,,, 30-31, 38, 150, 166, 169-179. 7.3,,., 10%. 38, 180-181., 3,, 4 (downstaging),,.

43 40-60%.,. 30, 166, 179-184.,.,.,, ( ).,, 5-fluorouracil, 5-FU, (radiosensitiser).,, -, /, 30, 38, 112, 150-151, 179-184. - (neoadjuvant), 5,. 165-166,180-181

44 8. 8.1,,,, (, ).,,. (screening),,,,. 112, 185-189., ( ),.,, 67, 73, 190-198..,. 67,198, : ) [Ki-67, (PCNA)], ) / (p53, K-ras, DCC/LOH 18q, cl-2, c-erb2/her2), ) DNA (microsatellite instability, MSI), ) (, VEGF), ) (, matrix ) ) [ (COX-2),

45 (DPD), (TS), 190, 197 (TP)]. 8.2 112, 199 : 1. :, ( ), ( ).. 2. / :. 3. :,,.,,.,,, (15-20mm). 25mm.,. 4. : (20%), 5, (>60%). 5. :. (0-2%).

46,., 5. 8.3 112, 199 : 1. :.,,,. 2. :.,. 3. :,,.,.. 4. :. 5. : 5. 6. :.

47 7. :,,.. 8. :,.. 9. - :,. 8.4 ( II),. p53. p53 17 (17p13.1) P53, (53kD). P53 G1 S, DNA, ( ). p53 50%., 31, 67, 190, 194, 197., p53 wild type ( ) p53 (20 ). p53,

48. p53,,. P53,., (European Group of Tumor Markers, EGTM) (ASCO),, 31, 38, 62, 67, 78, 190, 197-198, 200-202. cl-2. - Bcl-2 ( ). (t14:18),,. bcl-2, (bcl-xl), (bax, bcl-xs). bcl-2 p53. P53 bcl-2,,, 31, 190, 200 bax, bcl-2. bcl-2 P53., P53 bcl-2., bcl-2 P53, de novo. bcl-2, 31, 190, 200, 203-204. K-Ras. RAS (Rat Sarcoma virus) - (K-ras, H-ras, N-ras) GDP/GTP RAS (21kDa),,. K-ras

49. K-ras,,. K-ras,, 31, 67-68, 73, 78, 190, 194, 196, 198, 200-202 EGFR. Ras 50% 50%, 1cm. K-ras,, (61% 33% ). cetuximab panitumumab ( ).,. 12 13 K-ras 31, 67-68, 73, 78, 190, 194, 196,,198, 200-202, 204-208 -EGFR. c-myc. c-myc,,,. c-myc,, ( ), p53. 209 p53 p53 c. c-myc Bcl-2. c-myc, Bcl-2.. c-myc 70-80%. 67, 209-210 HER-2 (c-erbb-2).,,

50,. c-erbb-2 20-40%,. c-erbb-2 Duke. c-erbb-2 o, 31, 190. VEGF. (VEGF),,,.,, 31, 190, 197, 200, 206, 208. EGFR. (EGFR), ( ),., 7 7p12.1-12.3 26. ErbB (ErbB1, HER1).,. 31,68,78,200, 204, 208, 211-213 EGFR 60-70%. EGFR., -EGFR (cetumimab, panitumumab, gefitinib) EGFR. FISH. 12 13 K-ras

51 -EGFR /. 206, 211-213 68, 73, 196-197, 204, 18q (18qLOH). 18q DCC (deleted in colon cancer) SMAD2 SMAD4,. To DCC 18q21. DCC (adhesion molecule).,, G2M. SMAD4, 18q,, - (TGF-beta). TGF-beta,. SMAD4, 18q (SMAD2), 31, 38, 67,190, 201. (LOH, Loss of Heterozygosity) (,, DCC), 70%.,, 18qLOH, 18qLOH. DCC 18qLOH,, 31, 38, 67, 73, 78, 190, 197-198, 201-202, 205, 214. (Ki-67, PCNA). PCNA Ki-67, II. Ki-67 31, 190, 204.

52. (plasminogen-related molecules) (matrix metalloproteinases, MMPs). 78, 190, 200, 215,. (MSI)., DNA, (Replication Error, RER). ( ) ( ),. 30-40%, (MSI-High). <30-40% MSI (MSI-Low)., (MSS, Microsatellite 33, 62, 68, 73, 78, 190, 198, 202, 214 Stable). (MSI-H),., MSI-H,,,, MSI-L MSS., MSI-H 5-FU,. MSI- H 54,62, 67, 68, 73, 78, 190, 198, 201-202, 205, 214, 216-219 (irinotecan).

53 (TS). H, (dump) (dtmp), DNA S. TS 5-FU,. TS, TS 31, 78, 190, 197-198, 202 (DFS). Oncotype Dx., «Oncotype Dx»,. 12 3.. (recurrence score) 0 100. 1-30. 30-40 40,. 205,,,.,,. (Cyclooxygenase, COX- 2) (Dihydropyrimidine Dehydrogenase, DPD). 8.5 (COX-2), (- ) (- ),,

54. 220-222 (COX) H (Prostaglandin H Synthase, PGHS) (Prostaglandins, PG) (Thromboxane A 2, TXA 2 ) (Arachidonic Acid, )., 2 (Phospholipase A 2, PLA 2 ). PGG 2 PGH 2. [PGE 2, PGD 2, PGI 2 ( ), PGF 2 ] (TXA 2 ) ( 3).. (PG) (TX) PG 5, TX 6. 222-224 1994, (COX), COX-1 COX-2., ( 600 ), 70 kda. :,,., COX-3 ( COX-1b), / (splice-variant) COX-1. 224-227 COX-1.. (constitutively),,.,

55 2-4. COX-1,,,. 222-229,, 2 COX 2O 2 COX-1 COX-2 PGG 2 2e - PGH 2 PGE 2 PGI 2 PGD 2 PGF 2 TXA 2 3. (PG) (TX) (COX-1, COX-2). 224 COX-2,,,,, Henle. COX-2, (PAF), -1 (IL-1) (LPS). COX-2,,. COX-2

56,,, IL-3, IL-4 IL-10. 20.,. 9 COX-2. 222-229 9. COX-2. / IL-1 afgf PGE 2 IL-1 bfgf NO IL-6 IL-8 IGF stress IL-11 EGF 25- TNF LPS INF- PDGF TGF VEGF COX-2,. 604, 69 kda..,., ( ),.,. COX-1 ( 4). 434 523, COX-1 (Ile) COX-2 (Val), COX-2. 226-2 (PTGS2) 1991. 1 ( COX-1 9) 1q25.2-q25.3,

57. 8.3 kb ( COX-1 22 kb) 10 ( COX-1 11 ). 5, TATA, NF-IL6 (Nuclear Factor-IL-6), AP-2 (Activator Protein 2 binding site), Sp1 (Stimulatory protein1), NF-kB (Nuclear Factor kappa B), CRE (camp Response Element) E. -,. (MAPK, Mitogen Activated Protein Kinases),. MAPK 3 ERKs, JNKs/SAPKs p38 MAPK. PTGS2 Ras. Ras COX-2 mrna. COX-2, 78, 226, 230 (PDGF). 4. COX-2. (http://en.wikipedia.org/wiki/file:6cox.png),,, COX-2

58,. COX-2. COX-2 80% 40%,., RNA (COX-2 mrna), COX-1 78, 224, 231-235. COX-2, Dukes,,. Seehan., Fujita. COX-2 Dukes,. 232-233, 236 Fujita. mrna COX-2. 236 Dimberg. COX-2, Hong.,. 233,237-238 COX-2,. (MSI) MMR, COX-2. COX-2 HNPCC, 233, 239-240. COX-2,, (cross-talk).,,,.,. COX-2,

59. COX-2 E 2 (PGE 2 ),. PGE 2, ( 222, 227-230, 233, 241, ). COX-2. PGE 2 Bcl-2. Bcl-2, 228-229, 233, 242., PGE 2,., (PPAR, Peroxisome Proliferator-Activating Receptor). PPAR. H COX-2 PPAR mrna. 227,233,240,242-244 COX-2. COX-2 VEGF., VEGF,. COX-2, o bfgf, 78, 227-228, 233,240, 243-244 TGF -1, PTGF, -1. COX-2 PGE 2, in vitro, - (TNF- ) 220, 227-228, 244-10,.

60, COX-2, PGE 2, IV,., COX-2, NF-kB, K-ras 227-228, 233, 243-244., COX-2.,, PPAR, NF-kB AP-1 (activator protein-1).,, COX-2.,, p53 COX-2 TBP (TATAbinding protein, ) TATA. 230,, NF-kB, EGFR,, MAPK-AP-1., PPAR PPAR. NF-kB AP-1 COX-2, PPAR NF-kB AP-1, COX-2., CBP [c- AMP response element (CREB) binding protein] COX-2.,, p53 p53 ( p53 ), 230, 244 COX-2., :,,.

61 ( ). ( ),. 245-246 Giovannucci Ed.. 20,. 247 222, 248-251 (FAP). COX-,.,., 40-50%,.,, COX-2 (COXIBs). COX-2 (COXIBs).,., COX-2, FDA, Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the US Food and Drug Administration «... COXIBs celecoxib 220, 222-223, 252-257».

62 8.6 (DPD) 40, 5- (5-FU)., 10 30%,., 40-50%., 5-202, 258-260 FU. 5- (5-FU) Heidelberger 1957,.. 5-5 ( 5). 260-262 5-FU.,. 5-FU (TP) 5- -2 - (FUdR), (TK) 5- - 5- -2 - (FdUMP), 5-FU ( 5). 5,10- - (5,10-MTHF, CH 2 FH 4 ), 5- - (FdUMP) (TS). (TS) de novo 5 - - (dtmp) 5-2 - (dump). (TS) 5 - - (dtmp),

63 (dtdp) (dttp). (dttp) DNA ( ). (LV) 5,10- (CH 2 FH 4 ), FdUMP S 5-FU. 202, 263-266 5. 5- (5-FU). 265 5-FU,, (FUR, FUrd) (UP)., (UK) (FUMP). 5 - -1-1- (PRPP) (OPRT) 5- FU (FUMP). (FUDP) (FUTP). FUTP RNA RNA, RNA ( 5). 263-266

64 5- - (FdUMP) (FUDP) (FdUDP) (RR, ribonucleotide reductase). (FdU P) DNA DNA 5-FU. 263-266,, (DPD), 5-FU,. 85% 5-FU DPD 1-3 %. 5- FU, 5-FU. 5-FU DPD (DHFU), 5-FU. (DPYS,DHP) - - (FUPA) - ( -ureidopropionase, BUP1) - - - (FBAL) CO 2 ( 6). 263-267 6. 5-FU DPD. 266 DPD -,., DPD., DPD 15%,

65, DPD. 267-268 3-5% DPD, 5-FU,,,. :,.,,,,, (, ),, - [ - (hand-foot syndrome)].. 67,78,260,264 DPD DPD,,. DPD (DPYD) 1 1p22. 23 > 950 kb ( 7). 40 (Single Nucleotide Polymorphisms, SNPs) (deletion) (insertion). DPD. IVS14+1G>A (DPYD*2A), 14. 40-50% DPD <1%., DPYD 5-FU. DPD, DPD, DPD. 202, 266-275

66 7. DPD. IVS14+1G>A (DPYD*2A). 271 10 DPD,. ( ) IVS14+1G>A (DPYD*2A) DPD,.,,. IVS14+1G>A (DPYD*2A) 5-FU. 269, 271, 273-274 10. DPD. 271 85 T>C 2 464 T>A 5 496 A>G 6 1109delTA 10 1601G>A, 1627A>G 13 1896 T>C 14 IVS14+1G>A 14 2194G>A 18 2846A>T 22 DPD. 195, 202, 276 in vitro in vivo

67 DPD 5-FU. 78, 195, 202 Tanaka-Nozaki M.. 5-FU (P<0.05) DPD (r=-0.463, P<0.05). 277 DPD. DPD DPD., DPD DPD. mrna DPD mrna DPD. 278-281 Salonga. DPD 5-FU, 5-FU. 195, 281-282 (TP) / (DPD) 5-FU, TP DPD. 267, 278, 283-284, TP/DPD. 285-287,,.,,,,. 267, 276, 288-289

71 9., (Cyclooxygenase, COX-2) (Dihydropyrimidine Dehydrogenase, DPD),.,.

72 10. 96 ( 8).,... ( ).......... 96 AIX COX-2 85 (89%) RT PCR COX-2 84 (88%) RT PCR DPD 84 (88%) 8. (Remark Flow Chart). 10.1 / ( / ),

73 (, -tissue microarrays). TMA /. / ( ).,. 10.2 ( ), (TMA Model I, Beecher Instruments, Sun Prairie, WI, U.S.A.)...,., 100, 96, (Paraplast ; McCormick, St. Louis, Mo., USA) 583. 5, 0,6.,,,. 1,0., (14 ) ( ) ( ). Excel (2 worksheets),,.,., 3 0,6., >95%, 99% 5. 290-293

74 10.3 COX-2 ( 4H12, Novocastra TM, Leica Biosystems, Newcastle Upon Tyne, UK, 1:300). 2.5 m (Dako, Glostrup, Denmark).. (ethanol) 100%, 96%, 70% 30. (sodium citrate solution, ph 6.0) 20. TBS (TrisBuffered Saline), (Power Block TM, BioGenex, San Ramon, USA). HRP super sensitive non-biotin detection system (BioGenex). 3, 3 - (DAB) Mayer. 10.4 COX-2 (cut-off). ( ) 0-3 (0 = 0 5%, 1 = 6 25%, 2 = 26% 50%, 3 = 51% 100%), ( ) 0-3 (0=, 1 =, 2 =, 3 = )., ( ) = + ( =0-6). COX-2, 4,, <4. 294

75 10.5 RNA RNA 84 10 m. 12 (12%) RNA., 56 C., RNA TRIZOL-LS., 2 g RNA cdna ( DNA), Superscript III Rnase-H - RNA ( Invitrogen / Life Technologies)., cdna 20-40 ng RNA equivalents / l ( 1:20 ). -20 o C. DPYD ( 1p22) COX2/PTGS2 ( 1q25.2-q25.3) real time PCR (qrt-pcr). (Taqman), FAM 5 - - 3 (minor-groovebinders, MGB). PCR. : ( ) mrna DPYD, Hs00559279_m1 74 bp 1 2 ( NM_000110.3), ( ) mrna COX2/PTGS2, Hs00153133_m1, 75 bp 5 6, NM_000963.1. PCR ( ) mrna (housekeeping) - (GUSB),. #4333767T ( QRT-PCR Applied

76 Biosystems).,, (RNA [reference RNA, Applied Biosystems]) ( ). 20 l, real time PCR ABI7500 (Applied Biosystems), (45 ), SDS v1.4. : (cycle threshold, CT) <36, CT (CT CT GUSB ) <0.5. DPYD COX2/PTGS2, (40 CT), CT CT ( ). 10.6 (PCR) (PCR) DNA. DNA, 92ºC 96ºC. DNA. (50º-65ºC) DNA. (primers), 18-30, DNA.,,, DNA. DNA 72ºC. DNA DNA 5 3. 34, 295-297 PCR Thermus Aquaticus (Taq Polymerase). H Taq

77 Polymerase 2000. DNA- PCR. PCR 30-40. 34, 295-297,. (Real Time PCR), PCR, (.. ). real time PCR. real time PCR,,, 34, 295-297.

78 11.,. Mann-Whitney. Rho Spearman mrna (DPYD PTGS2). Fisher (Fisher s exact test) 2 ( 2 test),. (OS), (DFS).,. Kaplan-Meier log-rank test. Cox OS DFS. : (> 65 <65), ( ), ( - ), ( ), ( 3-4 1-2), ( + N0), ( - ), COX-2 ( ), DPYD ( ) PTGS2 ( ). SPSS (SPSS Windows, 15.0, SPSS Inc.)

79 12. A 12.1 96, 49 (51%) 47 (49%). 11. 32.5 90, (70). 96 25 (26.0%) <65, 71(74.0%) 65 ( 9). 55 (57.3%), 41 (42.7%) ( 10). 17, 13 1 75. (28.1%) 1-3, 12 (12.5%) 4, 57 (59.4%)., ( 11). ( ), 4 (4.2%) ( 1), 14 (14.6%) ( 2), 72 (75.0%) ( 3), 6 (6.2%) ( 4b) ( 12). ( ) 13. (38, 39,6%), 30 (31,2%) UICC ( 14). stler- Coller (mac), 34 (35.5%) 2 32 (33.3%) C2 ( 15). (Grade), 26 (27.1%) (Grade I), 17 (17.7%) (Grade III), (53, 55.2%) (Grade II) ( 16).

80 11. (N) % ( ) N=96 ( ) 70 (32.5-90) <65 25 26.0 65 71 74.0 49 51.0 47 49.0 55 57.3 41 42.7 13 (1-75) 0 (0-18) 0 57 59.4 1-3 27 28.1 4 12 12.5 TNM ( ) T1 4 4.2 T2 14 14.6 T3 72 75.0 T4b 6 6.2 TNM ( ) N0 57 59.4 N1a 11 11.5 N1b 13 13.5 N1c 3 3.1 N2a 7 7.3 N2b 5 5.2 (AJCC) I 16 16.7 IIA 38 39.6 IIC 3 3.1 IIIA 2 2.1 IIIB 30 31.2 IIIC 7 7.3 Astler-Coller (mac) A 3 3.1 B1 17 17.7 B2 34 35.5 B3 3 3.1 C1 3 3.1 C2 32 33.3 C3 4 4.2 (Grade) I 26 27.1 II 53 55.2 III 17 17.7

81 9.. 10..

82 11.. 12. ( ).

83 13. ( ). 14. AJCC.

84 15. mac. 16. (Grade).

85 12.2 59 (61,5%) 96. 12.,. 6, 1 12., 26 (44.1%) 5-FU/Leukovorin, 18 (30.5%) FOLFOX (5-FU/Lekovorin/Oxaliplatin) 13 (22.0%) FOLFIRI (5-FU/Leukovorin/Irinotecan). FOLFOXIRI (5- FU/ / Oxaliplatin/Irinotecan). 12. N % 59 61.5 Fluorouracil / Leucovorin 26 44.1 FOLFOX 18 30.5 FOLFOXIRI 1 1.7 FOLFIRI 13 22.0 Capecitabine ( ) 1 1.7 ( ) 6 (1-12) 12.3 82.7 16.1 95.2 21 (21.9%) 30 (31.2%) ( 13). (OS) 3 84.2% (CI: 76.9-91.4) 5 76.7% (CI: 68.1-85.3), 102.7 (

86 ) 2.1 102.7. 3 (DFS) 78.1% (CI: 69.7-86.3), 5 68.5% (CI: 59.1-77.9) 2.1 84.6.. 17 Kaplan-Meier (DFS) ( 17 ) (OS) ( 17 ). 13. (OS) (DFS). (Overall Survival, OS) 30 (31.2%) (95% CI) 102.7 (CI: yet)* 3 (95% CI) 84.2% (76.9-91.4) 5 (95% CI) 76.7% (68.1-85.3) 2.1-102.7 (Disease free survival, DFS) 21 (21.9%) (95% CI) NE yet* 3 (95% CI) 78.1% (69.7-86.3) 5 (95% CI) 68.5% (59.1-77.9) 2.1-84.6 ( ) 82.7 (16.1-95.2) * NE: Not Estimated : Kaplan-Meier ( ) (DFS) (OS) 18. (p=0.045), (p=0.31).

17. Kaplan-Meier (DFS) ( ) (OS) ( ). 87

88 18. Kaplan-Meier ( ) (DFS) (OS).

89 12.4 mrna DPYD PTGS2 (40- CT) 96, mrna 84 (88%). 12 (12%) RNA. DPYD 38.36, 34.39 41.90. PTGS2, 37.31, 29.11 42.43. 19 mrna DPYD PTGS2. Spearman mrna DPYD PTGS2 (p<0.001), Rho (0.477) ( 14). mrna 20. 42 40 38 36 34 32 30 28 DPYD (40-dCT) PTGS2 (40-dCT) 19. mrna DPYD PTGS2.

90 14. Spearman mrna DPYD PTGS2 DPYD PTGS2 Spearman s (Rho) 0.477 p-value <0.001 42 40 DPYD (40-dCT) 38 36 34 32 30 28 28 30 32 34 36 38 40 42 44 PTGS2 (40-dCT) 20. mrna (DPYD PTGS2).

91 12.5 COX-2 ( ) 96, COX-2 85 (89%). 11 (11%). COX-2. COX- 2 59 (69.4%) ( 1), 26 (30.6%) ( 2), 15., 15 ( : 0) 11 ( : 2-3). COX-2. ( 3). DPYD PTGS2 COX- 2 ( 21, 22). Mann-Whitney test. 1. COX-2.

92. 2. COX-2 15. COX-2 N (%) COX-2 (n=85) / 26 (30.6) / 59 (69.4).. 3... COX-2.. COX-2..

93 21. mrna DPYD COX-2 (Mann-Whitney test). 22. mrna PTGS2 COX-2 (Mann-Whitney test).

94 12.6 (OS) (DFS) (DFS) (OS). o Cox ( 16) (p=0.018), (p=0.124). O Kaplan-Meier (p=0.008), (p=0.12) ( 23)., ( ) (p>0.05), Cox, Kaplan-Meier ( 24, 25, 26). (p<0.05),, Cox, Kaplan- Meier ( 27). (Grade) (p<0.05) OS DFS, Cox, Kaplan-Meier ( 28). (AJCC), Cox Kaplan-Meier ( 29) (p>0.05). (p<0.05) Kaplan-Meier (p=0.016), Cox.

95 16. Cox (DFS) (OS) (DFS) (OS) ( ) HR 95% CI Wald-p HR 95% CI Wald-p <65 1 1 65 1.992 0.829-4.789 0.124 5.624 1.337-23.665 0.018 1 1 0.749 0.386-1.453 0.392 0.773 0.369-1.618 0.494 1 1 1.203 0.625-2.314 0.581 1.232 0.595-2.552 0.575 TNM ( ) T1-T2 1 1 T3-T4b 1.649 0.640-4.247 0.300 1.222 0.466-3.207 0.683 TNM ( ) N0 1 1 N+ 2.553 1.313-4.965 0.006 1.704 0.822-3.535 0.152 I-II 1 1 III 2.332 1.122-4.847 0.023 2.718 1.234-5.986 0.013 (AJCC) I 1 1 II 0.778 0.266-2.277 0.646 0.713 0.239-2.128 0.544 III 2.145 0.807-5.698 0.126 1.354 0.492-3.728 0.558 HR: Hazard Ratio : / CI : Confidence Interval :

96 23. Kaplan-Meier (DFS) (OS).

24. Kaplan-Meier (DFS) (OS). 97

98 25. Kaplan-Meier (DFS) (OS).

99 26. Kaplan-Meier ( ) (DFS) (OS).

100 27. Kaplan-Meier (N) (DFS) (OS).

101 28. Kaplan-Meier (Grade) (DFS) (OS).

102 29. Kaplan-Meier (AJCC) (DFS) (OS).

103 12.7,, OS, DFS. 17. COX-2, mrna DPYD PTGS2,,, ( ), ( ), (Grade) (AJCC). Fisher (Fisher s exact test) 2 ( 2 test),. (p>0.05) ( ). Cox (DFS) (OS) 18. (p>0.05). mrna DPYD PTGS2 ( ). (p>0.05). Fisher (Fisher s exact test). ( 19). 30-32 Kaplan-Meier (DFS) (OS), ( ). (p>0.05) DFS OS, ( ).

104 17. COX2 DPYD PTGS2 ( ) / / p p p 0.159 0.803 0.129 <65 3 (11.5) 16 (27.1) 11 (26.8) 10 (23.3) 7 (16.7) 14 (33.3) 65 23 (88.5) 43 (72.9) 30 (73.2) 33 (76.7) 35 (83.3) 28 (66.7) 0.350 0.285 0.827 16 (61.5) 29 (49.2) 24 (58.5) 20 (46.5) 21 (50.0) 23 (54.8) 10 (38.5) 30 (50.8) 17 (41.5) 23 (53.5) 21 (50.0) 19 (45.2) 0.486 0.830 0.511 16 (61.5) 31 (52.5) 23 (56.1) 23 (53.5) 25 (59.5) 21 (50.0) 10 (38.5) 28 (47.5) 18 (43.9) 20 (46.5) 17 (40.5) 21 (50.0) TNM ( ) 0.134 0.999 0.277 T1-T2 2 (7.7) 13 (22.0) 8 (19.5) 9 (20.9) 6 (14.3) 11 (26.2) T3-T4b 24 (92.3) 46 (78.0) 33 (80.5) 34 (79.1) 36 (85.7) 31 (73.8) TNM (N) 0.643 0.186 0.999 N0 14 (53.8) 35 (59.3) 28 (68.3) 23 (53.5) 26 (61.9) 25 (59.5) N+ 12 (46.2) 24 (40.7) 13 (31.7) 20 (46.5) 16 (38.1) 17 (40.5) 0.767 0.783 0.405 I-II 21 (80.8) 49 (83.1) 34 (82.9) 34 (79.1) 36 (85.7) 32 (76.2) III 5 (19.2) 10 (16.9) 7 (17.1) 9 (20.9) 6 (14.3) 10 (23.8) (AJCC) 0.434 0.377 0.584 I 2 (7.7) 11 (18.6) 8 (19.5) 7 (16.3) 6 (14.3) 9 (21.4) II 12 (46.2) 24 (40.7) 20 (48.8) 16 (37.2) 20 (47.6) 16 (38.1) III 12 (46.2) 24 (40.7) 13 (31.7) 20 (46.5) 16 (38.1) 17 (40.5)

105 18. Cox (DFS) (OS). (DFS) (OS) HR 95% CI Wald-p HR 95% CI Wald-p ( ) COX2 / 1 1 / 0.852 0.417-1.741 0.661 0.808 0.365-1.787 0.599 mrna * DPYD PTGS2 (< ) 1 1 ( ) 0.979 0.499-1.920 0.951 1.084 0.522-2.251 0.828 (< ) 1 1 ( ) 0.551 0.276-1.102 0.092 0.558 0.263-1.181 0.127 * mrna ( ) DFS OS. (p>0.05).

106 19.. COX-2 DPYD PTGS2 / / p p p 0.81 0.99 0.99 9 (34.6) 23 (39.0) 17 (41.5) 17 (39.5) 17 (40.5) 17 (40.5) 17 (65.4) 36 (61.0) 24 (58.5) 26 (60.5) 25 (59.5) 25 (59.5)

107 30. Kaplan-Meier COX-2 (DFS) (OS) ( ).

108 31. Kaplan-Meier PTGS2 (DFS) (OS) ( ).

109 32. Kaplan-Meier DPYD (DFS) (OS) ( ).

110 12.8 (OS) (DFS) 20. ( ), (Grade) mrna PTGS2/COX-2 (DFS). (Grade) (OS). 20. (OS) (DFS). (DFS) HR 95% CI Wald s p (N) N0 1 N+ 2.22 1.11-4.43 0.024 (Grade) I-II 1 III 2.32 1.08-4.98 0.031 PTGS2 1 0.48 0.24-0.98 0.043 (OS) HR 95% CI Wald s p <65 1 65 6.08 1.44-25.67 0.014 (Grade) I-II 1 III 3.00 1.36-6.63 0.007

111 13. ( ).,,.. COX-2. 298-300 o, COX-2 (QRT-PCR) ( ). DPD. ELISA, QRT-PCR,. 301 96, (M0). 82.7., 59 (61.5%), 5- FU/LV (44.1%). (>88%).. 302-303 32.5 90 ( ). (71 ) 65 26% (25 ) <65. Cox Kaplan- Meier (OS) 65, p=0.018 p=0.008. Cox / (HR) 65 5.624 OS. (DFS) / (HR) 65 1.992,

112 DFS, p=0.124 p=0.12,. Li-Chu Sun. 1367 OS 65 (p=0.004) 1.30 <65. 304 Storli. OS Cox (p=0.001), Kaplan-Meier (p<0.001). 305 Prandi. 65 OS (p=0.0008), DFS (p=0.0041). 306, Andreoni. OS >65 (p=0.12). 307 /. 308-309 49 (51%) 47 (49%). 0.773 OS 0.749 DFS, OS DFS Cox (p=0.494 p=0.392 ), Kaplan-Meier (p=0.49 p=0.39 ). Storli. 305, Andreoni. 307 OS (p=0.192 p=0.72 ). Chen. 331,, OS (p=0.987) DFS (p=0.768) Cox. 310, Prandi. OS (p=0.005) RR(F/ )=0.80 DFS (p=0.022) RR(F/M)=0.86) 306, Li-Chu Sun. 304 OS (p=0.026, HR(M/F) =1.22). 308, 311.,. 303 55 (57.3%) 41 (42.7%). Cox

113 (HR) 1.232 OS 1.203 DFS., OS (p=0.575) DFS (p=0.581). Kaplan-Meier, OS (p=0.57) DFS (p=0.58). OS Storli. (p=0.568) 305, Li-Chu Sun. (p=0.066) 304., Prandi. OS (p=0.38), DFS (p=0.54). 306 Andreoni., OS (p=0.061), / DFS (p<0.0001). 304, Gonsalves. OS (p<0.001). 312, TNM.,,,. (adjuvant). ( ), ( ) 3 (72, 75.0%). (14.6%) 2, 6 (6.2%) 4b, 4 (4.2%) 1., ( 1/ 2 vs. 3/ 4b) OS DFS Cox (p=0.683 p=0.300, ), Kaplan-Meier (p=0.68

114 p=0.30, )., Mehrkhani. 1090, ( 1/ 2 vs. 3/ 4) (p=0.015). 313 Storli. 304, Andreoni. 307,, ( ) OS (p<0.001 p<0.0001, ). Chen. 310, Gunderson. 314, ( ) OS (p<0.001), DFS (p<0.001). Zhou.,, OS (p=0.172), DFS (p=0.356). 315. 303, 59.4% (57 ) ( 0). ( +) (40.6%), 27 1-3 (28.1%) 12 4 (12.5%). Cox, ( +) OS (HR=1.704) DFS (HR=2.553)., ( ) OS (p=0.152), ( ) DFS (p=0.006). Kaplan-Meier ( ) DFS (p=0.004), OS (p=0.15)., Andreoni. 307, Mehrkhani. 313 ( ) OS (p<0.0001 p=0.016, )., Gunderson. 314 ( ) OS (p<0.001), DFS (p<0.001).,. 316 (Grade), ( / ) (AJC

115 category IIA). 303, (53, 55.2%) (Grade) (Grade II)., 26 (27.1%) (Grade I), 17 (17.7%) (Grade III). Cox, (Grade III) OS (HR=2.718) DFS (HR=2.332) (Grade II) (Grade I). (Grade I-II vs. Grade III) OS, DFS Cox (p=0.013 p=0.023, ), Kaplan-Meier (p=0.010 p=0.020, ). Mehrkhani. 313 (Grade I-II vs. Grade III) OS (p=0.005)., Li-Chu Sun. 304 (I vs. II vs. III) OS (p<0.001), HR=2.92., Chen. 310, Prandi. 306, (I vs. II vs. III) OS (p=0.006 p=0.00001, ), DFS (p=0.002 p=0.000, ).,,,,,, (AJC category I). 303, (38, 39,6%), 30 (31,2%), 16.7% (16 ) I, UICC (AJCC). Cox (HR) II 0.713 OS 0.778 DFS I, III 1.354 OS 2.145 DFS

116 I. (AJCC) OS (p=0.544 II, p=0.558 III), DFS (p=0.646 II), (trend) DFS III (p=0.126). Kaplan-Meier, (AJCC) DFS (p=0.016), OS (p=0.30). Storli. 305, I-IV, (AJCC) OS, Cox (p<0.001), Kaplan-Meier (p<0.001). Chen. 310, (I-II vs. III-IV) OS (p<0.001), DFS (p<0.001). OS,, (p<0.001). 304,307,313,317-318 COX-2 AIX (69.4%)., 21, COX-2 21-100%,,, 70%.,, 35.5% 299 100% 298,300.,, COX-2.,,. Fux., COX-2 (747),. 319,,,., COX-2 65 (73%) <65 (27%), (p=0.159). COX-2,

117, Buecher. (p=0.16). 320 Fux. 319, de Heer. 321,, COX-2 (p=0.32 p>0.05, )., Miladi-Abdennadher. COX-2 (p=0.02). 322 COX-2 (p=0.350). Karnes. (p=0.20) 323, Masunanga. (p=0.21) 294. Tomozawa. (p=0.59) 324 Wu. (p=0.455) 234. COX-2, (p=0.486). Sumaoro. (p=0.6427) 325, Sheehan. (p=0.10) 232, Antonacopoulou. (p>0.05). 299 Karnes. 323 (p=0.003), Birkenkamp. (p<0.005) 326 Ogino. (p=0.005) 327, COX-2., Zhang.,, COX-2 80% 60% (p=0.03). 238, COX-2 1-2 (22%) 3-4 (78%), (p=0.134). Lim. 328, Zafirellis. 300, Joo. 329, 330-331,, (p>0.05)., COX-2 Yamauchi. (p=0.016) 332 Sumaoro. (p=0.0004). 325 COX-2 (p=0.643). Wu. 235, Buecher. 320 Fux. 319 (p>0.05). Sumaoro.,,, (p<0.05). 325,333 Sumaoro. Habibollahi. (p<0.05) 334,

118 COX-2 Maghrabi. (p=0.07). 335,, COX-2 (Grade) (p=0.767) (AJCC) (p=0.434). COX-2,,. 232,235,238,298,300,319-320,324-325,328-331,335-337 Masunanga. 294, Ogino. 327 Antonacopoulou. 299,, COX-2 (p<0.05). COX-2.,. 235,298,300,319,321,324,327,329-331,338,,, (p<0.05). 232,238,294,299,325,328,332-333,335,337 COX-2 OS DFS,. COX-2. de Her. 321, COX-2 1038, COX-2 OS DFS. OS (p=0.006) DFS (p=0.004),. Soumaoro. 325, Buecher. 320, Konno. 339, COX-2 OS. 232,294,315,322,331-333,338, Zhang. 237, Ogino. 327, Fux (p>0.05). 235,328-329 COX-2 DFS. Fux. 319,, Antonacopoulou. 229 Zafirelis. 300, (p>0.05). Tomozawa. 324, Buecher. 320, Zhou. 315, Abdennadher. 322, DFS.

119 mrna 50%., 65 (66.7%) <65 (33.3%), (p=0.129). Church. (p=0.06), 51 III. 340 Antonacopoulou. 46 I-IV,,,. 299 Uschida. (p=0.30), ( IV). 341 PTGS2 (p=0.827) (p=0.511). Liu. 342 Antonacopoulou. 299,, (p>0.05)., Church. 340, Antonacopoulou. 299, Fujita. 236, (p>0.05)., Dimberg. PTGS2, (p<0.001). 237 PTGS2 (p=0.277) (p=0.999). Fujita.,, (p=0.061). 236 Liu., PTGS2, (p<0.05). 342 Fujita.,, (p=0.84). 236, PTGS2 I-II (76%) III (23.8%), (p=0.405). PTGS2 Antonacopoulou,,,

120. 299 Church., Uchida., Liu. 340-342 PTGS2 : 21.4% I, 38.1% II 40.5% III,,, (p=0.584). Fujita., Dimberg., Liu., Uhlmann., PTGS2. 236-237,342-343 PTGS2 Antonacopoulou, PTGS2 I (p<0.05), III IV,,,, (p>0.05). 299 PTGS2 HR=0.558 HR=0.551,. OS DFS,, DFS, (p=0.127 OS p=0.092 DFS). Church Uhlmann, PTGS2 OS (p>0.05). 340,343, Uchida., IV, (p=0.031). 341 COX-2 ( QRT-PCR) (p=0.98). Antonacopoulou.,,, RNA,, (p=0.0071), (r=0.573). 299 DPYD,., 43 (51%). DPYD (p=0.803) (p=0.285). Oi. 344, Soong. 345 Ichikawa. 346

121 DPYD., Westra. 280 Jensen. 347. DPYD, Hotta. 348, Shirota. 287 Kinoshita. 349,. Sumi. 350,, DPD, (p<0.05). DPYD (p=0.830). Ikeguchi. 351, Westra. 280 Jensen. 347., Kinoshita. Sumi. DPD. 349-350, DPYD 1-2 (79.1%) 3-4b (20.9%), (p=0.999). Lassmann. 285 Yamada. 279,352-353,,. Shirota.,, DPD (p=0.048). 287 DPYD, (p=0.186). Hiroyasu. 354, Yamada. 279,352-353 Westra. 280,,,., Shirota. DPD (p=0.002). 287 DPYD I-II (79.1%) III (20.9%), (p=0.783). Soong. 345 Ikeguchi. 355,,. Yamada., 279,352,. 353 Xiao. 356

122,, DPYD. I 16.3%, II 37.2% III 46.5%, (p=0.377). Ikeguchi. 351,355, Yamada. 352-353 Hiroyasu. 354,,. Tokunaga 357-358, Soong 345, Kinoshita 349, Shirota 287, DPD. DPYD OS DFS,. DPD OS (p=0.828) DFS (p=0.951). Kornmann 359, Uchida 360, 346,348,351,355,361 DPD OS. Soong. DPD II III, (p=0.003 II p=0.038 III), III (p>0.05). 345, Ichikawa 362, Tsuji 363, Koopman 364, 279,282,286-287,347,356-358, DPYD OS. DPD DFS. 279-280,286-287,344,347-348,361,364-366,,. 278,346,351,359,367 DPYD COX-2, mrna PTGS2, (Rho=0.477).,,,,. COX-2 DPD,.

123 21. COX-2, (OS) (DFS).. n + (%) T N Grade Stage OS DFS Karnes et al. 323 1998 107-0.89 0.20 0.003 - - - - - - Sheehan et al. 232 1999 76 - - - 0.10-0.02 0.27 0.03 0.02 - A-D Masunaga et al. 294 2000 100 76 0.24 0.21 0.79 - - 0.012 0.0002 0.037 - A-D Tomozawa et al. 324 2000 63 21 0.94 0.59 0.13 0.22 0.41 0.22 0.41-0.0051 A-C Zhang et al. 237 2002 112 C80/R60 NS NS 0.03 - - 0.35 0.005 0.54 - A-D Joo et al. 329 2002 60 70 - - - NS NS NS NS 0.401 - Yamauchi et al. 332 2002 232 71.6 - - - 0.016 - - 0.020 0.002 - Konno et al. 339 2002 56 25 - - - - - - - <0.05 - Wu et al. 235 2003 139 84.9 0.962 0.455 0.939 0.910 0.628 0.417 0.811 NS - I-IV Buecher et al. 320 2003 61 59 0.16 0.19 0.62 0.55 0.79 0.96-0.022 0.021 I-II Zhan et al. 331 2004 - NS NS NS NS - NS NS 0.0225 - A-D Soumaoro et al. 325 2004 288 70.8 0.2605 0.5224 0.6427 0.0004 0.0296 0.8012 0.0013 0.0006 - I-IV Birkenkamp et al. 326 2004 25 - - - <0.005 - - - - - - Fux et al. 319 2005 747-0.32-0.80 0.99 0.69 0.67 0.82 NS NS I-IV Yamac et al. 336 2005 83 - - - NS - - NS - - - Yao et al. 338 2005 126 25.4 NS NS NS NS NS NS NS 0.0067 <0.01 Advan

124 21. ( ) n + (%) T N Grade Stage OS DFS Soumaoro et al. 333 2006 150 72.7 - - - - <0.05 - <0.05 <0.05 - de Heer et al. 321 ( ) 2007 1038 99.5 (R+ vs. R-)* NS NS - NS NS - NS 0.61 (R-) 0.006 (R+) 0.57(R-) I-III 0.004(R+) Konstantinopoulos et al. 298 2007 60 100 - - - - - NS NS - - I-IV Lu et al. 337 2007 30 - NS NS - - <0.05 NS <0.05 - - I-III Ogino et al. 327 ( ) 2008 662 83 0.69 0.59 0.005 - - 0.0003 0.77 0.63 - I-IV Lim et al. 328 2008 231 42.4 0.299 0.111 0.163 0.795 0.066 0.852 0.028 0.894 - I-III Antonacopoulou et al. 299 2008 124 35.5 - - >0.05 - - <0.001 <0.001 NS NS I-IV Zafirellis et al. 300 2008 132 100 NS NS NS NS NS NS NS - NS I-III Han et al. 330 2010 40 80 NS NS - NS NS NS NS - - Habibollahi et al. 334 2010 17 - - - - - <0.05 - - - - Zhou et al. 315 2011 141 - - - - - - - - 0.002 0.000 II-III Abdennadher et al. 322 2011 70 68.6 0.02 - - - - - - 0.036 - Maghrabi et al. 335 2012 94 56 0.59 0.97 0.80-0.07 0.50 0.01-0.026 I-IV NS: Not Statistical Significant:= (p>0.05) * R+ vs. R- = (R+) (R-)

125 22. mrna PTGS2 (COX-2), (OS) (DFS).. n + (%) T N Grade Stage OS DFS Fujita et al. 236 1998 43 - NS NS NS 0.061 0.84-0.32 - - I-IV Dimberg et al. 237 1999 39 - - - <0.001 - - - NS - - A-D Church et al. 340 2004 51-0.06 0.2 0.84 - - 0.26-0.85 - III Uchida et al. 341 2005 40 35 0.30 0.10 - - - 0.89-0.031 - IV Liu et al. 342 2005 35 - NS NS - NS <0.05 NS NS - - Antonacopoulou et al. 299 2008 46 100 <0.05 (I-II) NS NS NS - - <0.05 - >0.05 (III-IV) - I-IV Uhlmann et al 343 2012 118 - - - - - - - NS NS - NS: Not Statistical Significant:= (p>0.05)

126 23. DPD, (OS) (DFS). n + (%) T N Grade Stage OS DFS Salonga et al. 282 2000 33 - - - - - - - - 0.03 - Hiroyasu et al. 354 2001 36 - - - - - 0.96-0.91 - - I-IV Ikeguchi et al. 351 2001 189 - - - NS - - NS NS NS NS Shirota et al. 287 2002 80 - NS Ns NS 0.048 0.002 NS 0.001 <0.05 <0.05 I-III Nishimura et al. 278 2002 88 - - - - - - - - - NS B-C Kornmann et al 367 2002 348 - - - - - - - - - NS II-III Ikeguchi et al. 355 2002 189 - - - - - - NS NS NS - Kornmann et al. 359 2003 295 - - - - - - - - 0.229 NS II-III Tokunaga et al. 357 2003 100 - - - - - - - 0.033 <0.05 - Ichikawa et al. 362 2003 37 - - - - - - - - <0.0001 - Oi et al. 344 2004 64 43.8 0.9749 0.8212 0.8011 0.2828 0.0409 0.1727 - - 0.0127 C Tsuji et al. 363 (S vs. S+ )* 02/2004 182 - - - - - - - - 0.02 S 0.03 S+X - II-III Tsuji et al. 365 12/2004 89 - - - - - - - - - 0.026 II-III Westra et al. 280 ( ) 2005 341 71 0.010 0.755 0.218 0.357 0.0785 0.069 - - 0.09 III Xiao et al. 356 2005 53 73.58 - - - - - <0.05 - <0.05 - Lassmann et al. 285 2006 102 - NS NS NS NS NS NS NS - - I-III

127 23. ( ) N + (%) T N Grade Stage OS DFS Ciaparrone et al. 286 2006 62 - - - - - - - - 0.005 0.007 B-C Hotta et al. 348 2006 22-0.194 >0.999 0.395 0.815 0.231 >0.999 0.607 0.076 0.046 II-IV Jensen et al. 347 2006 303 18.8 0.04 0.4 0.9 - - 0.5 0.5 0.01 0.02 II-III Yamada et al. 352 2006 79 - - - - NS NS NS NS - - Kinoshita et al. 349 2007 49 81.6 NS NS 0.003 - - - 0.002 - - I-IV Vallbohmer et al. 366 2007 37 100 - - - - - - - - 0.048 IV Nishioka et al. 361 2007 17 - - - - - - - - NS 0.047 Tokunaga et al. 358 2007 150 - - - - - - - 0.0064 0.0096 - II-IV Yamada et al. 353 02/2008 100 - - - NS NS NS <0.05 NS - - Yamada et el. 279 03/2008 103 - - - - 0.07 0.24 0.52-0.01 0.02 B-C Soong et al. 345 * 2008 858 66 NS NS - - - NS <0.0001 <0.05 S >0.05 S+ - II-III Ichikawa et al. 346 2008 40 - NS NS - NS NS NS - 0.90 NS II-III Uchida et al. 360 (Meta vs. primary) 2008 84 - - - - - - - - NS - Koopman et al. 364 2009 556 - - - - - - - 0.04 0.006 Sumi et al. 350 2010 202 - - <0.05 <0.05 - - - - - - NS: Not Statistical Significant:= (p>0.05) * S:Surgery=, = ** Meta vs. primary=

129 14., (DFS) (OS). mrna DPYD PTGS2, COX-2,,. : 1. (Grade) (OS). 2. ( +), (Grade) (AJCC) (DFS). 3.,. 4.. 5.,,,. 6. DPYD COX-2, mrna, mrna PTGS2, (Rho=0.477). 7. ( ), (Grade) mrna PTGS2/COX-2

130 (DFS)., (Grade) (OS).

131 15. ΠΕΡΙΛΗΨΗ Ο σκοπός της παρούσας διδακτορικής διατριβής ήταν να μελετηθεί με τη χρήση μεθόδων της μοριακής βιολογίας καθώς και ανοσοϊστοχημικών τεχνικών, η έκφραση της Κυκλοοξυγενάσης (Cyclooxygenase, COX-2) και της Διυδροπυριμιδινικής Δεϋδρογενάσης (Dihydropyrimidine Dehydrogenase, DPD) και η πιθανή προγνωστική και προβλεπτική σημασία τους σε όγκους ασθενών, που υποβλήθηκαν σε χειρουργική επέμβαση για εξαιρέσιμο ορθοκολικό καρκίνο, χωρίς μεταστατική νόσο. Στη μελέτη συμπεριλήφθηκαν 96 ασθενείς με καρκίνο παχέος εντέρου, από τους οποίους μετά την επέμβαση έλαβαν χημειοθεραπεία οι 59 ασθενείς (61.5%). Μετά από διάμεσο χρόνο παρακολούθησης 82.7 μηνών, παρατηρήθηκαν 21 περιπτώσεις υποτροπής της νόσου (21.9%) και 30 θάνατοι (31.2%). Από τις αναλύσεις των κλινικοπαθολογοανατομικών χαρακτηριστικών των ασθενών και του διαστήματος ελεύθερο νόσου (DFS), διαπιστώθηκε στατιστικά σημαντική συσχέτισή του με την ύπαρξη λεμφαδενικής διήθησης (N), τον ιστολογικό βαθμό κακοήθειας (Grade) και το στάδιο της νόσου (AJCC). Η αντίστοιχη ανάλυση των κλινικοπαθολογοανατομικών χαρακτηριστικών των ασθενών και της συνολικής επιβίωσης (OS), ανέδειξε σημαντικότητα στη σχέση της επιβίωσης μόνο με την ηλικία και τον ιστολογικό βαθμό κακοήθειας (Grade). Καταδείχτηκε, επίσης, στατιστικά σημαντική συσχέτιση μεταξύ της χημειοθεραπείας και της συνολικής επιβίωσης, αλλά όχι μεταξύ της χημειοθεραπείας με το ελεύθερο νόσου διάστημα. Σε 85 (89%) από τους παραπάνω ασθενείς έγινε μελέτη της έκφρασης της πρωτεΐνης COX-2 με ανοσοϊστοχημεία με τη χρήση μονοκλωνικού αντισώματος σε ιστικές μικροσυστοιχίες, ενώ σε 84 (88%) ασθενείς διερευνήθηκε η γονιδιακή έκφραση των mrna του DPYD και του PTGS2 με ποσοτική real-time PCR (QRT- PCR). Δεν παρατηρήθηκε στατιστικά σημαντική διαφορά της έκφρασης των mrna του DPYD και του PTGS2, με το διάστημα ελεύθερο νόσου (DFS) και τη συνολική επιβίωση (ΟS) (wald p>0,05 και για τους δύο δείκτες). Το 69.4% των όγκων των ασθενών της μελέτης είχαν υψηλή έκφραση της πρωτεΐνης COX-2, χωρίς όμως να προκύπτει στατιστικά σημαντική διαφορά ως προς το DFS και το OS (p>0.05). Επίσης, δεν υπήρξε στατιστικά σημαντική συσχέτιση (p>0.05) κανενός από του μοριακούς δείκτες με την ηλικία, το φύλο, την πρωτοπαθή εστία, την έκταση τους όγκου (Τ), την διήθηση λεμφαδένων (Ν), τον ιστολογικό βαθμό (Grade), το στάδιο

132 της νόσου (AJCC) και την χημειοθεραπεία. Η 5ετής συνολική επιβίωση ήταν 76.7% και το 5ετές ελεύθερο νόσου διάστημα 68.5%. Τέλος, από τα αποτελέσματα της πολυπαραγοντικής ανάλυσης προέκυψε ότι η ύπαρξη διήθησης λεμφαδένων (Ν), ο βαθμός κακοήθειας του όγκου (Grade) και η έκφραση mrna του όγκου για την PTGS2/COX-2 αποτελούν ανεξάρτητους προγνωστικούς παράγοντες για το ελεύθερο νόσου διάστημα (DFS). Ακόμα, η ηλικία και ο βαθμός κακοήθειας του όγκου (Grade) φαίνεται να αποτελούν ανεξάρτητους προγνωστικούς παράγοντες για την συνολική επιβίωση (OS).

133 16. SUMMARY The aim of this thesis was to study using methods of molecular biology and immunohistochemical techniques, the expression of cyclooxygenase (COX-2) and dihydropyrimidine dehydrogenase (DPD) and the potential prognostic and predictive significance in patients tumors that underwent surgery for resectable colorectal cancer without metastatic disease (Stage I-III). The study included 96 patients with colorectal cancer, from which 59 patients (61.5%) received adjuvant chemotherapy. With a median follow-up of 82.7 months (range 82.7-95.2), 21 relapses (21.9%) and 30 deaths (31.2%) were recorded. The analyzes of the clinicopathological characteristics of patients and disease-free survival (DFS), showed statistically significant correlation with the presence of lymph node invasion (N), histological differentiation (Grade) and stage of disease (AJCC). The analysis of the clinicopathological characteristics of patients and overall survival (OS) highlighted a statistically significant correlation of survival only with age and histological differentiation (Grade). It was also demonstrated a statistically significant association between chemotherapy and overall survival, but not between chemotherapy with disease free survival. In 85 (89%) of these patients tumors the expression of COX-2 protein studied by immunohistochemistry using monoclonal antibody on tissue microarrays, while in 84 (88%) tumors the gene expression of mrna of DPYD and PTGS2 was also investigated using qrt-pcr. Immunohistochemical analysis revealed that high protein expression levels for COX-2 were found in 69.4% of the tumors. Our results show that immunohistochemically assessed COX-2 protein expression levels, as well as mrna expression levels of DPYD and PTGS2 had no independent prognostic significance for OS and DFS in the colorectal cancer patient s cohort studied. No statistically significant association was also found for age, gender, primary site, T- stage, lymph nodes status, tumor grade, tumor stage (AJCC) and chemotherapy correlated with all markers of our study (p>0.05). The 5-year overall survival (OS) rate was 76.7%, while the 5-year disease-free survival (DFS) rate was 68.5%. Finally, the results of multivariate analysis showed that the presence of lymph node invasion (N), the histological differentiation (Grade) and the expression of mrna of PTGS2/COX-2 are independent prognostic factors for disease free survival

134 (DFS), whereas age and the histological differentiation (Grade) are independent prognostic factors for overall survival (OS).

135 368-369 (sequence):. (acrocentric):. (alleles, allelomorphs): (. ) (polymerase chain reaction PCR): DNA-. ( ) (conserved sequence): DNA. DNA (recombinant DNA): DNA DNA. (.) (.) (recombinant): ( )., (recombination):.. (aneuploidy):,. (linkage disequilibrioum):. (probe): ( ) DNA RNA. (open reading frame, ORF): DNA, (nonsense). (sister chromatid exchange, SCE): DNA. (illegitimate transcription):.

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142 (translation): mrna., (denaturation): 1. :. 2. :.. (non-disjunction):. (microdeletion):. (micronuclei):. (mitosis):. Svedberg (Svedberg units, S):. (monosomy):,. (monohybrid):. (monozygotic, identical twins):. (mosaic):,. HTF (HTF island): ( ) HpaII, DNA. (nucleotide):.. (oncogene):. (ecogenetic):. (familial):.

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