Objectives: The survival of stage II colorectal cancer (CRC) patients is approximately 70% at 5 years. Identification of the patient subgroup at high risk for tumour recurrence and death would allow more informed use of chemotherapy for this stage of disease. Several clinical and pathological factors have been reported to associate with worse survival. In the present study we investigated the prognostic significance of two major genetic alterations in CRC: microsatellite instability (MSI+) and the type of Ki-ras mutation. Methods: PCR-based molecular techniques were used to screen for MSI+ and Ki-ras mutation in 396 stage II CRC patients with an average follow-up time of 75 months. Clinicopathological information was obtained by retrospective review of pathology reports. Results: Prominent vascular invasion was identified in 19% of cases and was found to be an independent prognostic factor for poor outcome (relative risk = 2.08, 95% confidence interval: 1.22–3.57, p = 0.008). The MSI+ phenotype was found in 23% of proximal tumours and Ki-ras mutations in 38% of the overall series. Neither MSI+ nor the type of Ki-ras mutation showed prognostic significance in this cohort of stage II CRC. Conclusions: MSI+ and Ki-ras mutation type are not useful markers for the identification of high-risk stage II CRC patients. Further prospective and/or cohort studies are required to determine whether these molecular changes have predictive value for survival benefit from 5-fluorouracil-based adjuvant chemotherapy.

1.
Registry SC: Epidemiology of Cancer in South Australia. http://www.dhs.sa.gov.au/pehs/cancer-report2000.html, 2000.
2.
Meagher AP: Colorectal cancer: Is the surgeon a prognostic factor? A systematic review. Med J Aust 1999;171:308–310.
3.
Newland RC, Dent OF, Chapuis PH, Bokey L: Survival after curative resection of lymph node negative colorectal carcinoma. A prospective study of 910 patients. Cancer 1995;76:564–571.
4.
Merkel S, Wein A, Gunther K, Papadopoulos T, Hohenberger W, Hermanek P: High-risk groups of patients with stage II colon carcinoma. Cancer 2001;92:1435–1443.
5.
Kashtan H, Werbin N, Aladjem D, Barak Y, Wiznitzer T: Right and left colon carcinoma: A retrospective comparative study. J Surg Oncol 1987;35:245–248.
6.
Gervaz P, Bouzourene H, Cerottini JP, Chaubert P, Benhattar J, Secic M, Wexner S, Givel JC, Belin B: Dukes B colorectal cancer: Distinct genetic categories and clinical outcome based on proximal or distal tumor location. Dis Colon Rectum 2001;44:364–372; discussion 372–373.
7.
Sternberg A, Sibirsky O, Cohen D, Blumenson LE, Petrelli NJ: Validation of a new classification system for curatively resected colorectal adenocarcinoma. Cancer 1999;86:782–792.
8.
Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, Jones J, Rockette H: Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999;17:1349–1355.
9.
Taal BG, Van Tinteren H, Zoetmulder FA: Adjuvant 5FU plus levamisole in colonic or rectal cancer: Improved survival in stage II and III. Br J Cancer 2001;85:1437–1443.
10.
IMPACT Investigators: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 1999;17:1356–1363.
11.
Soong R, Grieu F, Robbins P, Dix B, Chen D, Parsons R, House A, Iacopetta B: p53 alterations are associated with improved prognosis in distal colonic carcinomas. Clin Cancer Res 1997;3:1405–1411.
12.
Leahy DT, Salman R, Mulcahy H, Sheahan K, O’Donoghue DP, Parfrey NA: Prognostic significance of p53 abnormalities in colorectal carcinoma detected by PCR-SSCP and immunohistochemical analysis. J Pathol 1996;180:364–370.
13.
Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B: Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 1999;104:263–269.
14.
Ahnen DJ, Feigl P, Quan G, Fenoglio-Preiser C, Lovato LC, Bunn PA Jr, Stemmerman G, Wells JD, Macdonald JS, Meyskens FL Jr: Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: A Southwest Oncology Group study. Cancer Res 1998;58:1149–1158.
15.
Elsaleh H, Powell B, McCaul K, Grieu F, Grant R, Joseph D, Iacopetta B: p53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res 2001;7:1343–1349.
16.
Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, Moon-Tasson L, Mahoney MR, Sargent DJ, O’Connell MJ, Witzig TE, Farr GH Jr, Goldberg RM, Thibodeau SN: Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 1999;91:1295–1303.
17.
Curran B, Lenehan K, Mulcahy H, Tighe O, Bennett MA, Kay EW, O’Donoghue DP, Leader M, Croke DT: Replication error phenotype, clinicopathological variables, and patient outcome in Dukes’ B stage II (T3,N0,M0) colorectal cancer. Gut 2000;46:200–204.
18.
Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML: Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 2001;10:917–923.
19.
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B: Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745–1750.
20.
Guidoboni M, Gafa R, Viel A, Doglioni C, Russo A, Santini A, Del Tin L, Macri E, Lanza G, Boiocchi M, Dolcetti R: Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol 2001;159:297–304.
21.
Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA: Kirsten ras mutations in patients with colorectal cancer: The multicenter ‘RASCAL’ study. J Natl Cancer Inst 1998;90:675–684.
22.
Gnanasampanthan G, Elsaleh H, McCaul K, Iacopetta B: Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes’ C colorectal cancer. J Pathol 2001;195:543–548.
23.
Iacopetta BJ, Welch J, Soong R, House AK, Zhou XP, Hamelin R: Mutation of the transforming growth factor-beta type II receptor gene in right-sided colorectal cancer: Relationship to clinicopathological features and genetic alterations. J Pathol 1998;184:390–395.
24.
Sobin LH, Wittekind C: TNM Classification of Malignant Tumours: Wiley-Liss, New York, 1997.
25.
Soong R, Iacopetta BJ: A rapid and nonisotopic method for the screening and sequencing of p53 gene mutations in formalin-fixed, paraffin-embedded tumors. Mod Pathol 1997;10:252–258.
26.
Iacopetta B, Grieu F: Routine detection of the replication error phenotype in clinical tumor specimens using fluorescence-SSCP. Biotechniques 2000;28:566–568, 570.
27.
Zhou XP, Hoang JM, Li YJ, Seruca R, Carneiro F, Sobrinho-Simoes M, Lothe RA, Gleeson CM, Russell SE, Muzeau F, Flejou JF, Hoang-Xuan K, Lidereau R, Thomas G, Hamelin R: Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer 1998;21:101–107.
28.
Iacopetta B, Elsaleh H, Grieu F, Joseph D, Sterrett G, Robbins P: Routine analysis of p53 mutation in clinical breast tumor specimens using fluorescence-based polymerase chain reaction and single strand conformation polymorphism. Diagn Mol Pathol 2000;9:20–25.
29.
Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML: Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: A population-based study. Cancer Epidemiol Biomarkers Prev 2000;9:1193–1197.
30.
Burdy G, Panis Y, Alves A, Nemeth J, Lavergne-Slove A, Valleur P: Identifying patients with T3-T4 node-negative colon cancer at high risk of recurrence. Dis Colon Rectum 2001;44:1682–1688.
31.
Mulcahy HE, Toner M, Patchett SE, Daly L, O’Donoghue DP: Identifying stage B colorectal cancer patients at high risk of tumor recurrence and death. Dis Colon Rectum 1997;40:326–331.
32.
Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, Shepherd LE, Seitz JF, Francini G: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001;345:1091–1097.
33.
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69–77.
34.
Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, Beranek M, Jandik P, Benamouzig R, Jullian E, Laurent-Puig P, Olschwang S, Muller O, Hoffmann I, Rabes HM, Zietz C, Troungos C, Valavanis C, Yuen ST, Ho JW, Croke CT, O’Donoghue DP, Giaretti W, Rapallo A, Russo A, Bazan V, Tanaka M, Omura K, Azuma T, Ohkusa T, Fujimori T, Ono Y, Pauly M, Faber C, Glaesener R, de Goeij AF, Arends JW, Andersen SN, Lovig T, Breivik J, Gaudernack G, Clausen OP, De Angelis PD, Meling GI, Rognum TO, Smith R, Goh HS, Font A, Rosell R, Sun XF, Zhang H, Benhattar J, Losi L, Lee JQ, Wang ST, Clarke PA, Bell S, Quirke P, Bubb VJ, Piris J, Cruickshank NR, Morton D, Fox JC, Al-Mulla F, Lees N, Hall CN, Snary D, Wilkinson K, Dillon D, Costa J, Pricolo VE, Finkelstein SD, Thebo JS, Senagore AJ, Halter SA, Wadler S, Malik S, Krtolica K, Urosevic N: Kirsten ras mutations in patients with colorectal cancer: The ‘RASCAL II’ study. Br J Cancer 2001;85:692–696.
35.
Andreyev J, Cunningham D: Markers, markers everywhere ... Prognosis in colorectal cancer – Time for a new approach. J Clin Oncol 2001;19:286–288.
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