PURPOSE
Extensive research into the molecular biology of colorectal cancer has identified a plethora of molecular markers reputed to provide independent prognostic information. p53 mutational status has been associated with both improved and reduced survival; however, tumors expressing a particular phenotype associated with defective mismatch repair consistently do better. This study was designed to examine site-specific survival implications of p53 and mismatch repair status.
METHODS
Mismatch repair (hMLH1 and hMSH2) and p53 status was investigated immunohistochemically in 111 proximal colon cancers along with tumor TNM stage, grade, and extramural vascular invasion. Fisher’s exact test was used to assess categoric data; univariate and multivariate models compared survival between the respective tumor phenotypes.
RESULTS
Thirty-two percent of tumors showed loss of expression of hMLH1 and in a multivariate analysis were associated with a significant survival advantage after adjustment for tumor stage, p53 status, and extramural vascular invasion (hazard ratio, 0.29; 95 percent confidence interval, 0.1–0.87; P = 0.027). Only two tumors showed loss of expression of hMSH2, which was not related further to survival. Aberrant p53 expression was detected in 39 percent of tumors. Such expression was found to be associated with a significantly reduced survival in univariate analysis (P = 0.037, log-rank test) but not in a multivariate model. Subgroup analysis showed no association between survival and p53 expression in mismatch repair proficient tumors.
CONCLUSIONS
Loss of hMLH1 expression is an independent predicator of improved survival in this series and perhaps the underlying cause of the observed survival difference associated with p53 expression.
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REFERENCES
To the article
Cancer Research UK. Bowel cancer factsheet. May 2002.
M Hilska J Gronroos Y Collan M Laato (2001) ArticleTitleSurgically treated adenocarcinomas of the right side of the colon during a ten year period: a retrospective study Ann Chir Gynaecol 90 45–9 Occurrence Handle12041928
ER Fearon B Vogelstein (1990) ArticleTitleA genetic model for colorectal tumorigenesis Cell 61 759–67 Occurrence Handle10.1016/0092-8674(90)90186-I Occurrence Handle1:CAS:528:DyaK3cXktlyhtrg%3D Occurrence Handle2188735
ER Fearon PA Jones (1992) ArticleTitleProgressing toward a molecular description of colorectal cancer development FASEB J 6 2783–90 Occurrence Handle1:CAS:528:DyaK38Xlt1yqu7o%3D Occurrence Handle1321771
SN Thibodeau AJ French JM Cunningham et al. (1998) ArticleTitleMicrosatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1 Cancer Res 58 1713–8 Occurrence Handle1:CAS:528:DyaK1cXislerurs%3D Occurrence Handle9563488
JR Jass KG Biden MC Cummings et al. (1999) ArticleTitleCharacterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways J Clin Pathol 52 455–60 Occurrence Handle1:STN:280:DC%2BD3c%2FivVGmtw%3D%3D Occurrence Handle10562815 Occurrence Handle10.1136/jcp.52.6.455
L Cawkwell S Gray H Murgatroyd et al. (1999) ArticleTitleChoice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair Gut 45 409–15 Occurrence Handle1:STN:280:DyaK1Mzns12jtQ%3D%3D Occurrence Handle10446111 Occurrence Handle10.1136/gut.45.3.409
NM Lindor LJ Burgart O Leontovich et al. (2002) ArticleTitleImmunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors J Clin Oncol 20 1043–8 Occurrence Handle10.1200/JCO.20.4.1043 Occurrence Handle1:CAS:528:DC%2BD38XitFOqur8%3D Occurrence Handle11844828
SN Thibodeau G Bren D Schaid (1993) ArticleTitleMicrosatellite instability in cancer of the proximal colon Science 260 816–9 Occurrence Handle1:CAS:528:DyaK3sXkt1GlsLs%3D Occurrence Handle8484122
R Gryfe H Kim ET Hsieh et al. (2000) ArticleTitleTumor microsatellite instability and clinical outcome in young patients with colorectal cancer N Engl J Med 342 69–77 Occurrence Handle10.1056/NEJM200001133420201 Occurrence Handle1:STN:280:DC%2BD3c%2FotVeitA%3D%3D Occurrence Handle10631274
WS Samowitz K Curtin KN Ma et al. (2001) ArticleTitleMicrosatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level Cancer Epidemiol Biomarkers Prev 10 917–23 Occurrence Handle1:CAS:528:DC%2BD3MXnt1Gis78%3D Occurrence Handle11535541
CM Ribic DJ Sargent MJ Moore et al. (2003) ArticleTitleTumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer N Engl J Med 349 247–57 Occurrence Handle10.1056/NEJMoa022289 Occurrence Handle1:CAS:528:DC%2BD3sXlsVGjsbY%3D Occurrence Handle12867608
K Kaserer J Schmaus U Bethge et al. (2000) ArticleTitleStaining patterns of p53 immunohistochemistry and their biological significance in colorectal cancer J Pathol 190 450–6 Occurrence Handle10.1002/(SICI)1096-9896(200003)190:4<450::AID-PATH545>3.3.CO;2-# Occurrence Handle1:CAS:528:DC%2BD3cXisF2rt74%3D Occurrence Handle10699994
CJ Allegra S Paik LH Colangelo et al. (2003) ArticleTitlePrognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes’ B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study J Clin Oncol 21 241–50 Occurrence Handle10.1200/JCO.2003.05.044 Occurrence Handle12525515 Occurrence Handle1:CAS:528:DC%2BD2cXpsVWqs78%3D
R Soong F Grieu P Robbins et al. (1997) ArticleTitlep53 alterations are associated with improved prognosis in distal colonic carcinomas Clin Cancer Res 3 1405–11 Occurrence Handle1:STN:280:DyaK1M7htFSktg%3D%3D Occurrence Handle9815825
R Soong B Powell H Elsaleh et al. (2000) ArticleTitlePrognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumor site, stage, adjuvant chemotherapy and type of mutation Eur J Cancer 36 2053–60 Occurrence Handle10.1016/S0959-8049(00)00285-9 Occurrence Handle1:CAS:528:DC%2BD3cXosFKhtLw%3D Occurrence Handle11044641
WS Samowitz K Curtin KN Ma et al. (2002) ArticleTitlePrognostic significance of p53 mutations in colon cancer at the population level Int J Cancer 99 597–602 Occurrence Handle10.1002/ijc.10405 Occurrence Handle1:CAS:528:DC%2BD38XjsFansb8%3D Occurrence Handle11992552
U Manne H Weiss R Myers et al. (1998) ArticleTitleNuclear accumulation of p53 in colorectal adenocarcinoma Cancer 83 2456–67 Occurrence Handle10.1002/(SICI)1097-0142(19981215)83:12<2456::AID-CNCR8>3.0.CO;2-5 Occurrence Handle1:STN:280:DyaK1M%2FovFyntw%3D%3D Occurrence Handle9874449
RK Phillips R Hittinger L Blesovsky JS Fry LP Fielding (1984) ArticleTitleLarge bowel cancer: surgical pathology and its relationship to survival Br J Surg 71 604–10 Occurrence Handle1:STN:280:DyaL2c3lvVejsg%3D%3D Occurrence Handle6743980
E Kaplan P Meier (1958) ArticleTitleNonparametric estimation from incomplete observations J Am Stat Assoc 53 457–81
D Cox (1972) ArticleTitleRegression models and life-tables J R Stat Soc [B] 34 187–202
JR Jass (1999) ArticleTitleTowards a molecular classification of colorectal cancer Int J Colorectal Dis 14 194–200 Occurrence Handle10.1007/s003840050211 Occurrence Handle1:STN:280:DC%2BD3c7ht1WmsQ%3D%3D Occurrence Handle10647627
To the Invited Editorial
MF Kane M Loda GM Gaida et al. (1997) ArticleTitleMethylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines Cancer Res 57 808–11 Occurrence Handle1:CAS:528:DyaK2sXhs1Kjtbs%3D Occurrence Handle9041175
CR Boland SN Thibodeau SR Hamilton et al. (1998) ArticleTitleA National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer Cancer Res 58 5248–57 Occurrence Handle1:CAS:528:DyaK1cXnsFSmtbk%3D Occurrence Handle9823339
JR Jass J Young BA Leggett (2002) ArticleTitleEvolution of colorectal cancer: change of pace and change of direction J Gastroenterol Hepatol 17 17–26 Occurrence Handle10.1046/j.1440-1746.2002.02635.x Occurrence Handle11987262
WS Samowitz JA Holden K Curtin et al. (2001) ArticleTitleInverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer Am J Pathol 158 1517–24 Occurrence Handle1:CAS:528:DC%2BD3MXjtVWht7o%3D Occurrence Handle11290569
B Klump O Nehls T Okech et al. (2004) ArticleTitleMolecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature Int J Colorect Dis 19 23–42 Occurrence Handle10.1007/s00384-003-0499-7 Occurrence Handle1:STN:280:DC%2BD3srmsl2gtQ%3D%3D
CM Ribic DJ Sargent MJ Moore et al. (2003) ArticleTitleTumor microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer N Engl J Med 349 247–57 Occurrence Handle10.1056/NEJMoa022289 Occurrence Handle1:CAS:528:DC%2BD3sXlsVGjsbY%3D Occurrence Handle12867608
M Guidoboni R Gafa A Viel et al. (2001) ArticleTitleMicrosatelite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis Am J Pathol 159 297–304 Occurrence Handle1:STN:280:DC%2BD3Mzpt1arsQ%3D%3D Occurrence Handle11438476
R Gafa I Maestri M Matteuzzi et al. (2000) ArticleTitleSporadic colorectal adenocarcinomas with high-frequency microsatellite instability Cancer 89 2025–37 Occurrence Handle10.1002/1097-0142(20001115)89:10<2025::AID-CNCR1>3.3.CO;2-J Occurrence Handle11066042 Occurrence Handle1:STN:280:DC%2BD3M%2FkvVaqsg%3D%3D
CM Wright OF Dent M Barker et al. (2000) ArticleTitleThe prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer Br J Surg 87 1197–202 Occurrence Handle10.1046/j.1365-2168.2000.01508.x Occurrence Handle1:STN:280:DC%2BD3M%2Fjs1OktQ%3D%3D Occurrence Handle10971428
A Hemminki J-P Mecklin H Järvinen LA Aaltonen H Joensuu (2000) ArticleTitleMicrosatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy Gastroenterology 119 921–28 Occurrence Handle1:STN:280:DC%2BD3cvptV2rtA%3D%3D Occurrence Handle11040179
H Elsaleh D Joseph F Grieu N Zeps B Iacopetta (2000) ArticleTitleAssociation of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer Lancet 355 1745–50 Occurrence Handle10.1016/S0140-6736(00)02261-3 Occurrence Handle1:STN:280:DC%2BD3c3ptVChsw%3D%3D Occurrence Handle10832824
JR Jass (1999) ArticleTitleTowards a molecular classification of colorectal cancer Int J Colorect Dis 14 194–200 Occurrence Handle10.1007/s003840050211 Occurrence Handle1:STN:280:DC%2BD3c7ht1WmsQ%3D%3D
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Smyth, E., Sharma, A., Sivarajasingham, N. et al. Prognostic Implications of hMLH1 and p53 Immunohistochemical Status in Right-Sided Colon Cancer . Dis Colon Rectum 47, 2086–2092 (2004). https://doi.org/10.1007/s10350-004-0710-0
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DOI: https://doi.org/10.1007/s10350-004-0710-0