Skip to main content
Top
Published in: Annals of Surgical Oncology 11/2010

01-11-2010 | Colorectal Cancer

Absence of hMLH1 or hMSH2 Expression as a Stage-Dependent Prognostic Factor in Sporadic Colorectal Cancers

Authors: Ji Won Park, MD, Hee Jin Chang, MD, Sohee Park, PhD, Byung Chang Kim, MD, Dae Yong Kim, MD, Ji-Yeon Baek, MD, Sun Young Kim, MD, Jae Hwan Oh, MD, Hyo Seong Choi, MD, Sung Chan Park, MD, Seung-Yong Jeong, MD

Published in: Annals of Surgical Oncology | Issue 11/2010

Login to get access

Abstract

Background

The predictive role of mismatch repair (MMR) status for survival after sporadic colorectal cancer remains a point of controversy. This study was designed to test the prognostic value of MMR status in sporadic colorectal cancers.

Methods

The study included 318 patients with sporadic colorectal cancer who underwent primary tumor resection. MMR status was determined by the immunohistochemical analysis of hMLH1 and hMSH2 expression.

Results

Thirty-six carcinomas (11.3%) showed abnormal MMR protein expression (22 hMLH1 negative and 14 hMSH2 negative) and were classified as MMR-defective tumors. An MMR defect was strongly associated with a reduced likelihood of lymph node (odds ratio, 0.32; 95% confidence interval [95% CI], 0.13–0.75) or distant organ metastases at diagnosis (odds ratio, 0.07; 95% CI, 0.01–0.62), independent of the clinicopathological features. Overall survival was significantly better in patients with MMR-defective tumors than in those with MMR-intact tumors (P = 0.013). In the subgroup analysis by stage, adjusted for other potential confounding variables, MMR status was not a statistically significant prognostic factor in stage I and II patients, while the MMR defect predicted a significantly better overall survival in stage III and IV patients (adjusted hazard ratio, 0.23; 95% CI, 0.06–0.97; P = 0.045).

Conclusions

At initial diagnosis, metastases were found at lower rates in MMR-defective tumors. MMR status may be a stage-dependent prognostic factor in patients with sporadic colorectal cancer.
Literature
1.
go back to reference Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36:801–18.PubMed Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36:801–18.PubMed
2.
go back to reference Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9:48–55.CrossRefPubMed Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9:48–55.CrossRefPubMed
3.
go back to reference Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.CrossRefPubMed Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.CrossRefPubMed
4.
go back to reference Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. 1996;56:4836–40.PubMed Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. 1996;56:4836–40.PubMed
5.
go back to reference Jass JR. Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci. 2000;910:62–73.CrossRefPubMed Jass JR. Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci. 2000;910:62–73.CrossRefPubMed
6.
go back to reference Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology. 1996;110:682–7.CrossRefPubMed Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology. 1996;110:682–7.CrossRefPubMed
7.
go back to reference Bubb VJ, Curtis LJ, Cunningham C, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996;12:2641–9.PubMed Bubb VJ, Curtis LJ, Cunningham C, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996;12:2641–9.PubMed
8.
go back to reference Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917–23.PubMed Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917–23.PubMed
9.
go back to reference Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.CrossRefPubMed Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.CrossRefPubMed
10.
go back to reference Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.CrossRefPubMed Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.CrossRefPubMed
11.
go back to reference Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. New York: Springer-Verlag, 2002.CrossRef Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. New York: Springer-Verlag, 2002.CrossRef
12.
go back to reference Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet. 1987;1:1303–6.CrossRefPubMed Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet. 1987;1:1303–6.CrossRefPubMed
13.
go back to reference Gafa R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer. 2000;89:2025–37.CrossRefPubMed Gafa R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer. 2000;89:2025–37.CrossRefPubMed
14.
go back to reference Jeong SY, Shin KH, Shin JH, et al. Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers. Dis Colon Rectum. 2003;46:1069–77.CrossRefPubMed Jeong SY, Shin KH, Shin JH, et al. Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers. Dis Colon Rectum. 2003;46:1069–77.CrossRefPubMed
15.
go back to reference Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.CrossRefPubMed Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.CrossRefPubMed
16.
go back to reference Shia J, Ellis NA, Klimstra DS. The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch. 2004;445:431–41.CrossRefPubMed Shia J, Ellis NA, Klimstra DS. The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch. 2004;445:431–41.CrossRefPubMed
17.
go back to reference Laghi L, Bianchi P, Malesci A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene 2008;27:6313–21.CrossRefPubMed Laghi L, Bianchi P, Malesci A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene 2008;27:6313–21.CrossRefPubMed
18.
go back to reference Müller W, Burgart LJ, Krause-Paulus R, et al. The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)—results of an international collaborative study. Fam Cancer. 2001;1:87–92.CrossRefPubMed Müller W, Burgart LJ, Krause-Paulus R, et al. The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)—results of an international collaborative study. Fam Cancer. 2001;1:87–92.CrossRefPubMed
19.
go back to reference Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut. 1999;45:409–15.CrossRefPubMed Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut. 1999;45:409–15.CrossRefPubMed
20.
go back to reference Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol. 2000;191:355–60.CrossRefPubMed Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol. 2000;191:355–60.CrossRefPubMed
21.
go back to reference Dieumegard B, Grandjouan S, Sabourin JC, et al. Extensive molecular screening for hereditary non-polyposis colorectal cancer. Br J Cancer. 2000;82:871–80.CrossRefPubMed Dieumegard B, Grandjouan S, Sabourin JC, et al. Extensive molecular screening for hereditary non-polyposis colorectal cancer. Br J Cancer. 2000;82:871–80.CrossRefPubMed
22.
go back to reference Iino H, Simms L, Young J, et al. DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer. Gut. 2000;47:37–42.CrossRefPubMed Iino H, Simms L, Young J, et al. DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer. Gut. 2000;47:37–42.CrossRefPubMed
24.
go back to reference Lanza G, Gafa R, Maestri I, et al. Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol. 2002;15:741–9.CrossRefPubMed Lanza G, Gafa R, Maestri I, et al. Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol. 2002;15:741–9.CrossRefPubMed
25.
go back to reference Rigau V, Sebbagh N, Olschwang S, et al. Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med. 2003;127:694–700.PubMed Rigau V, Sebbagh N, Olschwang S, et al. Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med. 2003;127:694–700.PubMed
26.
go back to reference Salahshor S, Koelble K, Rubio C, Lindblom A. Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Invest. 2001;81:535–41.PubMed Salahshor S, Koelble K, Rubio C, Lindblom A. Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Invest. 2001;81:535–41.PubMed
27.
go back to reference Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821–9.CrossRefPubMed Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821–9.CrossRefPubMed
28.
go back to reference Wahlberg SS, Schmeits J, Thomas G, et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res. 2002;62:3485–92.PubMed Wahlberg SS, Schmeits J, Thomas G, et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res. 2002;62:3485–92.PubMed
29.
go back to reference Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58:3455–60.PubMed Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58:3455–60.PubMed
30.
go back to reference Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870–5.CrossRefPubMed Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870–5.CrossRefPubMed
31.
go back to reference Kane MF, Loda M, Gaida GM, et al. Methylation 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. 1997;57:808–11.PubMed Kane MF, Loda M, Gaida GM, et al. Methylation 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. 1997;57:808–11.PubMed
32.
go back to reference Lim SB, Jeong SY, Lee MR, et al. Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis. 2004;19:533–7.CrossRefPubMed Lim SB, Jeong SY, Lee MR, et al. Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis. 2004;19:533–7.CrossRefPubMed
33.
go back to reference Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.CrossRefPubMed Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.CrossRefPubMed
34.
go back to reference Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.CrossRefPubMed Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.CrossRefPubMed
35.
go back to reference Lamberti C, Lundin S, Bogdanow M, et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis. 2007;22:145–52.CrossRefPubMed Lamberti C, Lundin S, Bogdanow M, et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis. 2007;22:145–52.CrossRefPubMed
36.
go back to reference Salahshor S, Kressner U, Fischer H, et al. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer. 1999;81:190–3.CrossRefPubMed Salahshor S, Kressner U, Fischer H, et al. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer. 1999;81:190–3.CrossRefPubMed
37.
go back to reference Lanza G, Gafa R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24:2359–67.CrossRefPubMed Lanza G, Gafa R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24:2359–67.CrossRefPubMed
38.
go back to reference Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–5.CrossRefPubMed Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–5.CrossRefPubMed
39.
go back to reference Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831–9.CrossRefPubMed Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831–9.CrossRefPubMed
40.
go back to reference Wright CM, Dent OF, Barker M, et al. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg. 2000;87:1197–202.CrossRefPubMed Wright CM, Dent OF, Barker M, et al. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg. 2000;87:1197–202.CrossRefPubMed
Metadata
Title
Absence of hMLH1 or hMSH2 Expression as a Stage-Dependent Prognostic Factor in Sporadic Colorectal Cancers
Authors
Ji Won Park, MD
Hee Jin Chang, MD
Sohee Park, PhD
Byung Chang Kim, MD
Dae Yong Kim, MD
Ji-Yeon Baek, MD
Sun Young Kim, MD
Jae Hwan Oh, MD
Hyo Seong Choi, MD
Sung Chan Park, MD
Seung-Yong Jeong, MD
Publication date
01-11-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 11/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-010-1135-8

Other articles of this Issue 11/2010

Annals of Surgical Oncology 11/2010 Go to the issue