Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diagnostic Pathology
Published in: Diagnostic Pathology 1/2013

Open Access 01-12-2013 | Research

Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer

Authors: Sakarias Wangefjord, Jenny Brändstedt, Kajsa Ericson Lindquist, Björn Nodin, Karin Jirström, Jakob Eberhard

Published in: Diagnostic Pathology | Issue 1/2013

Login to get access

Abstract

Background

Despite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.

Methods

Immunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).

Results

Positive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.

Conclusions

Findings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.

Virtual slides

The virtual slides for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​8778585058652609​
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
Armaghany T, Wilson JD, Chu Q, Mills G: Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 2012, 5: 19-27.PubMedCentralPubMed
3.
Pancione M, Remo A, Colantuoni V: Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Patholog Res Int. 2012, 2012: 509348-PubMedCentralPubMed
4.
5.
Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J: Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012, 27: 1423-1431. 10.1111/j.1440-1746.2012.07200.x.CrossRefPubMed
6.
7.
Brabletz T, Jung A, Kirchner T: Beta-catenin and the morphogenesis of colorectal cancer. Virchows Arch. 2002, 441: 1-11. 10.1007/s00428-002-0642-9.CrossRefPubMed
8.
9.
Klaus A, Birchmeier W: Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008, 8: 387-398. 10.1038/nrc2389.CrossRefPubMed
10.
Tetsu O, McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999, 398: 422-426. 10.1038/18884.CrossRefPubMed
11.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A: The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999, 96: 5522-5527. 10.1073/pnas.96.10.5522.PubMedCentralCrossRefPubMed
12.
Bondi J, Bukholm G, Nesland JM, Bukholm IR: Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas. APMIS. 2004, 112: 49-56. 10.1111/j.1600-0463.2004.apm1120109.x.CrossRefPubMed
13.
Cheah PY, Choo PH, Yao J, Eu KW, Seow-Choen F: A survival-stratification model of human colorectal carcinomas with beta-catenin and p27kip1. Cancer. 2002, 95: 2479-2486. 10.1002/cncr.10986.CrossRefPubMed
14.
Morikawa T, Kuchiba A, Yamauchi M, Meyerhardt JA, Shima K, Nosho K, Chan AT, Giovannucci E, Fuchs CS, Ogino S: Association of CTNNB1 (beta-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer. Jama. 2011, 305: 1685-1694. 10.1001/jama.2011.513.PubMedCentralCrossRefPubMed
15.
Drebber U, Madeja M, Odenthal M, Wedemeyer I, Monig SP, Brabender J, Bollschweiler E, Holscher AH, Schneider PM, Dienes HP, Vallbohmer D: beta-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis. Int J Color Dis. 2011, 26: 1127-1134. 10.1007/s00384-011-1213-9.CrossRef
16.
de la Chapelle A, Hampel H: Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010, 28: 3380-3387. 10.1200/JCO.2009.27.0652.PubMedCentralCrossRefPubMed
17.
18.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, 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: 247-257. 10.1056/NEJMoa022289.PubMedCentralCrossRefPubMed
19.
Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, Allegra CJ: Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. 2007, 25: 767-772. 10.1200/JCO.2006.05.8172.CrossRefPubMed
20.
Barratt PL, Seymour MT, Stenning SP, Georgiades I, Walker C, Birbeck K, Quirke P: DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet. 2002, 360: 1381-1391. 10.1016/S0140-6736(02)11402-4.CrossRefPubMed
21.
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.PubMed
22.
Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005, 23: 609-618.CrossRefPubMed
23.
Tajima A, Hess MT, Cabrera BL, Kolodner RD, Carethers JM: The mismatch repair complex hMutSα recognizes 5-fluorouracil-modified DNA: Implications for chemosensitivity and resistance. Gastroenterology. 2004, 127: 1678-1684. 10.1053/j.gastro.2004.10.001.CrossRefPubMed
24.
Issa JP: CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004, 4: 988-993. 10.1038/nrc1507.CrossRefPubMed
25.
Curtin K, Slattery ML, Samowitz WS: CpG island methylation in colorectal cancer: past, present and future. Patholog Res Int. 2011, 2011: 902674-PubMedCentralPubMed
26.
Wangefjord S, Manjer J, Gaber A, Nodin B, Eberhard J, Jirstrom K: Cyclin D1 expression in colorectal cancer is a favorable prognostic factor in men but not in women in a prospective, population-based cohort study. Biol Sex Differ. 2011, 2: 10-10.1186/2042-6410-2-10.PubMedCentralCrossRefPubMed
27.
Berglund G, Elmstähl S, Janzon L, Larsson SA: The malmo diet and cancer study. Design and feasibility. Journal of internal medicine. 1993, 233: 45-10.1111/j.1365-2796.1993.tb00647.x.CrossRefPubMed
28.
Larsson A, Johansson ME, Wangefjord S, Gaber A, Nodin B, Kucharzewska P, Welinder C, Belting M, Eberhard J, Johnsson A, et al.: Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer. Br J Cancer. 2011, 105: 666-672. 10.1038/bjc.2011.295.PubMedCentralCrossRefPubMed
29.
Eberhard J, Gaber A, Wangefjord S, Nodin B, Uhlen M, Ericson Lindquist K, Jirstrom K: A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer. 2012, 106: 931-938. 10.1038/bjc.2012.34.PubMedCentralCrossRefPubMed
30.
Ogino S, Kawasaki T, Kirkner GJ, Yamaji T, Loda M, Fuchs CS: Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP. Mod Pathol. 2007, 20: 15-22. 10.1038/modpathol.3800709.CrossRefPubMed
31.
Dahlin AM, Palmqvist R, Henriksson ML, Jacobsson M, Eklof V, Rutegard J, Oberg A, Van Guelpen BR: The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res. 2010, 16: 1845-1855. 10.1158/1078-0432.CCR-09-2594.CrossRefPubMed
32.
Jass JR, Biden KG, Cummings MC, Simms LA, Walsh M, Schoch E, Meltzer SJ, Wright C, Searle J, Young J, Leggett BA: Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol. 1999, 52: 455-460. 10.1136/jcp.52.6.455.PubMedCentralCrossRefPubMed
33.
Nodin B, Johannesson H, Wangefjord S, DP OC, Ericson-Lindquist K, Uhlen M, Jirstrom K, Eberhard J: Molecular correlates and prognostic significance of SATB1 expression in colorectal cancer. Diagn Pathol. 2012, 7: 115-10.1186/1746-1596-7-115.PubMedCentralCrossRefPubMed
34.
Des Guetz G: Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis. Anticancer Res. 2009, 29: 1615-1620.PubMed
35.
Elzagheid A: Nuclear β-catenin expression as a prognostic factor in advanced colorectal carcinoma. World J Gastroenterol. 2008, 14: 3866-10.3748/wjg.14.3866.PubMedCentralCrossRefPubMed
36.
Chung GG, Provost E, Kielhorn EP, Charette LA, Smith BL, Rimm DL: Tissue microarray analysis of beta-catenin in colorectal cancer shows nuclear phospho-beta-catenin is associated with a better prognosis. Clin Cancer Res. 2001, 7: 4013-4020.PubMed
37.
Norwood MG, Bailey N, Nanji M, Gillies RS, Nicholson A, Ubhi S, Darnton JJ, Steyn RS, Womack C, Hughes A, et al.: Cytoplasmic beta-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas. Histopathology. 2010, 57: 101-111. 10.1111/j.1365-2559.2010.03587.x.CrossRefPubMed
38.
Wanitsuwan W: Overall expression of beta-catenin outperforms its nuclear accumulation in predicting outcomes of colorectal cancers. World J Gastroenterol. 2008, 14: 6052-10.3748/wjg.14.6052.PubMedCentralCrossRefPubMed
39.
Martensson A, Oberg A, Jung A, Cederquist K, Stenling R, Palmqvist R: Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer. Oncol Rep. 2007, 17: 447-452.PubMed
40.
Lugli A, Zlobec I, Minoo P, Baker K, Tornillo L, Terracciano L, Jass JR: Prognostic significance of the wnt signalling pathway molecules APC, beta-catenin and E-cadherin in colorectal cancer: a tissue microarray-based analysis. Histopathology. 2007, 50: 453-464. 10.1111/j.1365-2559.2007.02620.x.CrossRefPubMed
41.
Buob D, Fauvel H, Buisine MP, Truant S, Mariette C, Porchet N, Wacrenier A, Copin MC, Leteurtre E: The complex intratumoral heterogeneity of colon cancer highlighted by laser microdissection. Dig Dis Sci. 2012, 57: 1271-1280. 10.1007/s10620-011-2023-1.CrossRefPubMed
42.
Brabletz T, Jung A, Hermann K, Günther K, Hohenberger W, Kirchner T: Nuclear Overexpression of the Oncoprotein β-Catenin in Colorectal Cancer is Localized Predominantly at the Invasion Front. Pathol Res Pract. 1998, 194: 701-704. 10.1016/S0344-0338(98)80129-5.CrossRefPubMed
43.
Horst D, Reu S, Kriegl L, Engel J, Kirchner T, Jung A: The intratumoral distribution of nuclear beta-catenin is a prognostic marker in colon cancer. Cancer. 2009, 115: 2063-2070. 10.1002/cncr.24254.CrossRefPubMed
44.
Cheng H, Liang H, Qin Y, Liu Y: Nuclear beta-catenin overexpression in metastatic sentinel lymph node is associated with synchronous liver metastasis in colorectal cancer. Diagn Pathol. 2011, 6: 109-10.1186/1746-1596-6-109.PubMedCentralCrossRefPubMed
45.
Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ, Dehari R, Meyerhardt JA, Fuchs CS, Ogino S: Correlation β-Catenin Localization with Cyclooxygenase-2 Expression and CpG Island Methylator Phenotype in Colorectal Cancer. Neoplasia. 2007, 9: 569-577. 10.1593/neo.07334.PubMedCentralCrossRefPubMed
46.
Jass JR: Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007, 50: 113-130. 10.1111/j.1365-2559.2006.02549.x.CrossRefPubMed
47.
Nosho K, Kawasaki T, Chan AT, Ohnishi M, Suemoto Y, Kirkner GJ, Fuchs CS, Ogino S: Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008, 53: 588-598. 10.1111/j.1365-2559.2008.03161.x.PubMedCentralCrossRefPubMed
48.
Ogino S, Kawasaki T, Kirkner GJ, Ogawa A, Dorfman I, Loda M, Fuchs CS: Down-regulation of p21 (CDKN1A/CIP1) is inversely associated with microsatellite instability and CpG island methylator phenotype (CIMP) in colorectal cancer. J Pathol. 2006, 210: 147-154. 10.1002/path.2030.CrossRefPubMed
49.
Brandstedt J, Wangefjord S, Nodin B, Gaber A, Manjer J, Jirstrom K: Gender, anthropometric factors and risk of colorectal cancer with particular reference to tumour location and TNM stage: a cohort study. Biol Sex Differ. 2012, 3: 23-10.1186/2042-6410-3-23.PubMedCentralCrossRefPubMed
Metadata
Title
Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer
Authors
Sakarias Wangefjord
Jenny Brändstedt
Kajsa Ericson Lindquist
Björn Nodin
Karin Jirström
Jakob Eberhard
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2013
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-8-10

Other articles of this Issue 1/2013

Diagnostic Pathology 1/2013 Go to the issue

Research

Analysis of HAX-1 gene expression in esophageal squamous cell carcinoma

Case Report

Sudden, unexpected death due to glioblastoma: report of three fatal cases and review of the literature

Case Report

Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder: a case report

Research

Expression and clinical significance of the proliferation marker minichromosome maintenance protein 2 (Mcm2) in diffuse astrocytomas WHO grade II

Case Report

Retroperitoneal paraganglioma with metastasis to the abdominal vertebra: a case report

Research

The association between XPC Lys939Gln gene polymorphism and urinary bladder cancer susceptibility: a systematic review and meta-analysis