Abstract. In the carcinogenesis of colorectal cancer (CRC)
genetic instability and dysfunction of the Wnt-signalling path-
way play important roles. Most Wnt-signalling dysfunctions
lead to the nuclear accumulation of ß-catenin. The aim of the
present study was to investigate whether nuclear accumulation
of ß-catenin is associated with prognosis and genetic instability.
We used immunohistochemistry to study nuclear ß-catenin
expression in 67 CRCs. The expression was evaluated in the
entire tumour section as mean values and in tumour budding at
the invasive margin. We compared the results with chromo-
somal and microsatellite instability (CIN vs. MSI), p53
accumulation, and clinicopathological variables including
survival. The nuclear accumulation of ß-catenin was
significantly associated with abnormal p53 expression and
aneuploidy, typically for CIN, whereas no tumour with nuclear
ß-catenin expression at the invasive margin displayed MSI.
The ß-catenin expression pattern did not correlate significantly
with CRC patient prognosis when including all stages. How-
ever, in the clinically most interesting prognostic group, Dukes'
stage B patients, high nuclear accumulation of ß-catenin was
associated with a poor prognosis (p=0.01). Our results suggest
that nuclear accumulation of ß-catenin in CRC is related to
CIN and may be of prognostic importance. However, larger
studies are needed to verify these findings.
Colorectal cancer remains the second leading cause of cancer
deaths in Western Countries. In contrast to many other
malignancies the survival rate has not changed significantly
during the last three decades (1).
Colorectal cancer (CRC) develops along two distinct
pathways: chromosomal instability (CIN) or microsatellite
instability (MSI) (2-4). Up to 85% of colorectal tumours show
chromosomal instability (CIN) which is accompanied by
accumulation of somatic mutations in tumour suppressor genes
as TP53 or the adenomatous polyposis coli (APC) and onco-
genes such as ß-catenin and KRAS (3,5,6). On the other hand,
MSI is caused by an impaired capacity of the DNA mismatch
repair system and only 10-15% of sporadic colorectal cancer
show MSI. These cancers are mostly diploid and show no
gross chromosomal changes (7).
In sporadic CRC the overall frequency of APC mutation
is around 60%, leading to loss of degradation of its down-
stream target, ß-catenin, the main effector of the Wnt pathway,
causing nuclear translocation and constitutive overexpression
Normally, APC forms a multimolecular complex with
ß-catenin, Axin/Conductin and GSK3ß, to target cytoplasmic
ß-catenin for proteasomal degradation. Since most APC
mutations result in truncated proteins lacking most of the
binding domains for ß-catenin and/or Axin, no efficient
degradation can take place, and thus ß-catenin will
accumulate (9,10). Although about 40% of the MSI colorectal
carcinomas contain wild-type APC, they may have other
defects in the Wnt pathway causing stabilization of ß-catenin
and thereby increased activity. For example dominant
mutations in the ß-catenin gene itself or the tumour suppressive
Conductin/Axin-2 gene have been found which all omit
efficient ß-catenin degradation (6,8).
Aberrant nuclear accumulation of ß-catenin leads to
association with transcription factors including lymphoid
enhancer factor-1 (LEF-1) or T cell factors (TCF) (11,12).
These molecules are DNA-binding proteins driving together
with ß-catenin the transcription of multiple target genes such as
c-myc, cyclin D1, MMP-7, laminin-5Á2 implicated in
proliferation, cell-cell attachment, and invasion (13-15).
Collectively, aberrant Wnt-signalling and nuclear ß-catenin
accumulation may serve as the underlying basis for invasion,
metastasis and poor prognosis (8,15).
The relationship between alterations in the Wnt-signalling
pathway and concomitant accumulation of nuclear ß-catenin
as well as differences in the ß-catenin expression between
CIN and MSI have not been fully clarified and divergent results
have been reported (16). However, in most sporadic CRC,
high degree of MSI has been reported to correlate with low
frequencies of APC and ß-catenin mutations and better
prognosis, while CIN is associated with poor outcome and
disruption of the Wnt signalling pathway (17,18).
ONCOLOGY REPORTS 17: 447-452, 2007
ß-catenin expression in relation to genetic instability
and prognosis in colorectal cancer
ANN MÅRTENSSON1, ÅKE ÖBERG3, ANDREAS JUNG4, KRISTINA CEDERQUIST2,
ROGER STENLING1and RICHARD PALMQVIST1
Departments of 1Medical Biosciences, Pathology, 2Clinical Genetics and 3Surgical and Perioperative Sciences, Surgery,
Umeå University, Umeå, Sweden; 4Department of Pathology, Institut für Pathologie, LMU, D-80337 München, Germany
Received June 29, 2006; Accepted September 20, 2006
Correspondence to: Dr Richard Palmqvist, Department of Medical
Biosciences, Pathology, Bld 6M, 2nd floor, Umeå University,
SE-901 85 Umeå, Sweden
Key words: ß-catenin, genetic instability, colorectal cancer, prognosis
21. Boland CR, Thibodeau SN, Hamilton SR, et al: A National
Cancer Institute Workshop on Microsatellite Instability for cancer
detection and familial predisposition: development of international
criteria for the determination of microsatellite instability in colo-
rectal cancer. Cancer Res 58: 5248-5257, 1998.
22. Lamlum H, Papadopoulou A, Ilyas M, et al: APC mutations are
sufficient for the growth of early colorectal adenomas. Proc Natl
Acad Sci USA 97: 2225-2228, 2000.
23. Bondi J, Bukholm G, Nesland JM, et al: Expression of non-
membranous beta-catenin and gamma-catenin, c-Myc and
cyclin D1 in relation to patient outcome in human colon
adenocarcinomas. APMIS 112: 49-56, 2004.
24. Cheah PY, Choo PH, Yao J, et al: A survival-stratification
model of human colorectal carcinomas with beta-catenin and
p27kip1. Cancer 95: 2479-2486, 2002.
25. Baldus ES, Mönig PS, Huxel S, et al: MUC1 and nuclear
ß-catenin are coexpressed at the invasion front of colorectal
carcinomas and are both correlated with tumor prognosis. Clin
Cancer Res 10: 2790-2796, 2004.
26. Roca F, Mauro VL, Bonadeo F, et al: Prognostic value of
E-cadherin, beta-catenin, MMPs (7 and 9) and TIMPs (1 and 2)
in patients with colorectal carcinoma. J Surg Oncol 93: 151-160,
27. Cianchi F, Messerini L, Palomba A, et al: Character of the
invasive margin in colorectal cancer: does it improve prognostic
information of Dukes staging? Dis Colon Rectum 40: 1170-1175,
28. Park KJ, Choi HJ, Roh MS, et al: Intensity of tumor budding
and its prognostic implications in invasive colon carcinoma. Dis
Colon Rectum 48: 1597-1602, 2005.
29. Palmqvist R, Rutegard JN, Bozoky B, et al: Human colorectal
cancers with an intact p16/cyclin D1/pRb pathway have up-
regulated p16 expression and decreased proliferation in small
invasive tumour clusters. Am J Pathol 157: 1947-1953, 2000.
30. Ueno H, Murphy J, Jass JR, et al: Tumour ‘budding’ as an index
to estimate the potential of aggressiveness in rectal cancer.
Histopathology 40: 127-132, 2002.
31. Brabletz T, Jung A, Hermann K, et al: Nuclear overexpression
of the oncoprotein beta-catenin in colorectal cancer is localized
predominantly at the invasion front. Pathol Res Pract 194:
32. Chung GG, Provost E, Kielhorn EP, et al: Tissue microarray
analysis of ß-catenin in colorectal cancer shows nuclear phospho-
ß-catenin is associated with a better prognosis. Clin Cancer Res
7: 4013-4020, 2001.
33. Kapiteijn E, Liefers GJ, Los LC, et al: Mechanisms of
oncogenesis in colon versus rectal cancer. J Pathol 195: 171-178,
34. Tomlinson I: Different pathways of colorectal carcinogenesis
and their clinical pictures. Ann NY Acad Sci 910: 10-18,
35. Sparks AB, Morin PJ, Vogelstein B, et al: Mutational analysis of
the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer
Res 58: 1130-1134, 1998.
36. Miyaki M, Iijima T, Kimura J, et al: Frequent mutation of beta-
catenin and APC genes in primary colorectal tumours from
patients with hereditary nonpolyposis colorectal cancer. Cancer
Res 59: 4506-4509, 1999.
MÅRTENSSON et al: ß-CATENIN IN COLORECTAL CANCER