Cancer Genetics and Cytogenetics 162 (2005) 68–73
Who takes the lead in the development of ulcerative
colitis–associated colorectal cancers: mutator,
suppressor, or methylator pathway?
Lara Maia
a,
*
, Joana Dinis
a
, Marı
´
lia Cravo
b
, Isabel Claro
b
,Ce
´
lia Baltazar
a
, Isabel Fonseca
c
,
Tavarela Veloso
d
, Ana F. Capelinha
e
,Fa
´
tima Carneiro
e,f
, Carlos Nobre-Leita
˜
o
b
a
Centro de Investigac
¸
a
˜
o em Patobiologia Molecular (CIPM),
b
Servic
¸
o de Gastrenterologia,
c
Servic
¸
o de Anatomia Patolo
´
gica,
Instituto Portugue
ˆ
s de Oncologia Francisco Gentil, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal
d
Servic
¸
o de Gastrenterologia,
e
Servic
¸
o de Anatomia Patolo
´
gica, Hospital de Sa
˜
o Joa
˜
o, Faculdade de Medicina do Porto, Oporto, Portugal
f
Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Oporto, Portugal
Received 12 November 2004; received in revised form 14 February 2005; accepted 17 February 2005
Abstract
Although several genetic alterations have been identified in patients with ulcerative colitis (UC),
it remains unclear whether these changes indicate an increased risk for malignancy. This paper
analyzes the involvement of suppressor, mutator, and methylator pathways in malignant transforma-
tion associated with UC. A total of 60 colonic samples (47 affected non-neoplastic mucosa, 7
dysplasia, and 6 carcinoma) from 51 UC patients were analyzed for 22 microsatellite markers. p53
gene exons 5–8 were analyzed by single-strand conformational polymorphism, and APC gene by
denaturing gradient gel electrophoresis (exons 1–14) and protein truncation test (exon 15). Methyla-
tion studies for MLH1 and CSPG2 genes were also performed. Microsatellite instability was absent
in all samples whereas allelic imbalance (AI) and loss of heterozygosity (LOH) were detected
mainly in samples with neoplastic transformation (P Ͻ 0.0001). AI and/or LOH at loci located on
chromosomes 5, 9, and 18 were significantly more frequent in neoplastic samples (P Ͻ 0.01), as
were TP53 gene mutations (P Ͻ 0.007). A single mutation was detected for APC gene in a cancer
sample. MLH1 gene methylation was absent in all analyzed samples, whereas CSPG2 gene methyla-
tion was detected in a single non-neoplastic sample. Our results suggest that the suppressor pathway
plays the main role in UC associated tumorigenic progression. LOH at specific loci located on
chromosomes 5, 9, and 18 appears to be specifically associated with malignancy risk.
Ć
2005
Elsevier Inc. All rights reserved.
1. Introduction
Ulcerative colitis (UC) is a chronic inflammatory disease
with an increased risk for malignant transformation, which
is higher inpatients with long-standingand extensive disease
[1,2]. Ulcerative colitis–associated colorectal cancers
(UCACRCs) arise from areas of dysplasia that are not easily
detected at the macroscopic level because they frequently
occur in flat mucosa [3–6]. A number of genetic alterations
havebeendescribedinthecolonicepitheliumof patientswith
UC, both in affected andnonaffectedmucosa,withor without
neoplastic transformation. Nonetheless, it remains unclear
* Corresponding author. Tel.: ϩ00351-21722980 ext. 1156; fax:
ϩ00351-217229895.
E-mail address: laramaia@iol.pt (L. Maia).
0165-4608/05/$ – see front matter
Ć
2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.cancergencyto.2005.02.017
whether these alterations are related with the continuous
inflammatory process to which this epithelium is exposed,
or if they can be interpreted as premalignant changes and be
used as such. This would have a major impact on the clinical
management of these patients, particularly when referring
them for prophylactic colectomy.
There are currently three well-characterized pathways
for colorectal tumorigenesis: the suppressor, mutator, and
methylator pathways. The first one is characterized by the
inactivation of several tumor suppressorgenes, namely APC,
TP53, and DCC, and is followed by familial adenomatous
polyposis–associated cancers, as well as by the great major-
ity of sporadic tumors [7,8]. The mutator pathway is charac-
teristic of tumors that arise in the context of hereditary
nonpolyposis colorectal cancer, as well as by 20% of spo-
radic tumors with the so-called mutator phenotype [9,10].