world cancer report - iarc

ane protein involved in cell adhesion.
The following genotypic/phenotypic relationships
have been demonstrated: APC
mutations in the first or last third of the
gene and attenuated polyposis; mutation
after codon 1444 and desmoid tumours;
mutations in the central region of the gene
and a severe phenotype. Commercial
genetic tests involve identification of the
mutant APC allele by in vitro detection of
truncated APC protein. Sigmoidoscopy is
used to screen gene carriers from the age
of10-12 years.
Hereditary nonpolyposis colorectal cancer
(often referred to as HNPCC) syndrome is
associated with germline mutations in six
DNA mismatch repair genes: MSH2 and
MSH3, MLH1, PMS1, PMS2, and MSH6.
The protein products of these genes correct
mismatches that arise during DNA
replication (Carcinogen activation and
DNA repair, p89). Mismatch repair deficiency
gives rise to instability in microsatellite
DNA and may aid in the diagnosis
of this syndrome via the Replication Error
positive (RER+) test. Surveillance of female
hereditary nonpolyposis colorectal cancer
syndrome patients includes exploration of
endometrium and ovaries and other potential
tumour sites by ultrasound. Kindreds
with the Muir-Torre phenotype, as well as a
subset of those with Turcot syndrome,
Fig. 5.36 Five-year relative survival rates after
diagnosis of colorectal cancer.
show mutations similar to those observed
in classical hereditary nonpolyposis colorectal
cancer.
Colon cancer has been the archetype for
the correlation of tumour pathology and
genetics since the publication of the first
such correlative statement by Vogelstein
et al. in 1988 (Multistage carcinogenesis,
p84). As a result of extensive analysis of
genetic alterations occurring during
tumorigenesis [7-12], understanding of
the complex and comprehensive nature of
these relationships has since expanded
(Fig. 5.31). Sporadic colorectal cancer
arises mainly through two distinct pathways.
In the first, chromosome instability,
the initial mutation is inactivation of the
APC tumour suppressor gene (Oncogenes
and tumour suppressor genes, p96) (all
tumours) followed by clonal accumulation
of alterations in additional oncogenes
(KRAS, 50% of tumours) and suppressor
genes on chromosomes 18 and 17 (DCC;
p53 gene, found in 70% of tumours and
associated with a shift to a malignant
tumour). The second, associated with
microsatellite instability, occurs in 15-20%
of sporadic colorectal cancers. Alterations
have been found to cluster in genes
encoding enzymes involved in the repair of
DNA mismatches (in particular MLH1 and
MSH2).
Histopathology related to poor prognosis
includes deep infiltration of the layers of
the bowel wall, poor differentiation, high
levels of angiogenesis in the tumour and
metastasis to numerous or distant lymph
nodes. Evidence of host response such as
intense inflammatory infiltrate is a
favourable prognostic feature. Predictive
factors relate to response to therapy [13].
The presence of wildtype p53 is associated
in vitro with a good response to many
agents. In contrast, mutant p53 is associated
with lack of response to postoperative
adjuvant chemotherapy with 5-FU-levamisole.
In sporadic colorectal cancer, as
well as in hereditary nonpolyposis colorectal
cancer syndrome, microsatellite
instability is a favourable indicator [12]
and the tumour may respond to 5-FUbased
chemotherapy. In the future, it is
expected that information regarding the
molecular biology of the tumour will give
Fig. 5.35 Double contrast barium enema revealing
an adenocarcinoma of the colon. Between the proximal
(top) and distal (bottom) segment of the colon,
the lumen is narrowed with an irregular surface
(arrow), due to tumour infiltration.
valuable information regarding prognosis
and response to treatment. For example,
microarray technology is based on the
simultaneous assay showing either deletion
or overexpression of multiple gene
fragments (around 20,000) and gives a
characteristic “fingerprint” of the tumour
[14].
Management
The management of familial colorectal
cancer requires the systematic genetic
and endoscopic screening of the proband
(the person presenting with a disorder,
whose case serves as a stimulus for a
genetic/familial study). Total colo-proctectomy
with ileo-anal anastomosis is performed
when adenomatous polyps are
detected in patients with familial adenomatous
polyposis. With hereditary nonpolyposis
colorectal cancer syndrome,
total colectomy is the treatment for confirmed
cancer, with a tendency to prophylactic
colectomy in presence of multiple
polyps. It has recently been shown that in
probands of hereditary nonpolyposis colorectal
cancer syndrome families carrying
the mutation, surveillance colonoscopy at
short (less than two years) intervals is a
safe method to detect the first neoplastic
lesions and prevents death from cancer.
Precursor adenomatous polyps are usually
resected at endoscopy by snare
polypectomy, when pedunculated, or by
strip resection combined with saline submucosal
injection, when sessile or flat.
Endoscopic treatment is safe for flat or
elevated lesions with intramucosal cancer
up to 2 cm in diameter; however this
Colorectal cancer 201