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