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144 1 UPPER GASTROINTESTINAL CANCER
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Marabelle, A., Le D.T., Ascierto P.A et al. (2020). Efficacy of Pembrolizumab
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Section II Colorectal and Anal Cancer
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9 Epidemiology, Microbiome, and Risk
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Factors Involved in Carcinogenesis of
Colorectal Cancer
Paul Moayyedi1 & Janusz A.Z. Jankowski
1
McMaster University, Canada
2
Comprehensive Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK
[Elements of Colorectal Cancer Epidemiology, Risk Factors, and Microbiome as also discussed in Chapter 1]
[Aspects of Nutrition in cancer and cancer prevention are also discussed in Chapter 1 and Chapter 29]
Epidemiology
Colorectal cancer (CRC) is the fourth commonest cancerrelated death. Colorectal cancer accounts for approximately
10% of cancer mortality in the West, making it the second
deadliest malignancy in the UK, the USA, and Australasia,
after lung cancer. Furthermore, at a global level there is evidence the mortality has increased globally by approximately
25% over the last two decades. The reasons for this are in part
due increased ageing in the population, decline of healthy diets
and exercise with concomitant increases in obesity as well as
consumption of more alcohol and cigarette use. This is particularly the case in Eastern Europe, South America, South
Eastern and Central Asia where red meat consumption remains
high. There is considerable heterogeneity of incidence, as populations with a high human development index (HDA), have
CRC rates, which are decreasing from the very high levels in
some select countries. There is considerable debate as to the
factors for this variation, but CRC screening programs and polypectomy, may be in part responsible.
Even in hereditary cancer syndromes, such as Lynch syndrome, with multisite lesions, colorectal cancer is now the main
site of presentation. This is a major change to the presentation
of Lynch syndrome where 50 years ago gastric cancer predominated. Despite the transformation of the therapeutic landscape
for both primary and metastatic colorectal cancer, there has
been only a limited increase in cure rates and long-term
survival (Dekker et al. 2019, Patel et al. 2022, Sinicrope 2022).
There is a slight predominance of cancers in males with a
female/male ratio of 0.9/1. In addition, 75% of rectal cancer
and 80% of colonic cancer occurs > 60 years of age. There is
also a predominance in more-developed countries such as
North America, Europe, and Australasia compared with less
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
2
developed countries of Africa, most of Asia, Latin America,
and the Pacific islands.
There has been an increase in the number of early-onset
CRC (CRC occurring before 50 years) especially in the
Australia, Europe, Japan, Taiwan, and the USA.
Microbiome
It is estimated that for every human cell there is at least one bacterial cell. In the colon the microbiota is approximately 10
14
10
microbes and approximately 50–60% of the dry weight of
stool is from the microbiota (Wong and Yu 2019). Organisms are
present throughout the alimentary tract, but the greatest variety
and number are found in the colon. Normal microbiota is essentially for digestion of food through fermentation, provision of key
nutrients and energy, stimulating colonic contraction, suppressing growth of parasites, maintaining immunity, and hostile organisms as well as secreting factors and short chain Fatty acids that
enhance mucosal growth. Conversely dysbiosis is associated with
many gastrointestinal diseases ranging from bloating predominant irritable bowel disease, initiation of inflammatory bowel
disease, and most importantly the catalysis of colorectal cancer.
Several organisms in particular are linked with colorectal cancer
including Streptococcus bovis (S. bovis), Streptococcus gallolyti-
cus (S. Gallolyticus), Escherichia coli (E. Coli), Enterococcus faec a-
lis (E. faecalis), Enterotoxigenic Bacteroides fragiles (ETBF), and
oral Fusobacterium nucleatum (F. nucleatum). It is thought that
these organisms cause inflammation which then acts to increase
cell turnover, damage cells especially the DNA in stem cells and
drive the growth of aberrant crypts in the hospital environment.
The key issue with microbiota is to have as diverse a spectrum
of bacteria, fungi, and viruses as possible, as this favors colorectal
health. There is evidence that highly variable vegetarian diets or
mixed vegetarian and pescatarian diets are strongly correlated with
the widest spectrum of microbiota. Conversely, chronic inflammation such as occurs in inflammatory bowel disease decreases
microbiotic diversity resulting in procarcinogenetic dysbiosis.
13
to
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Risk Factors
There are major contributions from both genetic and environmental
factors to the aetiology of colorectal cancer (Song et al. 2015).
5–10% of colorectal cancer incidence in the west can be attributed to those who have classical hereditary colorectal cancer syndromes. The commonest of these are, the Lynch syndrome, Familial
Adenomatosis Polyposis syndrome, MUTYH syndrome, Peutz
Jeghers syndrome, serrated polyposis, and juvenile polyposis.
1% of colorectal cancer is associated with chronic colitis due
to either ulcerative colitis or Crohn’s Disease.
The remaining ~ 90% of colorectal cancer can be attributed
at least in part to modifiable risk, many of the predisposing
environmental factors are mentioned above. These cancers are
very amenable to screening and surveillance programs as they
arise from the adenoma-carcinoma sequence.
There are also protective factors including whole grains,
fresh fruits, vegetables, calcium in milk, and vitamin D predominantly from cruciferous vegetable and oily fish. In
addition, 30 mins of daily moderate exercise also mitigates risk.
Low dose aspirin intake is associated with a 20–45% reduced
incidence depending on the duration of salicylate therapy.
Statins and hormone replacement therapy in women seem to
have a more modest chemo preventive effect.
These modifiable factors are thought to change the risk of
colorectal cancer by a relative risk of 1.8 to 0.5.
Key Take Home Messages
1 Most colorectal cancers can be delayed or even prevented
with adherence to healthy lifestyle factors with zero tolerance
of cigarette smoke.
2
Obesity showed be handled by progressive escalation of
interactions.
3
Maintenance of healthy microbiota is essential for colonic
health.
4
Low dose aspirin is useful as an adjunct in a proportion of
those with known diseases that predispose colorectal cancer.
Areas Needing Further Research
1 The optimal microbiota regimen to ingest to prevent colorectal cancer.
2
The long-term value of low dose aspirin in primary prevention.
Capsule endoscopy sampling technology.
3
Trusted Websites for Further Reading
https://www.nih.gov/news-events/news-releases/new-tool-
developed-predict-colorectal-cancer-risk
https://www.nice.org.uk/guidance/conditions-and-diseases/
cancer/colorectal-cancer
References
Dekker, E., Tanis, P.J., Vleugels, J.L.A. et al. (2019 October 19). Colorectal
cancer. Lancet 394 (10207): 1467–1480.
Patel, S.G., Karlitz, J.J., Yen, T. et al. (2022 March). The rising tide of early-
onset colorectal cancer: a comprehensive review of epidemiology,
clinical features, biology, risk factors, prevention, and early detection.
Lancet Gastroenterol Hepatol 7 (3): 262–274.
Sinicrope, F.A. (2022 April 21). Increasing incidence of Early-Onset
colorectal cancer. N Engl J Med 386 (16): 1547–1558.
Song, M., Garrett, W.S., and Chan, A.T. (2015 May). Nutrients, foods, and
colorectal cancer prevention. Gastroenterology 148 (6): 1244–1260.
Wong, S.H. and Yu, J. (2019 November). Gut microbiota in colorectal
cancer: mechanisms of action and clinical applications. Nat Rev
Gastroenterol Hepatol 16 (11): 690–704.
10 Genomics, Histopathology, and
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Molecular Pathology of Sporadic and
Hereditary Colorectal Cancer
Iannish Sadien, Betania Mahler-Araujo & Justin Davies
Cambridge Colorectal Unit, Department of Pathology, Addenbrooke’s Hospital, Cambridge University Hospitals
NHS Foundation Trust, Cambridge, UK
Introduction
Colorectal cancer (CRC) is the third commonest cancer
(after lung and breast), and is the second leading cause of
cancer-related mortality (Bray etal. 2018). Advances in our
understanding of pathophysiology and the adoption of
modern detection and treatment modalities have led to continuous improvement in outcomes in the Western world
(Arnold etal. 2017). Worryingly however, these gains look
set to be overtaken by the rising incidence of CRC in developing countries. The growing incidence of CRC in young
patients is also likely to add further complexity to screening
and treatment decisions (Gandhi etal. 2017). The majority
of CRC cases are sporadic, with only 5–10% linked to a
hereditary predisposition syndrome (Syngal et al. 2015).
However, these rare syndromes have helped us understand
the molecular mechanisms of CRC initiation and progression. In the past few years, considerable effort has been
invested to understand the genetic and transcriptomic profiles of CRC, adding to our current knowledge of this heterogeneous disease. Three main pathways have been
implicated, namely chromosomal instability (CIN), microsatellite instability (MSI), and the serrated neoplasia
pathway. In this chapter, we will begin by reviewing the
colonic microarchitecture in homeostasis. We will then see
how this fine balance gets affected by the pathways mentioned above and highlight how these tumors lend themselves to specific therapeutic options.
Role of Intestinal Stem Cells in Tumor
Formation
The intestinal lining is a rapidly self-renewing epithelial
monolayer whose growth is fueled by intestinal stem cells
(ISCs) that reside at the bottom of the crypts, which are
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
invaginations of the epithelial layer (Figure1) (Radtke and
Clevers 2005). In health, these long-lived ISCs give rise to
transit-amplifying cells, which produce the short-lived differentiated cells of the epithelium. ISCs that populate a crypt
compete with each other for space (Snippert et al. 2014).
Through a process of neutral drift, over time, a particular
ISC will dominate the whole stem cell compartment
(becomes fixed). This process is greatly speeded in the
presence of a mutation conferring a competitive advantage
(Vermeulen et al. 2013) or through other non-mutagenic
modulators such as diet and ageing (Bruens et al. 2020;
Nalapareddy etal. 2017).
As they are long-lived and display high levels of Wnt
activation (like CRC cells), ISCs have been postulated to be
the cell of origin of intestinal tumors. Indeed, using a
genetically engineered mouse model, Barker and colleagues
showed that targeted deletion of the Adenomatous Polyposis
Coli (APC) gene in ISCs led to tumor formation within days
(Barker etal. 2009), demonstrating that loss of this tumor
suppressor gene and Wnt-regulator in ISCs was sufficient
for tumor initiation. Similarly, activating mutations in
CTNNB1 (ß-catenin, an important activator of the Wnt
pathway) in ISCs were found to lead to tumorigenesis
(Sangiorgi and Capecchi 2008; Zhu etal. 2009).
In spite of this, some evidence in humans points away from
this “bottom up” model. When sporadic adenomas were
micro-dissected, the areas of dysplasia were found mostly to
be on the luminal surface of the colon with normal crypt morphology underneath and only cells at the top of the crypts had
mutations in APC (Shih etal. 2001). More recently, a multiomics approach has begun to shed light on this debate. Using
a combination of histology, sequencing, and transcriptomic
profiling, Chen and colleagues identified at least two different
transcriptional pathways for human colorectal polyp formation
and suggested that conventional adenomas originate from
ISCs (bottom-up pathway) while serrated polyps originate
from more differentiated cells (top-down pathway) (Chen
etal. 2021).
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Figure1 On edge view of a small intestinal crypt. Colonic architecture is similar with two exceptions, which are the absence of villi and Paneth cells.
TA: transit-amplifying.
Conventional (Or Chromosomal
Instability) Pathway
The majority (70–90%) of CRC arise from the conventional
adenoma-carcinoma pathway. This involves the stepwise
accumulation of mutations, typically starting with loss of
function mutations in APC (Fearon and Vogelstein 1990).
APC is a Key Regulator of Wnt Signaling
The product of the tumor suppressor gene APC is 2,843 amino
acid long. It is a key regulator of the Wnt pathway, which is crucial for cellular proliferation and organ development (Cadigan
and Nusse 1997). In the absence of Wnt ligands, APC forms a
destruction complex with Axin, Casein-kinase I and GSK-3ß,
which targets the effector ß-catenin for proteasomal degradation by phosphorylating it (Figure2) (Aberle etal. 1997; Orford
et al. 1997). In contrast, in the presence of Wnt ligands,
ß-catenin is able to translocate to the nucleus, where it binds to
members of the T-cell factor (TCF)-lymphoid enhancer factor
(LEF) family of transcription factors, which regulate several
crucial genes such as the proto-oncogene c-myc and the cell
cycle regular cyclin-D1 (He etal. 1998; Tetsu and McCormick
1999). Therefore, overactivation of the Wnt pathway and epithelial hyperproliferation result from loss of function mutations in APC or gain of function mutations in CTNNB1.
APC Contributes to Chromosomal Stability
As well as single nucleotide variations and small insertions and
deletions (indels), large scale chromosomal rearrangements
and copy number changes are common in CRC. This chromosomal instability is thought to result from defective cell division
during mitosis, and a role for APC in this process has been
Figure2 Schematic representation of Wnt signaling pathway.
suggested. Fodde and colleagues showed that APC-mutant
mouse embryonic stem cells containing the Min (multiple
intestinal neoplasia) or Apc1638T alleles showed extensive
chromosome and spindle aberrations (Fodde et al. 2001).
Subsequent work has shown that APC localizes to the ends of
microtubules in kinetochores during mitosis, shedding light on
the mechanism of chromosomal instability following the loss of
APC (Kaplan etal. 2001).
Sequence of Events in CIN
The multistep model of colorectal carcinogenesis proposes
that mutations in APC occur early in the development of colorectal polyps (Figure3) (Fearon and Vogelstein 1990; Jones
etal. 2008). Indeed, 60–80% of sporadic CRCs have somatic
mutations in APC (Figure4) (Narayan and Roy 2003). These
10 GENOMICS, HISTOPATHOLOGY, AND MOLECULAR PATHOLOGY OF SPORADIC AND HEREDITARY COLORECTAL CANCER 151
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Figure3 Proposed sequence of events in the conventional
adenoma-carcinoma sequence.
Figure4 Top 20 cancer driver mutations in colorectal
adenocarcinoma, ranked in order of decreasing frequency. Data
extracted from 11 published studies comprising 3619 samples
(Source: cBioportal).
mutations in APC tend to cluster between codons 1286 and
1513, in a region called the mutational cluster region (MCR)
(Mori etal. 1992).
This is followed by mutations in KRAS, which is an important activator of the RAF/MAPK, JNK and PI3-K pathways.
Mutations in KRAS occur in up to 68% of sporadic CRCs and
activating mutations lead to constitutive activation of the
downstream pathways, promoting cell proliferation, and
survival independent of the EGFR receptor (Armaghany etal.
2012; McLellan etal. 1993). Interestingly, most activating mutations in KRAS are point mutations at codons 12, 13, and 35,
which has led to much effort in finding specific KRAS inhibitors (Jiri etal. 2022).
Mutations in TP53, which is a protein that induces G1 cellcycle arrest and induces cell death (apoptosis) in the presence
of DNA damage, are thought to occur during the transition
from adenoma to invasive cancer (Armaghany et al. 2012).
TP53 mutated CRCs have been shown to have a worse prognosis compared to those with wild-type CRC, and is associated
with resistance to radiotherapy in patients with rectal cancer
(Munro etal. 2005).
Up to 70% of CRCs demonstrate loss of chromosome 18q
and these are associated with a poorer prognosis (Popat and
Houlston 2005). This has led to the suggestion that there might
be tumor suppressor genes at that locus which strongly
influence survival. SMAD4, which is coded by a gene located at
chromosome 18q21.1, is an important tumor suppressor which
mediates the intracellular signaling of the TGF-beta pathway
(Zhou etal. 1998). Tanaka and colleagues demonstrated that
18q loss and SMAD4 expression were correlated, and hypothesized that SMAD4 is the tumor suppressor gene whose loss is
critical during 18q loss (Tanaka et al. 2006). Indeed, loss of
SMAD4 is associated with more aggressive disease and with
resistance to chemotherapy (Wasserman etal. 2019).
Familial Adenomatous Polyposis Syndrome
Familial adenomatous polyposis (FAP) syndrome is an autosomal dominant inherited condition that predisposes to CRC.
Although it only contributes about 1% of all CRC cases, studies
of FAP have shed considerable light on the process of tumor
formation in colonic epithelium. FAP occurs in 1 in 8,300 to
14 000 patients, with 50% of those developing colorectal adenomas by the age of 16 years (Kim and Bodmer 2021). The
lifetime risk of CRC in patients with FAP exceeds 90% if left
untreated and there are also increased risks of duodenal cancer, pancreatic cancer, medulloblastoma, papillary thyroid
cancer, and hepatoblastoma (Stoffel and Boland 2015).
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Patients with FAP carry germline mutations in APC. In spite
of its autosomal dominant inheritance, 30% of patients with
germline APC mutations have no family history and are presumed to have de novo APC mutations (Bisgaard etal. 1994).
Benign extracolonic manifestations of FAP include epidermoid cysts, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and osteomas (Kim and Bodmer 2021;
Morton etal. 2005).
The phenotype displayed (age of onset, type, and number
of intestinal polyps and extracolonic polyps) has been shown
to correlate with the type and location of APC mutation
incurred. Mutations located towards the proximal portion of
the protein (before codon 1249) are associated with fewer
than 1000 polyps (sparse polyposis), while those between
codon 1250 and 1330 with >5000 polyps (profuse polyposis)
(Friedl et al. 2001; Lal and Gallinger 2000; Leppert et al.
1990). Similarly, mutations that are located very close to the
N-terminus of the protein or distal to codon 1578 lead to a
milder phenotype with a reduced number of polyps (less
than 100) and an age of onset that is 10–15 years later than
in classical FAP, in a condition called attenuated FAP (AFAP)
(Spirio etal. 1992).
The diagnosis of FAP relies primarily on the number and history of colorectal adenomas. Patients with 100 or more polyps,
or with fewer than 100 polyps but with a family history of FAP
are clinically diagnosed with FAP. A clinical diagnosis of FAP is
usually followed by sequencing of APC to identify the pathogenic variant. As they are at risk for duodenal polyposis and
cancer, patients with confirmed FAP are also recommended a
screening gastroscopy from the age of 25 years, and then at regular intervals according to the Spigelman classification
(Spigelman et al. 1989). Patients with a first-degree relative
with a clinical diagnosis of FAP are considered at risk and are
offered regular surveillance colonoscopies starting at 12–14
years of age (Monahan etal. 2020).
The management of FAP is mainly surgical, with prophylactic surgery being the treatment of choice. Non-steroidal
anti-inflammatory drugs (NSAIDs) such as sulindac have
been shown to induce polyp regression in some patients but
this effect was not sustained following treatment cessation
(Giardiello etal. 1993). Due to the high penetrance of colorectal cancer in patients with FAP, prophylactic surgery is recommended shortly after diagnosis. The principles of surgery
in these patients are the removal of all at-risk colorectal
mucosa and restoration of bowel continuity if it is safe to do
so (Setti-Carraro and Nicholls 1996). Surgical options include
total colectomy and ileorectal anastomosis (in patients with
limited rectal polyp burden and willing for regular endoscopic surveillance), proctocolectomy and ileal pouch-anal
anastomosis, total proctocolectomy and end ileostomy or
proctocolectomy and continent ileostomy (Lal and Gallinger
2000).
Microsatellite Instability Pathway
In contrast to the CIN pathway, there is a distinct group of
CRCs that does not show large chromosomal abnormalities.
These diploid tumors have a different type of genetic instability
in which the abnormalities lie at the nucleotide level. The propensity for deletion or gain of short DNA sequences in these
tumors has been termed microsatellite instability (MSI).
Changes in Microsatellites Can Alter
Downstream Genes
Microsatellites are short sequences in genomic DNA that comprise repetition of one to four nucleotides. These mono/di/tri
or tetranucleotides can be repeated ten to hundreds of times in
the sequence. The most common microsatellite in humans is
the repetition of cytosine-adenine dinucleotide (CACACACA
… or [CA]
they are prone to errors during DNA replication. Under normal
conditions, these mistakes are corrected by highly conserved
DNA repair mechanisms during cell replication. However, if
the repair process is defective (such as in Lynch syndrome),
microsatellite sequences can be altered, leading to microsatellite instability (MSI). A change in the length of a microsatellite
can lead to a frameshift mutation in genes downstream to the
microsatellite sequence, which shifts the reading frame of RNA
polymerase, with the end result being a change in the amino
acid sequence of the gene product.
Thibodeau and colleagues identified a subset of CRCs with
highly variable microsatellites, and identified that 89% of these
MSI tumors were in the proximal colon and that patients with
MSI CRCs had a better prognosis (Thibodeau et al. 1993).
Therefore, they hypothesized that the MSI pathway could represent an alternative pathway to CRC formation.
Lynch Syndrome
It became clear in the mid-1990s that Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer
(HNPCC) and originally described by Warthin in 1913 and
further characterized by Lynch in the mid-1960s, is associated
with MSI (Lynch and Lynch 1985; Peltomäki etal. 1993). Lynch
syndrome is responsible for up to 2–6% of CRCs (Aaltonen
etal. 1998; Lamberti etal. 2006). The syndrome is characterized by increased risk of carcinogenesis in the gastrointestinal
tract, endometrium, and ovary, and rarely in the urogenital
tract, hepatobiliary tract, and pancreas (Aarnio et al. 1999).
The lifetime 5–6% risk of developing CRC that is seen in the
normal population is increased to 70–80% in Lynch syndrome
(Aarnio etal. 1999; Chung and Rustgi 2003). As a result of this,
regular colonoscopic surveillance is recommended and has
been shown to reduce CRC-related mortality from 22% to 8%
). Due to the repetitive nature of these sequences,
n
10 GENOMICS, HISTOPATHOLOGY, AND MOLECULAR PATHOLOGY OF SPORADIC AND HEREDITARY COLORECTAL CANCER 153
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(Monahan etal. 2020). The CAPP2 randomized control trial
has shown that chemoprophylaxis with aspirin can reduce the
risk of CRC formation in this group of patients (hazard ratio
0.41, 95% confidence interval 0.19–0.86, p 0.02) (Burn et al.
2011).
Just like FAP, Lynch syndrome has an autosomal dominant
inheritance. The underlying cause is usually a germline mutation in one of the DNA mismatch repair genes. The most commonly mutated genes are human MutL homologue 1 (MLH1)
found on chromosome 3p and human MutS homologue 2
(MSH2) located on chromosome 2p. Other less commonly
involved genes in Lynch syndrome are human MutS homologue (MSH6), and human postmeiotic segregation increased 2
(PMS2) and 1 (PMS1). Tumors which are deficient in these
mismatch repair mechanisms (MMR-d) have high levels of
MSI (MSI-H) and show loss of the corresponding DNA mismatch repair protein by immunohistochemistry (Valle et al.
2019). Deletions affecting the polyadenylation site located in
exon 9 of the Epithelial Cell Adhesion Molecule (EPCAM) gene
located upstream of MSH2 are associated with 2–3% of Lynch
syndrome cases (Huth etal. 2012). Deletions in EPCAM lead to
a transcriptional read-through, best regarded as epigenetic
silencing of MSH2.
Unlike polyposis syndromes, Lynch syndrome usually pres-
ents with sparse colorectal tumors which cannot usually be distinguished clinically from sporadic tumors. Therefore, clinical
criteria have been defined to identify these patients and those
at risk. The Amsterdam and Bethesda Criteria (Table1) help
identify patients based on family history and the characteristics
of the index tumor (Umar etal. 2004; Vasen etal. 1999).
Further testing for mutations in microsatellites is recommended in those individuals who fulfill any of the Bethesda
criteria (Burt and Neklason 2005; Kaz and Brentnall 2006).
Two methods are available to detect dMMR/MSI phenotype:
(i) expression of MMR proteins (MLH1, MSH2, MSH6, and
PMS2) in tumor tissue by immunohistochemistry (IHC) and (ii)
DNA MSI testing by PCR fragment analysis (Figure 5). MMR
immunohistochemistry presents a sensitivity between 85% and
98% and specificity between 85% and 100% whereas the sensitivity of MSI testing by PCR ranges between 67% and 100%, with
a specificity between 61% and 98% depending on the panel used
(Guyot D’Asnières De Salins etal. 2021; Snowsill etal. 2017). The
terminology used in MMR immunohistochemistry can be confusing as a pathological finding implies a loss of the normal
nuclear staining, in which the tumor should be referred to as
MMR deficient. The terminology negative and positive may be
misleading and should be avoided.
The PCR-based method demonstrates increased sensitivity
and accuracy when tumor tissue and germline DNA (the latter can be extracted from adjacent normal tissue) are processed separately and then compared. Tumors that show
instability in at least 30% of the examined microsatellites are
termed microsatellite instability high (MSI-H), those with
less than 30% are microsatellite instability low (MSI-L), and
those with no mutation are microsatellite stable (MSS) tumors
(C. R. Boland etal. 1998). Since usually five microsatellites are
used for testing, in practice this means that a tumor is called
MSI-H if at least two out of five microsatellites are unstable.
Traditionally, two PCR fragment analysis-based DNA microsatellite analysis panels have been established: the Bethesda
Table 1 Amsterdam and Bethesda criteria for the identification of patients with Lynch syndrome.
Amsterdam II criteria (1999)
All criteria must be met:
• Three or more relatives with histologically confirmed colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis, one
affected relative being a first-degree relative of the other two; FAP should be excluded.
• Two or more successive generations are affected.
• At least one relative was diagnosed before the age of 50 years.
Revised Bethesda guidelines (2004)
One or more of the following criteria must be met:
• Colorectal cancer before the age of 50 years
• Synchronous or metachronous colorectal cancer or other Lynch syndrome-related tumors,
• Colorectal cancer with MSI-H morphology
• Colorectal cancer (regardless of age) and a first-degree relative with colorectal cancer or a Lynch syndrome-related tumor before the age of 50 years.
• Colorectal cancer (regardless of age) and two or more first- or second-degree relatives diagnosed with colorectal cancer or an Lynch syndrome-
related tumor (regardless of age).
1
Lynch syndrome-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually
glioblastoma) tumors, sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel.
2
Presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring cell differentiation or medullary growth pattern.
2
before the age of 60 years.
1
regardless of age.
154 2 COLORECTAL AND ANAL CANCER
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Figure5 Example of a colorectal adenocarcinoma with loss of
expression of MLH1. The immunohistochemistry reaction shows negative
neoplastic glands within a positive background stroma.
panel, which assesses DNA mismatches in two mononucleotide repeats (BAT-25 and BAT-26) and three dinucleotide
repeats (D5S346, DS123 and D17S250), and the modified MSI
panel which assesses five mononucleotide repeats (BAT-25,
BAT-26, NR-21, NR-24, and MONO-27). Both panels show
overlapping performance in terms of MSI-H calling (Murphy
et al. 2006). The sensitivity of the PCR-based diagnosis
increases when the percentage of tumor cells in the tissue
analyzed exceeds 30%.
Progress in technology and in particular the use of large targeted next generation sequencing (NGS) panels now allows the
establishment of the diagnosis of MSI-H cancer (NGS-MSI).
This methodology has shown high diagnostic concordance
with traditional PCR fragment analysis (Vanderwalde et al.
2018).
It is worth noting that MSI can be also seen in about 15% of
sporadic CRCs, and therefore an MSI-H tumor itself is not
diagnostic for Lynch syndrome.
Hereditary CRC with MMR/MSI Discrepancy
About half of CRC families that meet the Amsterdam criteria
have no identifiable germline mutations in the MMR genes.
These families also have a lower lifetime CRC risk than families
with Lynch syndrome and there is no increased risk of extracolonic tumors (Lindor et al. 2005). Analysis of these MMRproficient tumors has failed to identify other genes that could
explain these inherited forms of CRC, with the only candidate
gene that has shown an association being RPS20 (ribosomal
protein S20) (Nieminen et al. 2014). In addition to this, rare
germline MLH1 promoter hypermethylation has been identified as a potential cause (Hitchins etal. 2005).
Sporadic MSI-Associated Colorectal Cancer
The vast majority of CRCs are sporadic, and most of these
follow the conventional/chromosomal instability pathway.
However, as mentioned before, about 15% of sporadic CRCs
are associated with deficiency in the DNA mismatch repair
machinery leading to DNA microsatellite instability. In contrast to Lynch syndrome, which relates to germline pathogenic variants in the genes encoding DNA mismatch repair
proteins, these tumors show sporadic somatic inactivation of
MMR genes. In the vast majority of cases, MSI in sporadic
CRCs relates to epigenetic downregulation of MLH1. These
epigenetic changes usually involve the methylation of cytosine residues in cytosine and guanine-rich regions (called
CpG islands) in promoter sequences of the genes involved. As
a consequence, there is no transcription of the gene. The
majority (approximately 80%) of sporadic dMMR cases are
caused by methylation of the MLH1 gene promoter, whereas
more than 70% of hereditary cases are associated with germline mutations in the MLH1 and MSH2 genes (Koopman etal.
2009; Latham etal. 2019).
Classification of sporadic CRCs based on microsatellite instability has profound clinical implications. MSI-H CRCs have
consistently been shown to have a better prognosis compared to
those with intact mismatch repair mechanisms. A systematic
review of 32 studies comprising a total of 7,642 cases showed a
combined hazard ratio for overall survival of 0.65 (95%
confidence interval 0.59 to 0.71) for MSI-H compared to MSS
CRCs (S Popat etal. 2005). One of the potential mechanisms for
this appears to be the higher expression of neo tumor-specific
peptides in MSI-H tumors (Linnebacher etal. 2001). These neoantigens are displayed by the major histocompatibility complex
(MHC) on the surface of tumor cells, which in turn triggers a
T-cell mediated cytotoxic anti-tumor immune response
(Schumacher and Schreiber 2015). As well as its use in prognostication, MSI status impacts treatment strategy. For example,
Jover and colleagues demonstrated that dMMR tumors do not
respond to 5-fluorouracil based chemotherapy (Jover et al.
2009). Likewise, the immune checkpoint inhibitors nivolumab
and pembrolizumab which block the programmed death (PD-
1) receptor have been approved for the treatment of colorectal
cancer with MSI-H or deficient MMR status (Le et al. 2015;
Overman etal. 2017).
Serrated Neoplasia Pathway
More recently, a serrated neoplasia pathway to colorectal carcinogenesis has been described. The precursor lesion in this
pathway is the serrated polyp. Although they represent a heterogeneous group, the characteristic feature of serrated polyps
is the saw-toothed infolding of the crypt epithelium (Leggett
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