Download Compare and contrast the two major genetic pathways of hereditary

Michael G. Woo
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UNIVERSITY OF TORONTO MEDICAL JOURNAL
A Comparison of the Two Major Genetic Pathways of
Hereditary Colon Cancer
Michael G. Woo1,2* (MSc., PhD. candidate)
1Department
of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON,
Canada
2Chronic
Disease Program, Ottawa Hospital Research Institute, The Ottawa Hospital
(Civic Campus), Ottawa, Ontario, Canada
*Correspondence to: E-mail: [email protected]
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Michael G. Woo
ABSTRACT
The lifetime risk of colorectal cancer (CRC) is approximately 5 percent in the general
population1-2. However, approximately 20 percent of colorectal cancer occurs in people
who have a family history of CRC1, which suggests that there is a heritable basis for this
disease. Indeed, a small proportion of these cases are inherited in an autosomal
dominant manner, diagnosed as familial adenomatous polyposis (FAP) or nonpolyposis
colorectal cancer (HNPCC)3. The identification and cloning of the genes responsible for
FAP and HNPCC has allowed for considerable advances in the understanding of cancer
genetics. Strategies for patient selection has improved based on family pedigree
analysis, the well characterized and well defined sequence of events involved in the
various stages of CRC tumour development, and the availability of biopsies for genetic
studies. In this review, we will compare and contrast the two major genetic pathways of
hereditary colorectal cancer, familial adenomatous polyposis and hereditary
nonpolyposis colorectal cancer, with respect to the clinical presentation and pathological
manifestations.
KEYWORDS: hereditary colorectal cancer (CRC), familial adenomatous polyposis
(FAP), nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, APC, microsatellite
instability (MSI), mismatch-repair (MMR).
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INTRODUCTION
In Canada, colorectal cancer (CRC) is the third most common cause of cancer by
gender. In 2010, it is estimated that 22,500 Canadians will be diagnosed with CRC and
9,100 will die from this disease 4. The onset of CRC typically occurs in individuals over
the age of 50 and develops from environmental and genetic factors 5-6. Approximately
5% of CRC are the consequence of highly penetrant germline mutations, resulting in the
development of various hereditary colorectal cancer syndromes 7. The two major forms
of hereditary colorectal cancer are: (1) familial adenomatous polyposis (FAP) and (2)
hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome). These account for
less than 1%, and close to 5% of colorectal cancers respectively 2, 8-9. Although both
symptoms are hereditary, they differ in clinical and molecular features. FAP is generally
associated with cancer of the distal colon and is a consequence of mutations in the
adenomatous polyposis coli (APC) gene 2. Lynch syndrome generally involves cancer
development in the proximal colon, with cancer cells arising from microsatellite
instability (MSI) and is associated with mutations in the genes involved with DNA
mismatch-repair (MMR) 2, 10. The hereditary forms of CRC are prime models of the
genetic basis of cancer development. The following review discusses the genetic basis
of hereditary CRC with a description of the clinical and pathological manifestations
contrasting FAP and HNPCC.
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FAMILIAL ADENOMATOUS POLYPOSIS
Clinical Features
FAP is an autosomal dominant disease affecting an estimated 1 in 15,000 births 11. The
most characteristic clinical feature of FAP is the presence of hundreds to thousands of
adenomatous polyps spread throughout the colon 2. These polyps typically develop
during puberty, and are characterized as polyps of less than 1 cm in size. These can
appear pedunculated or sessile, and are histologically characterized as tubular, villous,
or tubulovillous 9. If left untreated, these polyps proliferate and degenerate into
malignant adenocarcinomas with nearly 100% certainty of the patient developing CRC
by the age of 40 to 50 years 3, 9. As a result, surgery is often required to prevent cancer
development typically in the form of total proctocolectomy with ileoanal anastomosis
and routine screening for polyp recurrence 2.
A less aggressive form of this syndrome is called “attenuated familial polyposis (AFAP)”
or “adenomatous polyposis coli (AAPC)”. Patients with AFAP develop fewer colonic
adenomatous polyps (100 or less) that are smaller and flatter in size than those in FAP
9.
As a result, the onset of CRC in these patients occurs at a later age than with classic
FAP.
In addition to gastrointestinal polyposis, there are several extra-intestinal manifestations
associated with FAP 12. One major manifestation is the development of intra-abdominal
desmoid tumours that develop as a result of surgical trauma, hormonal exposure and/or
mutations to the APC gene 9. Although not malignant, these tumours are locally
invasive fibrinous masses that typically localize to the small bowel mesentery. They
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cause complications by obstructing the small bowel or ureters, occluding mesenteric
blood vessels and larger veins as well as compressing peripheral nerves. As such,
desmoids are a significant cause of morbidity and is reported to cause ~21% of deaths
of FAP patients 9.
As well, approximately 66% of FAP patients will have congenital hypertrophy of the
retinal pigment epithelium (CHPRE). CHPRE in FAP is best detected by
opthalmoscopy after papillary dilation and appears as multiple lesions (>4) that are
bilateral or large 13. Although these lesions do not affect vision or have any malignant
potential, CHRPE is a useful predictor of FAP susceptibility and can be detected at
birth.
Other manifestations include, gastric fundic gland polyps characterized by cystic
dilatation and irregular budding, hepatoblastoma, brain tumours, foveolar epithelial
dysplasia, supernumerary teeth, and adrenal cortical adenomas 8-9. Thyroid cancer,
gastric, duodenal and ampullary adenocarcimonas may also arise in cases affected by
FAP 2.
Molecular Features
In the late 1980s and early 1990s, cytogenetic analysis, linkage and positional cloning
studies showed that mutations in the Adenomatous polyposis coli (APC) tumoursuppressor gene underlie FAP 2. Emphasizing its role in the development of CRC,
reports also indicate that somatic mutations of APC are important early events in 6080% of sporadic CRC cases 2, 14.
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The APC gene, found on human chromosome 5, contains 15 exons and codes for a
predicted 310-kDa wild-type APC protein 2. Germline mutations in the APC have been
shown to occur throughout the 15 exons, most of which are nonsense mutations
causing altered reading frames leading to truncated forms of the APC proteins 12.
Alternative splicing of the APC protein affects its stability and activity and has made it
possible to accurately characterize the various FAP-associated syndromes based on a
genotype–phenotype correlation. For example, classic FAP is characterized by
mutations present in codons 169-1,600 but mutations found upstream of codon 158 or
downstream of codon 1900 results in an attenuated FAP 12-13. The attenuated variant of
FAP is characterized by reduced amount of polyposis attributed to the hypomorphic
mutation of the APC gene 12.
The APC tumour suppressor protein is involved in the canonical Wnt signaling pathway,
where -catenin is the central signaling molecule. This pathway controls cellular
proliferation, differentiation and morphogenesis throughout human development and
dysregulation of this pathway is a hallmark of many cancers including CRC. APC, along
with Axin, glycogen synthase kinase (GSK)-3, and casein kinase I (CKI), are
components of a degradation complex that mediates -catenin ubiquitination and
turnover 2, 15. Mutations to the APC gene stabilize cytoplasmic -catenin, allowing for its
accumulation and translocation to the nucleus resulting in activation of target genes.
Aberrant activation of Wnt genes promote tumour growth and invasion (ex. c-myc and
cyclinD1) 2. Other genes involved in the tumorigenesis of FAP include Tp53 and KRAS.
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HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (HNPCC)
Clinical Features
Hereditary non-polyposis colorectal cancer is a misnomer as this syndrome predisposes
patients to cancer of the colon in addition to cancers of various other organs (such as
the endometrium, stomach, ovaries) 12. As well, the term “nonpolyposis” is misleading
as adenomatous polyps do indeed develop and can transition to carcinomas 9. As
such, the name Lynch syndrome, credited to the oncologist Dr. Henry Lynch, who
devoted much of his practice to the treatment of this form of hereditary colorectal
cancer, is more appropriate 13.
As with FAP, Lynch syndrome is an autosomal dominant disease. It is the most
common cause of heritable CRC affecting multiple generations and it accounts for 3-5%
of all CRC cases in the US 16. Lynch syndrome is characterized by an early onset of
CRC with adenocarcinomas usually present in the proximal colon 3, 8. Diagnosis occurs
at 44-48 years of age compared to 63 years in sporadic cases, with a penetrance of
~80% by age 70 17. Other distinguishing features that characterize families affected by
this syndrome include the presence of common primary cancers throughout the family
pedigree, the development of tumours at an earlier age compared to the norm of that
cancer type, the pathological features of disease, and the identification of germline
mutations in affected family members 3, 12, 17.
In contrast to FAP, multiple adenomas are not present at a young age. However,
patients diagnosed with Lynch syndrome develop colorectal and extracolorectal cancers
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at an earlier age than the general population 9. The extracolonic malignancies these
patients develop include small bowel carcinomas, sebaceous skin tumours,
hepatobiliary tumours, brain tumours (glioblastoma rather than medulloblastoma which
is found to be common in FAP), and in women, endometrial adenocarcinomas and
ovarian carcinomas 13, 17. The presence of tumour-infiltrating lymphocytes (TILs) as well
as intraepithelial T-lymphocytes is characteristic of high frequency microsatellite
instability (MSI-H), a characteristic phenotype of Lynch syndrome 8, 12. Additional
features associated with Lynch syndrome include a variety of poorly differentiated
tumours, excess mucoid and signet-cell features as well as a Crohn-like reaction 9.
The ambiguity between FAP and Lynch syndrome increases at later stages of cancer
development, in regards to their clinical presentation. Therefore accurate diagnosis is
dependent on the patient’s clinical presentation and genetic background in combination
with family history of cancer. In 1991, the International Collaborative Group on Lynch
syndrome developed a set of clinical criteria known as the “Amsterdam Criteria” to
identify families at risk for Lynch syndrome. These criteria were specifically designed to
diagnose individuals with Lynch Syndrome but failed to include the phenotypic
extracolonic features 9. After several modifications and revisions to the Amsterdam
Criteria as well as an additional set of guidelines (Bethesda and revised Bethesda) that
improved on genetic screening analysis, subtypes of CRC are more accurately
diagnosed 2, 18.
Molecular Features
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In the early 1990s, it was discovered that tumours from HNPCC patients shared a
common molecular trait known as microsatellite instability (MSI) 10. Microsatellite
instabilities are frameshift mutations in gene sequences that contribute to cancer
pathogenesis. MSI can be classified as being of high frequency (MSI-H), low frequency
(MSI-L) or stable (MSI-S) based on the number of genetic markers affected (BAT26,
BAT25, D5S346, D2S123 and D17S250) 2. If two or more of these markers are
unstable, the MSI is considered to be of high frequency, as are 90% of cases suspected
to display Lynch syndrome 2, 8. The discovery of MSI as a hallmark of Lynch syndrome
quickly led to the identification of a class of genes called mismatch-repair (MMR). MMR
genes regulate the cellular machinery that repairs DNA replication abnormalities. The
DNA mismatch repair system consists of a protein complex that recognizes and repairs
DNA nucleotide base mispairs, and small nucleotide insertions/deletions resulting from
DNA replication 19-20. Such a crucial role has qualified MMR deficiency as a mutator
phenotype, since mutations in these genes facilitate the multiple genetic hits and high
mutation rates in certain cancers 12.
Lynch syndrome is characterized by germline mutations in DNA mismatch repair (MMR)
genes, of which mutations to MLH1, MSH2 MSH6 are the most prominent17 with a
penetrance of 80% for CRC 17. Other MMR genes such as PMS1, PMS2 and MLH3 are
less common and will not be discussed further. As MMR heterozygous cells repair DNA
normally, the wild-type allele must be knocked out in somatic cells for MMR to be
impaired. A second “hit” may occur by deletion, mutation or methylation of CpG islands
as seen in the MLH1 promoter 12.
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Germline mutations in MSH2 and MLH1 can occur throughout the gene and are
typically missense and nonsense mutations leading to inframe deletions and large
genomic deletions 12. Mutations in these genes account for >90% of Lynch cases 8-9.
Although there are no typical “hot spot” mutations in MLH1, various reports indicate a
common A→T transversion mutation in intron 5 of MSH2 resulting in loss of expression
12.
In most cases the location of the mutation on the gene appears to have no
consequence on the penetrance of the genotype, suggesting that most mutations result
in null or loss-of-function. In fact, mutations to either MSH2 or MLH1 show little or no
difference in penetrance, suggesting both genes to be equally important in MMR.
Mutations in the MSH6 gene account for the additional 5-10% of Lynch syndrome and
are associated with an attenuated form of the disease. As with AFAP, this syndrome is
characterized by lower penetrance of CRC and a later age of onset 12.
Interestingly, similar to FAP, the existence of hypomorphic alleles have been proposed
to account for Lynch cases characterized by decreased gene expression with no
detectable change in sequence. It is suspected that mutations (yet to be identified)
affect introns or control regions deregulating expression and degradation of
transcripts12.
CONCLUSION
FAP and Lynch syndrome are the two major forms of hereditary CRC.
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Our understanding of the clinical and genetic manifestations associated with heritable
colon cancer has vastly improved over the past two decades and provides a leading
model for the study of cancer genetics. The discovery of the molecular pathways
specific to FAP (APC gene mutations) and Lynch syndrome (MMR in MSH2 and MLH1)
have allowed for increased accuracy in diagnosing each CRC subtype. As well,
diagnosis is facilitated by the identification of the various stages of tumour progression
that generally follows a well defined sequence of events. Both FAP and Lynch
syndrome are characterized by the development of adenomatous polyps to fully
invasive and metastatic adenocarcinomas. The combination of germline mutations and
sporadic (or somatic) mutations in the APC and MMR-associated tumour suppressor
genes underlie a disease that can now be monitored and diagnosed through family
pedigree analysis. Although the eventual (preventative) strategy is prophylactic surgery
the confirmation of genotype-phenotype analysis by genetic screening will reduce CRCassociated morbidity and mortality by extending the age of required surgical treatment,
predicting future family cases and by improving surveillance of cancer development.
CONFLICTS OF INTEREST
There are no conflicts of interest associated with the preparation of this manuscript.
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