REVIEW
Genetic testing in colorectal cancer: who, when, how and why
Nicholas O. Davidson

Division of Gastroenterology, Washington University School of Medicine,
St. Louis, MO, U.S.A.
(Received for publication on November 8, 2006)(Revised for publication on January 23, 2007)(Accepted for publication on February 15, 2007)

Abstract. Colorectal cancer (CRC) is among the most prevalent and preventable forms ofcancer worldwide, accounting for over 600,000 deaths in 2005. Both genetic and environmental factors contribute to cancer etiology and estimates suggest that at least one third of
CRC has a familial component. There is increased awareness of a strong genetic component
to CRC risk, with the identification of several high penetrance alleles that predict increased
CRC susceptibility. These include familial adenomatous polyposis (FAP), linked to mutations
or deletions of the APC tumor suppressor gene, as well as Lynch syndrome (formerly known
as hereditary non-polyposis colorectal cancer or HNPCC), which is linked to mutations ordeletions of one or more mismatch repair genes including MLH1, MSH2 and MSH6. In addition, mutations in genes encoding key signaling molecules have been linked to autosomal
dominant hamartomatous syndromes that are associated with increased susceptibility to
CRC. These include Peutz-Jeghers syndrome, which is linked to mutations in STK11/LKB and
Juvenile polyposis, which is linked to mutations in the genes encoding SMAD4 and BMPR1A.
In addition to these high penetrance autosomal dominant alleles, recessive mutations in the
MYH mismatch repair gene are associated with a phenotype similar to FAP. With the widespread availability of genetic testing for these alleles, physicians will be faced with a complex array of choices in terms of advocating who should be tested, when should such testingtake place, how it should be conducted and interpreted and why it changes the management
and outcomes for the patient and his or her family. (Keio J Med 56 (1) : 14－ 20, March 2007)
Key words: tumor suppressor gene, hereditary mutations, high penetrance alleles, screening

Introduction

and important new advances that support this suggestion
and will outline some of the challenges in implementation of this paradigm in practice.

Colorectal cancer (CRC) is the second leading causeof cancer related death in the United States and inflicts amajor toll worldwide.1 Advances in elucidating the genetic basis for many common polygenic disorders - whichhave emerged coincident with completion of the humangenome sequencing project - have heightened awarenessthat many common cancers also have strong hereditaryor familial components. Indeed, a recent review2 has suggested that up to one third of patients with CRC have an
identifiable familial component. Collectively then, theseadvances suggest that our view of CRC should be modified to reflect the consensus that it is a genetic disease.
This article will attempt to summarize the backgroundWho should be tested?
Genetic testing offers the opportunity to confirm asuspected diagnosis of several forms of hereditary CRC.
The goal of this review is to outline specific guiding
principles for each of the hereditary CRC syndromes
for which genetic mutations have been defined and forwhich genetic screening is available [for detailed reviews, see.3-5 As a prelude to such discussion it is worth
considering some general themes in considering whoshould be offered genetic testing. Genetic testing can

Reprint requests to: Nicholas O. Davidson, M.D., Division of Gastroenterology, Box 8124, Washington University School of Medicine, 660 South Euclid
Avenue, St. Louis, MO 63110, U.S.A., E-mail: nod@wustl.edu
14Keio J Med 2007; 56 (1): 14－ 20

15

Table 1 Proposed categories of hereditary colorectal cancer syndromes for which genetic testing is possible
Polyposis Syndromes

Non-polyposis Syndromes

Adenomatous Polyposis

Hyperplastic Polyposis

Hamartomatous Polyposis

Lynch Syndrome

Familial Non-polyposis
CRC

Classical FAP - Autosomal dominant●

K-RAS, B-RAF
Mutations

Peutz-Jeghers

MMR Gene Mutations

Undefined genetic basis

APC Mutations
Autosomal recessive● MYH Mutation●●

STK11/LKB Mutations.

●

Juvenile Polyposis● SMAD4/BMPR1A
Mutations
Attenuated FAP - Autosomal
dominant● APC (I1307K)● Autosomal
Recessive● MYH Mutation

MLH1 Mutations
MSH2 Mutations● MSH6 Mutations● PMS2 Mutations●

Cowden Syndrome●

PTEN Mutations

be offered to “at risk” family members in order to classify carrier status for known alleles and to assign a likely
risk of disease. There are several categories of patients
who clearly merit such genetic testing for CRC. The firstgroup consists of patients suspected of syndromic risk
based on clinical findings.3, 5 This would include an early
age of onset (<40 years), the presence of multiple (>10)
polyps, synchronous or metachronous cancers (either
CRC and/or associated cancers) and/or a family history
positive for any of these features. A second group consists of patients within a family carrying a clinical diagnosis of hereditary CRC, but for whom the pathogenic
mutation is unknown. In this instance, identification of themutant allele in the proband could be useful in screening
other members of the family in order to exclude carriers.
A third group would be patients within a family known
to have a genetic basis for CRC and in which the mutant
allele is known. In this instance, genetic testing of otherfamily members would be of utility in excluding carriers and in counseling affected members. Clinical genetic
testing of patients who manifest these characteristics will
be discussed further below under the relevant diseasecategory
Genetic Testing for Defined Hereditary CRC syndromes: What can we test for and how do we decide
who should get tested?
Screening for carrier status in hereditary CRC syndromes can be offered for several genetic mutations, including familial adenomatous polyposis (FAP) and hamartomatous polyposis syndromes including Peutz-Jeghers
syndrome and Juvenile polyposis syndrome (Table 1). In
addition, genetic testing can be offered to patients with

non-polyposis forms of hereditary CRC, specifically
Lynch syndrome (Table 1). The detailed application ofthese genetic tests, as well as their interpretation andusefulness, differs, however, depending on the syndrome
under consideration and the mutant alleles involved. For
the purposes of the present discussion, this review will
focus predominantly on testing for familial adenomatous
polyposis and hereditary non-polyposis CRC. Readers
are referred to excellent reviews for expanded discussionof Juvenile polyposis and other rare hamartomatous syndromes (for example see5).
Familial Adenomotous Polyposis
In familial adenomatous polyposis (FAP), the classical phenotype involves development of hundreds tothousands of adenomatous polyps carpeting the colonicmucosa. This phenotype becomes manifest typically by
age 35 years and demonstrates an autosomal dominant
inheritance pattern with high penetrance.2 FAP is foundin ~1 per 7-10,000 births in the United States population
and accounts for less than 1% of all CRC. In its classical form, almost 100% of these adenomatous polyps are
considered to be cancer prone. FAP is typically a monogenic disease, the result of mutations or deletions of the
adenomatous polyposis coli (APC) gene. In its classicalform, FAP is relatively easy to recognize and genetic
testing is important since its autosomal dominant inheritance pattern with high penetrance together imply a highlikelihood of vertical transmission. Accordingly the following groups of individuals should be screened. First,
individuals with some but not all the features of classical
FAP should be tested. This would include individuals
with more than 10 but less than 100 polyps. Secondly,

16

individuals should be tested who manifest clinicallydefined FAP (ie adenomatous colonic polyposis), butwhere the mutation has not been defined within the family. This would also include individuals with no family
history of FAP. However, in this regard it is important
to bear in mind that up to 25% of cases of FAP arise
as spontaneous APC mutations and these patients will
therefore have no family history of the disease.5 Thirdly,
relatives within an FAP cohort family should be tested
once the founder mutation is known, since genetic testing will be informative in predicting or excluding carrier
status. This is a crucial issue since a negative genetic test
result for a family member who has a proband with an
identified mutation in the APC gene means that the family member (who tests negative) is at no greater risk forcolon cancer than the general population, and the impactof genetic screening clearly has a major effect on the patients’ perceptions and needs for future screening.6
There are several important issues to keep in mind
when considering genetic testing for FAP. It is crucial
that patients and family members fully understand theimplications of genetic testing, including the value ofboth positive and negative results. Even with the best
technology, disease-causing mutations in the APC geneare detectable in ~85% patients with phenotypic classical
FAP. In addition, as noted above, while the typical inheritance pattern is autosomal dominant, approximately
25% of cases arise as spontaneous new mutations andthese patients will not have an immediate relative withcolonic polyposis.3, 5 In these cases, where the proband
presents with a phenotype consistent with classical FAP
but with either a negative family history or with features consistent with an autosomal recessive pattern ofinheritance (for example, skipped generations often in
the presence of multiple affected members of a single
generation) it is worth considering testing for MYH mutations.7, 8 The MYH gene encodes a homolog of a bacterial DNA excision repair gene and mutations within thisgene lead in turn to the accumulation of mutations within
the APC gene. Two common mutations in the MYH
gene (Y165C, G382D) account for the majority of cases
where this proves to be the defective allele in phenotypic
FAP.9, 10
There is also a distinct category of subjects with an attenuated form of FAP (AFAP), characterized by a laterage of onset (over age 40), fewer adenomatous polyps(generally <50) and with a lower cumulative CRC risk.
Some of these patients will be discovered to harbor mutations in the extreme 3’ or 5’ end of the APC gene.11, 12
Others, particularly those of Ashkenazi Jewish extraction, will be found to harbor the I1307K mutation.1 3, 1 4This particular mutation is highly prevalent among
Ashkenazim and carriers have a lifetime CRC risk in therange of 10-20%.15 Other considerations in patients presenting with an attenuated phenotype include testing forDavidson NO: Genetic testing in colorectal cancer

MYH mutations, particularly those in whom APC testingis negative. This is important since there appear to beboth low penetrance as well as high penetrance MYH alleles, suggesting that yet to be understood genetic and/or
environmental modifiers may play a role in modulating
the attenuated phenotype.2 Finally, clinicians should beaware that the presence of multiple (>20) colonic polyps
is consistent with a diagnosis of hyperplastic polyposis
syndrome, rather than AFAP. In this situation, biopsy ofthe polyps will reveal hyperplastic rather than adenomatous features.1 6 Hyperplastic polyposis is an important
entity to recognize since its genetic basis and molecularpathogenesis are distinct from that of FAP but family members are at increased risk of developing CRC.17
There is an emerging literature pointing to the importance of the hyperplastic polyposis pathway in a subset
of familial CRC. In this alternative pathway, the serrated
polyp represents the precursor lesion rather than the
adenomatous polyp.1 8 Individuals and families with hyperplastic polyposis and CRC tend to present later and todemonstrate BRAF mutations along with microsatellite
instability as a result of hMLH1 promoter methylation(see below).18 This alternate pathway has been describedin both European and North American populations
and up to 16% of adenocarcinomas of the cecum andascending colon may reveal a serrated phenotype.1 9, 2 0
Although much remains to be understood concerning themolecular pathways that influence the progression of theserrated polyp, it is important for clinicians to recognize
this distinctive manifestation of CRC risk.
Important considerations need to be kept in mind when
considering genetic testing for FAP. It is essential thatpatients and their immediate family members be offered genetic counseling, in order that they understandthe implications and potential limitations as well as thepossible benefits.2 1 This includes acknowledgement of
the positive and negative predictive values to such tests.
There are also important psychological issues that must
be confronted for these families, including access tocounselors experienced in explaining in detail the concepts involved. Patients undergoing genetic testing needto provide informed consent and genetic testing should
be conducted through an approved facility, where accurate interpretation is assured.21 Information and usefulmaterial can be accessed through the following links:
www.genetests.org
www.geneclinics.org
www3.ncbi.nlm.nih.gov
www.hereditarycc.org
Peutz Jeghers Syndrome
Peutz Jeghers syndrome (PJS) is an autosomal dominant cancer syndrome with an incomplete penetrance
pattern and a variable phenotype.2 2 The pathologicalKeio J Med 2007; 56 (1): 14－ 20

hallmark of PJS is the presence of distinctive hamartomatous polyps throughout the gastrointestinal tract in association with pathognomonic hyperpigmented mucocutaneous spots in the perioral and buccal mucosa. Polyps
typically appear during the first two decades of life andpatients frequently present because of intussusception asa result of small intestinal hamartomas. In addition, patients with PJS are at greatly increased risk for a numberof cancers, including throughout the GI tract (esophagus,
stomach, pancreas, small intestine and colon) as well as
at extraintestinal sites, principally breast.22
PJS is caused by mutations or deletions in the STK11
gene and informative mutations are found in 30-70% of
sporadic cases and ~70% individuals with a positive family history. Genetic testing for mutations in the STK11
gene is recommended for at-risk individuals, principally
the first degree relatives of probands with confirmed
PJS. This includes consideration for testing children of
affected family members, since there is a very high rateof intussusception in carriers.2 2 Once the STK11 genemutation is identified in a PJS patient, family members
and at-risk individuals can be tested specifically for that
mutation, since the results are highly informative. At riskfamily members in whom a mutation is not found in the
STK11 gene are recommended to undergo small intestinal imaging and colonoscopy as well as periodic upper
endoscopy in order to identify and remove large hamartomatous polyps as well to undergo regular periodic
surveillance for other cancers (breast, testis, pancreas).22
Hereditary, non-polyposis colorectal cancers(Lynch Syndrome)
The non-polyposis forms of hereditary colon cancer
are much more common than the syndromes outlined
above, with estimates that it may account for 3-5% of allcases of CRC.2 Lynch syndrome is an autosomal dominant disease with pleomorphic features characterized byearly onset of colon cancer (< age 40 years) often in association with a family history positive for either coloncancer or for other associated cancers, including endometrial, ovarian, brain, small intestinal, pancreatic, urinary tract cancers.23, 24 Criteria were established over 15
years ago to establish clinical criteria for the diagnosisof this common form of hereditary CRC (the so-called
Amsterdam criteria). These included the presence of atleast 3 members of a kindred with CRC (excluding FAP)
with at least one member being a first degree relative of
the other 2, that at least two generations be involved andthat one was age <50 years.1 These criteria have been
modified sequentially and the current, so-called Modified Bethesda criteria now classify a patient as having
Lynch syndrome if there is CRC diagnosed <50 years, orif the patient has a synchronous or metachronous CRC or
if the patient has an extracolonic cancer (see above) diagnosed at any age, or if the patient with CRC (any age)17

has a first degree relative with CRC diagnosed at age<50 years and/or colorectal adenomas diagnosed at age<40 years.1 In addition, a patient with CRC diagnosed atage <60 years would be classified as Lynch syndrome if
the tumor contained the mutational signature of defective
mismatch repair (microsatellite instability, MSI), which is
described below. Individuals diagnosed with Lynch syndrome, as well as their immediate family members, havea greatly increased lifetime risk of developing colorectal
cancer and female carriers carry an equally substantial
lifetime risk of developing endometrial cancer. Thesefeatures of Lynch syndrome make it particularly important to recognize in order to offer preventive screening
for at-risk family members. These recommendations
include frequent colonoscopy (at 1-2 year intervals)
starting at age 20-25 or at least 10 years earlier than theearliest age of onset of cancer in a family member.24 In
addition, endometrial cancer surveillance is recommended with frequent transvaginal ultrasound examination.2 4These screening recommendations make it imperative toestablish an unequivocal diagnosis of Lynch syndrome
where possible.
The mutational signature of Lynch syndrome, MSI, ispresent in most if not all cancers arising in patients withthis disease complex and results from mutations, deletions or defects in one of several DNA mismatch repair
genes.25 The genes most frequently involved are hMLH1
and hMSH2 (which together account for ~90% of thegermline mutations that account for Lynch syndrome) as
well as hMSH6 (which accounts for the majority (~7%)
of the remaining mutations) and a small minority caused
by hPMS2.4 Genetic testing through commercially available conventional DNA sequence analysis is currently
offered only to detect mutations in hMLH1 and hMSH2
genes.24
Problems in diagnosing Lynch syndrome
Having outlined the basic elements of this disease
complex, it is important to understand that reaching an
unambiguous diagnosis of Lynch syndrome is often
quite challenging. There are at least three major reasonsfor this difficulty. First, clinical suspicion of Lynch
syndrome largely rests on a clinical diagnosis based on
information concerning the extended family history ofa suspected proband. In this regard, a detailed family
history is often not documented in the patients’ medical
record-- particularly with respect to the presence of associated cancers (endometrial, ovarian, ureteric etc)
in maternal or paternal relatives.2 6 The absence of thisinformation might lead to the clinician overlooking possible Lynch syndrome in a patient presenting with new
onset CRC. The second issue that has led to confusion
and ambiguity with respect to establishing a moleculardiagnosis of Lynch syndrome is that less than half ofpatients will have a pathogenic mutation in one of the18Davidson NO: Genetic testing in colorectal cancer

mismatch repair genes.4 DNA sequencing of the twoleading candidate genes (hMLH1 and hMSH2) led to therealization that many of the sequence variations noted
were silent polymorphisms or missense mutations of unknown significance.4 This is an important problem since
the emerging information from several centers supports adivergence in the classification of Lynch syndrome intoclassical genotypic families with MSI and/or an identified mismatch repair gene mutation and families withphenotypic features only.2 7 A rational approach to thisissue is discussed in detail below. The third issue thatcomplicates establishing an unequivocal diagnosis of
Lynch syndrome is the observation that the mutationalsignature of DNA mismatch repair (MSI) is present in~15% of sporadic CRC.2 In this setting, MSI is associated with acquired silencing (through promoter methylation) of the hMLH1 gene and not a heritable mutationin the germline. As noted above, promoter hypermethylation is an important epigenetic mechanism of genesilencing-as exemplified by MSI appearing in the setting of hyperplastic polyposis and the serrated adenoma
to adenocarcinoma transition.
Suggested algorithm for genetic testing of patientsand family members with suspected Lynch syndrome
In view of the aforementioned problems and complications in establishing a diagnosis of Lynch syndrome, it isextremely important to elicit a detailed family history ofother cancers, the age of diagnosis and where possible toobtain the tumor specimen for MSI testing. Tumors thatmanifest MSI should be examined by immunohistochemical staining for the protein products of the mismatch
repair genes (ie MLH1, MSH2, MSH6 and PMS2).2 8
Using this approach, the clinician will be able to detect
loss of staining of one of the candidate mismatch repair
genes and would then conclude that there is likely to be
an inactivating mutation in the corresponding gene. Lossof staining of a mismatch repair gene, coupled with MSI
would then be a reasonable basis to pursue mutational
analysis of the corresponding gene in order to identify
informative mutations that could then be used to screen
at-risk family members. A recent report has outlined auseful web-based questionnaire that uses a balanced algorithm of clinical information (age of diagnosis, gender,
location of tumor, presence of synchronous or metachronous tumors, family history of CRC or endometrial cancer) as well as immunohistochemical staining to predictthe likelihood of Lynch syndrome.2 9 This questionnaire
can be accessed at:
http://www1.hgu.mrc.ac.uk/Softdata/MMRpredict.php
Other considerations for who should be offeredgenetic testing for Lynch syndrome
Any patient with CRC diagnosed at <40 years impor-tant category of patients should be offered genetic testing for Lynch syndrome.30 This is important since a highproportion of young patients with CRC do not meet strictclinical criteria for Lynch syndrome. In addition, young
patients with CRC tend to have less right sided predominance of their colon cancers than the typical Lynch syndrome patients.30 However, almost three quarters of thetumors from young patients with CRC will show MSI
and approximately half of these will have mismatch repair gene mutations. Finally, over 40% of young patientswith CRC will develop a second cancer within 12 years,
the majority of these being GI tract cancers.30
New information concerning suspected
Lynch syndrome patients who do not carry
the molecular fingerprint of MSI
Three new studies have added considerable insight into
the management and genetic classification of patientswith phenotypic Lynch syndrome.2 9, 3 1, 3 2 These studies
addressed the question of whether the disease process
was fundamentally distinct in patients based on the presence or absence of MSI and the findings provide important new insights for the management of these patientsand their at-risk family members. As discussed above,
patients with classic Lynch syndrome have a constellation of clinical features in conjunction with the molecular fingerprint of MSI, frequently accompanied by alterations in the expression of mismatch repair genes.27 Thereis, however, another group of patients who manifest theclinical features of Lynch syndrome (early onset CRC,
positive family history, etc) but where the tumor does
not demonstrate MSI and the genetic basis for the cancer susceptibility is unknown. There are important features concerning this subset of patients, who have beenreferred to as familial non-polyposis colorectal cancer
type X.31 These include the finding that the standardized
incidence ratios for CRC are elevated in first degree relatives (as in classical Lynch syndrome) but that the incidence of other Lynch syndrome associated cancers (endometrial, ovarian, stomach etc) were not higher than in
an age-adjusted general population.3 1 This information
is of particular relevance in terms of counseling femalefamily members who may be at risk, since their need forintensive screening for endometrial cancer surveillance
is no longer recommended. In addition, the average age
at which CRC was detected in the family members fromthe familial non-polyposis colorectal cancer syndromecohort (type X) was approximately 60 years, comparedto less than age 50 in classical Lynch syndrome.3 1 This
information is particularly useful in terms of providing
guidelines for the initiation of screening colonoscopy(5-10 years younger than the earliest CRC diagnosis in
the family) and for the intervals between screening (every 5 years). These patients and their family members
should be counseled that they do not have a sinister can-

Keio J Med 2007; 56 (1): 14－ 20

cer predisposition syndrome. In particular, since womenfamily members with Lynch syndrome carry a 40-60%
lifetime risk of endometrial cancer, this diagnosis carries
major implications for their continued surveillance.33
Summary comments
Newer advances in the molecular genetics of colorectal
cancer pathogenesis will undoubtedly continue to evolve.
As public awareness of the human genome project expands and commercialization of the tools for diagnostic
genomic applications continue to expand, it will be important for physicians to stay well informed about thelimitations, interpretation and utility of these approaches
and to be able to apply them in a scientifically soundmanner to the management of their patients.
Acknowledgements
This work was supported through grants from the National Institutes of Health (HL-38180, DK-56260 and
DK-52574).
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