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23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
315
uncontrolled colorectal polyp burden is an
indication for colorectal surgery. Total abdominal colectomy and ileorectal anastomosis are
the preferred operation unless the pathology is
in the rectum.
Evaluation ofAt-Risk Relatives
• For individuals with a specic known mutation, at-risk family members should be tested
for that mutation. Approximately 50% of individuals will have an affected parent, and parents should be evaluated for PJS traits. If one
of the parents is affected, then testing should
be offered to the siblings of the proband.
Additionally, all children of the proband have
a 50% risk of inheriting the mutation and
should be tested accordingly. Genetic testing
for at-risk family members may be performed
at age 8 after appropriate genetic counseling
and informed consent. If a specic mutation is
not identied in the affected individual, at-risk
family members are surveyed as if they potentially have the disease. This includes surveillance of the colon, stomach, small bowel,
pancreas, breast, ovary, uterus, cervix, and testes as described above.
PTEN Hamartoma Tumor Syndrome (PHTS)
• PHTS is a spectrum of extremely rare hereditary syndromes that are characterized by hamartomatous polyps in the gastrointestinal tract
and abnormalities of the skull, skeleton, and
skin. The two main syndromes are Cowden
syndrome and Bannayan-Riley-Ruvalcaba
syndrome (BRRS).
Clinical Presentation
• About 95% of Cowden syndrome patients
have colorectal polyps, ranging from few to
hundreds in number and are distributed
throughout the colorectum. The most common
polyps are hamartomas, accounting for about
30% of all polyps. Other types of polyps
include adenomas, juvenile polyps, inammatory polyps, leiomyomas, lipomas, bromas,
neurobromas, and ganglioneuromas. The
majority of patients have multiple histologic
types of polyps.
• About 30% of Cowden syndrome patients
have macrocephaly. Trichilemmomas are considered to be pathognomonic. Other benign
and malignant lesions of the breast, thyroid,
uterus, and skin are seen in Cowden
syndrome.
Underlying Genetics
• Cowden syndrome and BRRS are both autosomally dominant inherited disorders associated with a PTEN mutation. PTEN is a tumor
suppressor gene that encodes a phosphatase
that is involved in the PI3K/AKT signaling
pathway. It plays a key role in apoptosis.
Approximately 80% of patients who meet the
diagnostic criteria for Cowden syndrome, and
60% of patients with BRRS, have PTEN
mutations.
Diagnosis
• The International Cowden Consortium developed clinical diagnostic criteria for Cowden
syndrome, including both major and minor
criteria. Major criteria include breast cancer,
thyroid cancer (especially follicular), macrocephaly, endometrial cancer, and LhermitteDuclos disease. Minor features include benign
thyroid changes (such as a goiter), mental
retardation, hamartomatous intestinal polyps,
brocystic changes in the breast, lipomas,
bromas, and genitourinary tumors (such as
kidney cancer or uterine broids) or
malformations.
• Cowden syndrome is diagnosed if a patient
has either macrocephaly or Lhermitte-Duclos
disease and one other major feature. A diagnosis of Cowden is also made when a person has
one major feature and three minor features or
at least four minor features. Denitive diagnosis is based on a PTEN mutation.
• Specic diagnostic criteria for BRRS are not
established, but patients with macrocephaly,
hamartomatous colonic polyposis, lipomas,
and pigmented macules of the glans penis
should be considered for genetic testing.
316
M. F. Kalady and Y. NancyYou
CRC andExtracolonic Risk
• A recent study reported CRC in 13% of PTEN
mutation carriers in Cowden syndrome with
early age of onset, all before the age of
50years. The adjusted standardized incidence
ratio was 224 (95% condence interval,
109.3–411.3; P<0.0001). Other groups have
supported a 9–16% lifetime risk for CRC
cancer.
• Most of PTHS cancer risk is extracolonic.
Women have a 50% lifetime risk of developing breast cancer and a 5–10% lifetime risk of
developing endometrial cancer. Men and
women with Cowden syndrome have a 10%
lifetime risk of developing epithelial thyroid
cancer.
• Approximately half of the patients with BRRS
will have hamartomatous polyps in the
digestive tract, particularly in the ileum and
colon. These polyps can become symptomatic, but are not believed to increase the risk of
colon cancer. Patients with BRRS have similar
extracolonic malignancy risks as those with
Cowden syndrome.
CRC Risk Management
• There is debate regarding the need for colonoscopy screening in PTHS.Given the recent
ndings of increased CRC risk, we recommend starting colonoscopy at age 35, with
repeat examinations every 1–2 years.
Colectomy should be considered if the polyp
burden cannot be controlled endoscopically or
if cancer develops.
Serrated Polyposis Syndrome (SPS)
Clinical Presentation
• SPS is usually asymptomatic and is often
detected on screening colonoscopy.
• More than 90% of SPS patients are of white
European descent. It affects both men and
women nearly equally with a slight female inclination. The median age at diagnosis ranges from
44 to 62years, with extremes of age including
SPS in a 10-year-old and a man in his eighties.
• SPS encompasses a variety of clinical phenotypes and is likely a heterogeneous disease that
has not yet been characterized genetically.
• The primary feature of SPS is serrated polyps – a family of polyps characterized by a
classic serrated or sawtooth appearance of the
arrangement of glands. This includes hyperplastic polyps, sessile serrated adenomas
(SSAs) which are also called sessile serrated
polyps (SSPs), SSAs or SSPs with dysplasia,
and serrated adenomas.
• Different phenotypes have been described
based on the size and number of serrated polyps. Some patients have multiple small polyps
distributed throughout the colon, while others
have a few large, right-sided polyps. The cancer risk is similar for both phenotypes. In
addition to serrated polyps, SPS patients often
are prone to having adenomas.
Underlying Genetics
Evaluation ofAt-Risk Relatives
• At-risk relatives should be counseled and
tested for the presence of PTEN mutation. For
families with PTHS but no detected gene
mutation, at-risk individuals should be initially surveyed as if they have the disease.
Screening includes evaluation of the colorectum, stomach, small bowel, thyroid, breast,
uterine, kidney, and skin.
• A causative germline mutation has not been
identied for SPS.There is no genetic testing
for this syndrome.
Diagnosis
• SPS is diagnosed by clinical criteria as dened
by the World Health Organization as follows:
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
317
(1) >20 serrated polyps of any size, distributed
throughout the colon; (2) at least ve serrated
polyps proximal to the sigmoid colon with
two or more of these being >10mm; and (3)
any number of serrated polyps proximal to the
sigmoid colon in an individual who has a rstdegree relative with SPS.
CRC Risk
• Although the true incidence of CRC in SPS is
yet to be dened by prospective studies, it is consistently reported as increased compared to the
general population. Reports are variable from
multiple relatively small series, ranging from 0%
to 77%, with an estimate of around 25%.
• The initial SPS diagnosis is often made at the
time of cancer diagnosis, and thus the natural
history progression from SPS to cancer is
uncertain.
Management
Screening
• For patients with an established SPS diagnosis, colonoscopy should be performed every
1–2years. Management guidelines are based
on clinical experience and expert opinion.
• Although some studies suggest an association
with extracolonic malignancies, the data are
not strong enough to justify surveillance recommendations for extracolonic neoplasia.
hyperplastic polyps, representative biopsies
should be performed.
• Screening colonoscopies should be done
yearly, with consideration of the number, size,
and histology of the polyps to adjust the interval. If successive colonoscopies reveal no polyps, the interval to the next examination may
be extended to 2–3years, but this should be
considered on a case-by-case basis.
• Endoscopic management alone is often difcult as polyps are large, at, and right-sided. If
the polyp burden cannot successfully be controlled via colonoscopy and polypectomies,
surgery should be considered.
• The development of CRC or adenoma with
high-grade dysplasia that cannot be adequately
or safely removed endoscopically are also
indications for surgery.
• As the risk of neoplasia is not limited to the
specic location of the index neoplasm but
rather the entire colorectal mucosa, extended
surgery should be entertained. This includes a
subtotal or total colectomy and ileosigmoid or
ileorectal anastomosis, respectively. Decisionmaking for the extent of surgery should be
taken for each individual and evaluated within
the context of medical comorbidities and anal
sphincter function. A segmental colectomy
may be considered for patients with focal disease (few large right-sided polyps) and who
are not medically t for extended resection.
• Any remaining colorectum should undergo
annual endoscopy to prevent and manage
future neoplasia.
Treatment
• Treatment is determined by the clinical phenotype and patient’s wishes. The goal of treatment for SPS patients is to decrease or
eliminate CRC risk by removing polyps before
they become cancer.
• Expert panels recommend removing any single polyp larger than 5mm for histologic evaluation. For clusters of small (3–4 mm)
left-sided polyps, which are likely benign
Evaluation ofAt-Risk Relatives
• Compared to the general population, rstdegree relatives of patients with SPS have an
approximately vefold increased CRC
incidence.
• As there is no genetic test to screen for SPS,
colonoscopy serves as the screening
mechanism.
318
M. F. Kalady and Y. NancyYou
• Expert panels recommend colonoscopy
screening for rst-degree relatives, particularly those older than 40 years. Endoscopic
ndings and polyp histology should guide the
interval to the next colonoscopy.
• First-degree relatives do not have increased
risk of extracolonic malignancy.
Lynch Syndrome
• Lynch syndrome (LS), previously used as a
synonym for hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, accounts for
3–5% of all CRCs and 10–19% of CRCs diagnosed before age 50.
• The underlying genetic cause is a germline
mutation in a DNA mismatch repair (MMR)
gene, which results in a nonfunctioning MMR
protein. Lynch syndrome, as currently dened,
is a genetic diagnosis.
• The syndrome follows an autosomal dominant
inheritance pattern.
• Tumors are typically microsatellite unstable
(MSI-H) and exhibit loss of expression of
mismatch repair proteins on
immunohistochemistry.
• There are several conditions that should be
distinguished from LS:
– Familial colorectal cancer type X: patients
meeting Amsterdam criteria for HNPCC
who have microsatellite-stable, rather than
microsatellite-unstable, tumors.
• The CRC risk is between that of the
general population and patients with
LS; patients develop CRC at later ages
compared to LS, and do not have
increased extracolonic malignancy risk.
The exact genotype remains to be
elucidated.
– Constitutional mismatch repair deciency
(CMMRD) syndrome: in contrast to LS
where an inherited mutation is present in
one allelic copy of a MMR gene, a rare
group of patients has inherited mutations of
the MMR gene in both of their alleles.
• Patients exhibit a distinct phenotype
with the development of CRC at very
young ages (before age 20), multiple
adenomatous polyps numbering
between 10 and 100, café au lait skin
lesions, hematologic malignancies, and
brain tumors.
– Finally, there are patients who present with
MSI-H tumors, but subsequent germline
mutation testing fails to detect a pathogenic
mutation in any of the major MMR genes.
The terms “Lynch-like syndrome,” “suspected LS,” or “mutation-negative LS”
have been utilized, and the molecular characterization of these patients represents
areas of active research.
Underlying Genetics
andMolecular Prole
• Patients with LS harbor an inherited dominant
mutation in a MMR gene on one allele. This
germline mutation, propagated through all
somatic cells, confers susceptibility for cancer
but requires a “second hit” within the specic
somatic tissue for malignant transformation
(Fig.23.5). The “second hit” alters the wildtype copy of the allele, leading to loss of DNA
MMR activity in the somatic cell and, further,
cancer development. Thus, malignant tumor
cells in patients with LS harbor DNA MMR
gene mutations in both alleles (one inherited
and another acquired as a “second hit”).
• The four major DNA MMR genes responsible
for LS are MLH1, MSH2, MSH6, and PMS2.
Additionally, mutations in the gene EPCAM
(or TACSTD1) upstream of MSH2 can silence
or disrupt MSH2 expression and lead to clinical features similar to LS.Based on data from
12,624 observations worldwide, it has been
estimated that MLH1 accounts for 39%, MSH2
for 34%, MSH6 for 20%, and PMS2 for 8% of
the entries in the International Society for
Gastrointestinal Hereditary Tumours
(InSiGHT) database (www.insight-group.org/
mutations/), and up to 3% of the cases are due
to EPCAM mutations.
• Tumor phenotype. The underlying genetic
mutations and mismatch repair deciency
Germline mutation (Inherited disease)
(first hit is acquired)
Two normal copies
in every cell
Second copy mutated
also acquired)
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
Fig. 23.5 A germline
MMR gene mutation
confers susceptibility for
cancer but requires a
“second hit” within the
specic somatic tissue
for it to develop into a
malignancy. The
“second hit” causes the
wild-type copy of the
allele to also become
mutated, leading to loss
of DNA MMR activity
in the somatic cell and,
further, cancer
development
One copy
mutated
in every cell
(first hit is inherited)
Somatic mutation (Sporadic disease)
Second copy
mutated
in cell
(second hit is acquired)
319
of the gene
yield molecular changes within the tumor that
can be examined as part of the screening process toward a LS diagnosis.
– Microsatellite instability. DNA microsatel-
lites are tandem sequences of mono-, di-,
or trinucleotide repeats that are particularly
susceptible to replication errors when
MMR function is impaired. These differences can be measured by the PCR-based
MSI test, which assesses a standard panel
of (typically ve) microsatellite markers in
paired tumor and normal tissue by consensus; a tumor is considered MSI-H if 30% or
more of the markers tested show instability
and microsatellite stable (MSS) if none of
the markers are unstable. MSI-low connotation is reserved for tumors that have some
markers that are unstable but fewer than
30%. MSI-low is infrequently encountered,
and its clinical signicance has been
regarded similar to that of MSS tumors.
– Immunohistochemistry. Measuring expres-
sion of mismatch repair proteins using
immunohistochemistry is the other means
One copy
mutated in cell
in cell (second hit is
of determining mismatch repair prociency
or deciency of a tumor. In vivo, the MMR
protein products function as dimers, with
MSH2 forming a complex with MSH6 and
MLH1 with PMS2 protein. Thus, mutations in either MSH2 or EPCAM genes
typically result in loss of staining in both
MSH2 and MSH6 protein products, while
mutations that lead to loss of MLH1 protein result in the loss of staining for both
MLH1 and PMS2 proteins. On the other
hand, mutations in MSH6 and PMS2 genes
typically result only in the loss of the
respective single gene product. IHC has
demonstrated 92% sensitivity for identifying defective MMR in tumors from known
LS patients with a germline pathogenic
mutation.
• BRAF mutations. As discussed above, the
vast majority of MSI-H in CRC is caused by
methylation of the MLH1 gene promoter as
seen in the methylator pathway. Mutations in
the BRAF oncogene are strongly associated
with the methylator pathway and are rare in
320
M. F. Kalady and Y. NancyYou
LS-related CRC. Thus, the presence of a
somatic BRAF mutation within a CRC is
often used to rule out further screening for a
LS diagnosis. Patients with absence of MLH1
expression on immunohistochemistry should
have their tumor analyzed for BRAF mutation. If BRAF is mutated, then LS is unlikely.
If BRAF is normal, LS is likely.
Distinguishing Lynch fromSporadic
Epigenetic Changes: Methylation
ofMLH1 Gene Promoter
• Approximately 85% of mismatch repair deciency in CRC is caused by methylation of the
promoter region of MLH1 gene. This epigenetic phenomenon silences MLH1 expression
in the tumor tissue. These tumors characteristically arise in elderly female patients and in
the right colon. Identifying MLH1 promoter
methylation from tumor tissue can help eliminate the diagnosis of LS. However, should
MLH1 promoter methylation be encountered
in young patients with a family history suggestive of LS, the clinicians should be aware
of two rare exceptions: (1) the patient may
have LS with an inherited MLH1 mutation and
MLH1 promoter methylation may have developed as the “second hit” leading to cancer
development and (2) germline MLH1 hypermethylation has been reported in rare families
which exhibit characteristic cancers associated with LS.
Clinical Presentation andSpectrum
ofDisease
Genotype-Phenotype Correlations
• While the clinical hallmarks of LS are CRC
and extracolonic malignancies, the cancer
risks are highly variable within and among
families with LS.Genotype-phenotype correlation studies have shown that the lifetime
risks of LS-related malignancies vary by gender and the mutated gene (Table23.4).
Muir-Torre Syndrome (MTS)
• Muir-Torre syndrome (MTS) is a clinical
variant of LS, where patients are affected by
skin sebaceous gland neoplasms (sebaceous
Table 23.4 Summary of reported cumulative risks of colorectal and extra-colorectal cancers by age 70in patients with
Lynch syndrome
Cancer Mutated gene Cumulative risk, % Mean age at diagnosis (years)
Colorectal MLH1/MSH2 Male
Female
MSH6 Male
Female
PMS2 Male
Female
Endometrial MLH1/MSH2 14–54 48–62
MSH6 17–71 54–57
PMS2 15 49
Ovary 4–20 43–45
Stomach 0.2–13 49–55
Genitourinary 0.2–25 52–60
Hepatobiliary 0.02–4 54–57
Small bowel 0.4–12 46–49
Brain/central nervous system 1–4 50
Sebaceous skin neoplasms 1–9 Unknown
Modied from Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, etal. Guidelines on genetic
evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. The American Journal of Gastroenterology. 2014;109(8):1159–79
These reported risks and mean ages of diagnosis should not be used to exclude the possibility of Lynch syndrome in a
patient who has suggestive clinical feature
27–74
22–53
18–22
10–18
20
15
27–46
54–63
47–66
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
321
adenomas and carcinomas) and/or hair follicle
neoplasms (keratoacanthomas).
• MTS can be associated with mutations in any
of the MMR genes, but MSH2 mutation
appears most common.
• Sebaceous adenoma, especially when multiple or when arising from the trunk or extremities, is characteristic for MTS. Sebaceous
tumors can occur before, with, or after the
development of other cancers, and CRC and
genitourinary tumors are the most common
visceral malignancies associated with MTS.
• Referral for genetic counseling and for colonoscopic screening should be considered in
patients with sebaceous neoplasm, especially
when there is suggestive personal or family
history. However, there is currently no uniform recommendation for systemic screening
of sebaceous neoplasms for dMMR.
Turcot’s Syndrome
• Turcot’s syndrome describes patients with
CRC and brain tumors. Turcot’s syndrome is
not considered an independent entity, and it
can be associated with two main types of
germline genetic defects: mutation of the APC
gene in association with anaplastic astrocytoma, ependymoma, or medulloblastoma or
mutation of an MMR gene that is usually associated with glioblastoma. Although excellent
survival of more than 3years has been reported
in patients with Turcot’s syndrome, whether
LS patients with these tumors have more favorable prognosis remains unestablished.
CRC, but left-sided colon cancers, rectal cancers, and synchronous lesions at different sites
of the colon and rectum are also common
presentations.
• Among LS patients who have had an initial
CRC treated by less than a total colectomy, the
risk for metachronous CRC is 16% at 10years,
41% at 20years, and 62% at 30years.
• The adenoma-to-carcinoma progresses more
rapidly in LS patients secondary to more rapid
accumulation of errors due to the deciency in
MMR genes. Adenoma may progress to carcinoma within 2–3 years, compared with
4–10years in the general population.
• Up to 70% of the mutation carriers develop at
least one adenoma by age 60. The adenomas
tend to be larger, at, and are more likely to
show high-grade dysplasia at the time of
diagnosis.
• It has been estimated that endoscopic polypectomy can prevent one CRC for every 2.8
adenoma removed in a LS patient, compared
to one CRC for every 41–119 adenomas in the
general population.
• Unique histologic features have been
described for MSI-H CRCs, including greater
proportion of tumors showing poor differentiation, mucinous or signet ring cell histology,
tumor inltrating lymphocytes, and lymphoid
(Crohn’s-like pattern and/or peritumoral lymphocytes) host response.
Endometrial andOvarian Cancer Risk
Colorectal Cancer Risk
• The lifetime risk for CRC ranges from 30 to
74% among MLH1 and MSH2 mutation carriers, but only 15–20% among PMS2 carriers
and 10–22% among MSH6 carriers.
• The mean age of diagnosis for LS-related
CRC is 44–61 years, signicantly younger
than the average age of CRC onset in the
United States which is 72years.
• The LS-associated CRCs show a predilection
for the right colon when compared to sporadic
• Endometrial cancer is the most common
extracolonic malignancy in patients with
LS. It poses the highest risk in women with
MSH6 and MSH2 mutations, in whom the lifetime risk can be up to 44% (Table23.4). The
lowest risk (15%) is observed among PMS2
mutation carriers. The mean age at diagnosis
ranges between 48 and 62years. LS-associated
endometrial cancers are more commonly of
endometrioid histology and arise from the
lower uterine segment. Synchronous endometrial and ovarian cancers have been reported in
7–21% of the women with LS.
322
M. F. Kalady and Y. NancyYou
Other LS-Associated Cancer Risk
• The spectrum of other extracolonic cancers
associated with LS is wide and continues to
evolve. Classically, LS is associated with
increased lifetime risk of genitourinary tumors
including transitional cell carcinoma of the
ureter, renal pelvis, and bladder; cancers of the
stomach, hepatobiliary tract, and small bowel;
brain cancer (glioblastoma); and sebaceous
skin neoplasms (Table23.4).
Diagnosis
• LS is diagnosed by the identication of a
germline mutation in one of the MMR genes
as described above. Current commercial
germline testing detects both sequence
changes as well as large rearrangements in
these genes. It is most commonly performed
on DNA isolated from peripheral blood or
buccal mucosa samples. Independent of tumor
tissue, germline testing can be performed in
patients who are affected or unaffected by
malignancy.
• Genetic testing should be preceded by genetic
counseling to ensure that the patients are fully
informed of the signicance, advantages, and
disadvantages of genetic testing.
– In 2008, Genetic Information Nondiscrimi
nation Act (GINA) removed the nding of
a pathogenic germline mutation as a preexisting condition for health insurance or
employment purposes; thus patients should
not fear loss of coverage because of a
genetic diagnosis of LS.
Screening andDiagnostic Strategies
CRC inaPatient Without Known LS
• This is the most frequently encountered indication for testing in clinical practice. Over the
past several decades, the approach to diagnostic testing has moved from a selective
approach, where patients deemed to be at elevated risk of harboring MMR mutations by
clinicopathologic criteria undergo testing, to a
universal approach, where CRCs are screened
using MSI or immunohistochemistry.
• The selective approaches utilize clinicopathologic criteria and prediction models to select
patients to undergo germline mutation testing.
Although selective approaches do not depend
on the availability of tumor tissue and of tumor
molecular tests (i.e., IHC, MSI), they are subject
to the accuracy, availability, and the recall bias
of the personal and family histories obtained.
• As tumor molecular testing has become
increasingly available, a universal screening
approach for all CRCs for MMR deciency
has been advocated as the most sensitive strategy to identify patients at risk for LS. This
two-step approach involves a screening step
where all CRCs are tested for evidence of
MMR deciency independent of somatic
mechanisms, followed by a conrmatory step
where patients undergo germline MMR mutation testing. Tumors may be testing for MSI
and/or MMR protein expression. If the tumor
is MSI-H and/or if one of the MMR proteins is
not expressed, further exploration is
warranted.
– Since the majority of CRC MSI is not
caused by MLH1 loss secondary to hypermethylation of the MLH1 promoter region,
strategies to evaluate MSI with MLH1 IHC
loss have been used before proceeding with
genetic testing. CRC lacking expression of
MLH1 may be further evaluated for DNA
hypermethylation of the MLH1 promoter
or for BRAF mutations, which are highly
associated with sporadic MSI-H tumors. If
the tumor is methylated and/or has a BRAF
mutation, the likelihood of LS is less, and
testing does not need to be pursued unless
there is a strong suspicion based on clinical
or family history. If MSH2, MSH26, or
PMS2 is lost, then it is highly likely to be
caused by a germline mutation, and
directed testing for that particular gene proceeds along those lines. One algorithmic
approach to screening for LS in CRC is
demonstrated in Fig.23.6.
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
323
Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2
Loss of expression of MLH1, MSH2,
MSH6, PMS2, microsatelite-high
(>30% allelic shift)
Loss of MLH1
MLH1 promoter hypermethylation
MLH1 promoter
hypermethylation
BRAF mutation
Fig. 23.6 One algorithm for testing of colorectal tumors for MMR deciency as a rst step to screen for patients with
Lynch syndrome
and / or
BRAF mutation
Wildtype
and / or
Usual Care
Colorectal cancer tissue:
and / or
MSI (PCR)
Intact expression of MLH1, MSH2,
MSH6, PMS2 microsatellite stable
(0% allelic shift)
Loss of MSH2, MSH6, PMS2
Usual Care
Confirmatory germline testing
for MLH1, MSH2, MSH6, PMS2
gene mutations
• Whichever strategy is used, one must be able
to interpret and take action on germline testing
results. In general, germline testing yields one
of three possible results: (1) a deleterious
(pathogenic) mutation, (2) a variant of
unknown signicance, or (3) uninformative
negative or no mutation found. Finding of a
pathogenic mutation conrms the diagnosis of
LS in the patient. The latter two ndings
should be considered inconclusive, in the setting of a dMMR tumor without evidence of
MLH1 promoter methylation and/or BRAF
mutation. Patients with a MSI-H tumor and
loss of MMR protein expression but without a
conrmatory germline mutation are considered to have “Lynch-like syndrome.” In the
absence of clearly dened cancer risks for
patients with Lynch-like syndrome, it remains
the most prudent today to clinically manage
these patients and families in the same way as
LS patients. One caveat is that strategies that
involve only germline testing (i.e., based on
Amsterdam criteria or predictive models)
without accompanying tumor MMR status
testing are thus at risk for missing patients
who might have “Lynch-like syndrome.”
Individual withaFamily Diagnosis ofLS
• Once a pathogenic mutation is identied in a
proband, all at-risk blood-relatives should
undergo site-specic germline testing for the
known family mutation.
• In these cases of site-specic testing (for
affected relatives) or predictive testing (for
unaffected relatives), there are two possible
results: (1) true positive (when the specic
mutation is identied, the individual is
conrmed to have LS) and (2) true negative
(this is a conclusive negative result and effectively rules out LS in the individual, who carries only general population risks for
malignancies).
324
Table 23.5 Summary of possible surveillance regimen for Lynch syndrome patients
Cancer Test
Colorectal Colonoscopy 1–2 20–25 or 2–5years prior to
Endometrial and
ovarian
Gastric/small
bowel
Urinary tract Consideration for urinalysis 1 25–30
Sebaceous
Neoplasms
Brain/central
nervous system
Modied from the National Comprehensive Cancer Network Guideline on Genetic/Familial High-risk Assessment:
Colorectal. Version 1.2015. www.nccn.org
Transvaginal ultrasound with endometrial
sampling consideration for serum CA-125
Consideration for extended
esophagoduodenoscopy
Physical examination 1 25–30
Physical/neurologic examination 1 25–30
Frequency
(years) Age to commence (years)
1–2years 30–35
3–5 30–35
M. F. Kalady and Y. NancyYou
earliest colon cancer before
age 25
Individual Whose Family Meets Amsterdam Criteria but Does Not Have Any Clinical Phenotype
• It is not uncommon for a healthy individual
from an Amsterdam criteria family to seek
consult regarding his/her own screening recommendations. The initial evaluation should
begin with a detailed personal and family cancer history. The most informative individual to
evaluate would be a relative with a
LS-associated cancer, particularly at a young
age. If tumor is available, screening may be
conducted as discussed above. If a pathogenic
mutation is found, then directed germline testing can be performed for at-risk relatives. If
tumor screening is not feasible, germline
testing of an affected individual within the
context of appropriate genetic counseling is an
option. We do not recommend broad germline
genetic testing for an unaffected individual as
the yield is low and inconclusive results such
as variant of unknown signicance or uninformative negative would be clinically difcult to
interpret in an unaffected individual.
for recurrent, metachronous, or other syndromic cancers in affected individuals
(Table23.5).
• Recent guidelines have suggested varying the
age to initiate colonoscopy depending on family history (at least 2–5years younger than the
earliest affected age in the family).
• LS patients are also at increased risk for developing extracolonic malignancies that can
potentially benet from screening of asymptomatic individuals. A denitive survival benet has not been proven by prospective studies,
and management is based on expert opinion
and published guidelines.
Modiers ofRisk forColorectal
andOther Cancers
• High meat and high snack contents of a diet,
smoking, and obesity increase the risk of
developing colorectal neoplasia.
• Aspirin has been shown in some studies to be
associated with reduced risk of LS-related
cancers. However, currently the evidence is
not sufciently mature to recommend routine
use of high-dose aspirin in LS patients.
Clinical Management
Screening
• For patients with LS, key elements of their
lifelong care include screening for cancers
in unaffected individuals and surveillance
Surgery forColorectal Cancer
• Surgical treatment of LS-associated colon
cancer starts with the same oncologic princi-
ples as those for sporadic colon cancer.
Colectomy should be performed with adequate proximal, distal, and radial resection