Open Journal of Genetics, 2013, 3, 50-58 OJGen Published Online August 2013 (
Hereditary gastrointestinal polyposis: Diagnosis,
genetic test and risk assessment
Marina De Rosa*, Francesca Duraturo, Raffaella Liccardo, Paola Izzo
Dipartimento di Medicina Molecolare e Biotecnologie Mediche and CEINGE Biotecnologie Avanzate, Università di Napoli Federico
II, Naples, Italy
Email: *
Received 23 May 2013; revised 28 June 2013; accepted 10 July 2013
Copyright © 2013 Marina De Rosa et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Colorectal cancer (CRC) is the second cause of cancer
deaths, with over 1 million new cases estimated every
year. Familial adenomatous polyposis, MUTYH-as-
sociated polyposis and hamartomatous polyposis are
inherited syndromes that account for 2% - 5% of all
colon cancer. The mutated genes responsible for the
vast majority of these disorders, are now known
SMAD4, BMPR1A, and PTEN) and specific muta-
tions have been identified. Molecular caracterization
of inherited CRCs allows pre-symptomatic diagnosis
identifying at-risk individuals and improving cancer
surveillance. Adenomatous poly posis includes familial
adenomatous polyposis (FAP), attenuated FAP (A FAP),
and MUTYH-associated polyposis (MAP). Hamar-
tomatous polyposis comprises Peutz-Jeghers syn-
drome (PJS), juvenile polyposis syndrome (JPS) and
“PTEN hamartoma tumour syndrome” (PHTS).
MAP is an autosomal recessive condition, while all
other disorders are inherited in an autosomal domi-
nant manner. Differential dyagnosis could be very dif-
ficult between syndromes because of their phenotypic
variability. Attenuated FAP, MAP and Lynch syn-
drome could be all associated with fewer numbers of
adenomas (3 - 10 polyps), nevertheless, each syn-
drome has distinct cancer risks, characteristic clinical
features, and separate genetic etiologies. Thus, differ-
ential diagnosis is essential for correct management of
the specific disease. In our laboratory we set up a me-
thodology for genetic tests of the colorectal polyposis
syndrome. In these reviews we summarize the litera-
ture data and our experience about diagnosis, genetic
tests and cancer risk assesment associated with colo-
rectal polyposis. According to literature data, in our
experience, there is a portion of analyzing patients
that remain without identified mutation, after mole-
cular screening of the specific gene involved in the
pathogenesis of the disease. Since the sensibility of
used techniques, such as DHPLC, MLPA and sequen-
cing, is now very high, we suggest that a different ap-
proach to molecular diagnosis of polyposis syndromes
is necessary. In our laboratory, we are now planning
to set up analysis of a larger pannel of genes that
could be involved in colorectal poliposis syndromes,
using a next generation sequencing techniques. In our
opinion, a better characterization of molecular basis
of the polyposis syndromes will allow a more efficient
cancer prevention.
Keywords: Familial Adenomatous Polyposis (FAP);
MUTYH-Associated Polyposis (MAP); Peutz-Jeghers
Syndrome (PJS); PTEN Hamartoma Tumour Syndrome
For familial hereditary polyposis the differential diagno-
sis includes FAP, AFAP, MAP and the hamartomatous
polyposis syndromes [1,2].
2.1. Clinical Description
Familial adenomatous polyposis (FAP) is a rare auto-
somal dominantly inherited disease, associated with mu-
tations in the adenomatous polyposis coli (APC; MIM#
175100) gene located at chromosome 5q21. The inci-
dence for FAP is estimated at about 1 in 10,000 individu-
als and it accounts for about 1% of all colorectal cancers
*Corresponding author.
M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58 51
[3]. Affected individuals develop hundred to thousands
of adenomatous polyps at a young age (second decade of
life) that, if untreated, inevitably progress to colorectal
carcinoma. Consequently, a genetic test is crucial 1) to
identify mutation-carrying relatives for preventive meas-
ures, and 2) to reassure relatives who are free from gene
mutations [1,2]. Although, APC germline disease-causing
mutations have a penetrance close to 100%, recent evi-
dence points to very close genotype/phenotype relation-
ships and a marked variation in the phenotypic expres-
sion of FAP. Severe phenotypes, characterized by more
than 5000 polyps and early onset of the disease, are as-
sociated with mutations between codons 1250 and 1464,
whereas patients with classical FAP have hundreds to
thousands of adenomatous polyps in the colorectum dur-
ing the second and third decades of life [4]. Germline
mutations between codons 168 and 1680 and whole APC
deletions are associated with classical phenotypes. At-
tenuated FAP, showing few polyps (about 10 - 100), are
caused by mutations at the extreme 5’ or 3’ ends of the
APC gene or it could give rise to mutations in alterna-
tively spliced exon [5]. Phenotypic variation of FAP,
genetically indistinguishable, are Turcot syndrome (colo-
rectal multiple adenomas associated with brain tumours)
and Gardner syndrome (colorectal multiple adenomas
with epidermoid cysts, osteomas, dental anomalies, and
desmoid tumours) [1].
2.2. Extra Colonic Manifestations
FAP patients may also develop extracolonic manifesta-
tions. Both FAP and AFAP often arise with polyps in the
upper gastrointestinal tract. About 50% of affected indi-
viduals develop profuse polyposis of gastric fundic gland
and/or adenomatous polyps in the stomach [1]. Adeno-
matous polyps of the duodenum are observed in more
than 50% of individuals and are commonly found in the
second and third portions [6]. However, the most fre-
quent extra colonic manifestations are congenital hyper-
trophy of the retinal pigment epithelium (CHRPE), which
is present in about 80% of cases, and desmoid tumours,
which are seen in about 13% of FAP families, often re-
curring in the mesentery or in the abdominal wall after
resection. A papillary thyroid carcinoma and heaptoblas-
toma in the children of people with FAP have also been
reported [7].
The lifetime cancer risk of FAP patients is about 1% of
gastric cancer [8], 4% - 12% for duodenal cancer and
about 10% of thyroid cancer. They also present elevated
risk to develop stomach, liver (hepatoblastoma) and CNS
(medulloblastoma) cancer. Nonmalignant lesion also oc-
curs including osteomas (of the skull and mandible), epi-
dermoid cysts, fibromas and dental abnormalities (un-
erupted teeth or congenital absence of teeth). These find-
ings are less common in attenuated FAP [1].
2.3. Genetics
FAP and attenuated FAP are caused by germline muta-
tions in the APC gene and are inherited in an autosomal
dominant manner, so the children of a subject affected by
FAP have a 50% risk of developing the disease. De novo
mutations are responsible for approximately 25% of FAP
cases [9]. In 10% to 15% of de novo mutations a somatic
APC mosaicism may be present [10]. APC is an ubiqui-
tously expressed tumour suppressor gene located on the
long arm of chromosome 5 at position 5q21. It contains
at least 21 exons, 17 of which are coding exons and 4 are
untranslated exons. The APC gene encodes a large pro-
tein of 309 kilo-Daltons containing multiple domains [3].
By interacting with several cellular proteins, it is mainly
involved in Wnt signaling, in part by regulating β-catenin
levels, but also in intercellular adhesion, cytoskeleton
stabilization, signal transduction, apoptosis and cell-cy-
cle control, and it probably exerts a nuclear function in
chromosome segregation.
APC binds to β-catenin inducing ubiquitin-mediated
β-catenin degradation and, in this way, it negatively re-
gulates transcription of β-catenin targets [11]. Its func-
tional domains include heptad repeats at the amino-ter-
minal end (amino acids 6 - 57) that mediate homodimer
formation, the armadillo repeat (amino acids 453 - 767)
that binds to Asef, two motifs that interact with β-catenin
at amino acids 1020 - 1169 and 1262 - 2033, respectively,
and microtubule-, EB1- and hDLG-binding domains.
2.4. Genotype-Phenotype Correlations
Although, APC germline disease-causing mutations have
a penetrance close to 100%, recent evidence points to the
very close genotype/phenotype relationships and the cli-
nical manifestations and severity of FAP vary greatly
with the mutation site [1]. The disorder is classically cha-
racterized by more than 100 colorectal adenomas, early
onset of colorectal carcinoma, and specific extracolonic
features. Attenuated Familial adenomatous polyposis (AF-
AP) is a milder form of the disease in which patients
have less than 100 adenomas. AFAP patients with do-
minant inheritance harbor germ-line mutations in the 5’
or 3’ regions of the APC gene, to codon 1517 or distal to
codon 1900, or in regions affected by alternative splicing
events. Severe phenotypes, characterized by more than
5000 polyps and early onset of the disease, are associated
with mutations between codons 1250 and 1464, whereas
patients with classical FAP have hundreds to thousands
of adenomatous polyps in the colorectum during the sec-
ond and third decades of life [4,12]. Mutations contrib-
uting to classical FAP occur between exon 5 and the 5’
portion of exon 15 [11]. CHRPE is associated with muta-
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M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58
tions between codons 457 and 1444 [13]. Desmoid tu-
mours, found in approximately 10% of FAP patients, are
present in patients with mutations between codons 1403
and 1578. Although rare, FAP patients have an increased
risk of hepatoblastoma associated with mutations be-
tween codons 457 and 1309 [14].
3.1. Clinical Description
Another group of patients showing recessive inheritance
and FAP or AFAP phenotype often tests negative for
APC mutations but harbor inherited biallelic mutations in
the base-excision repair (BER) gene MYH (MUTYH;
OMIM# 604933, Gene Bank NM_012222.1). MUTYH
(MYH) gene is localized on chromosome 1 at position 1p
and acts together with MTH1 and OGG1 as part of the
base excision repair machinery [15,16]. MAP patients
develop adenomatous polyposis of the colon-rectum and
show an increased risk of CRC. Although the colonic
phenotype of MAP is of attenuated FAP, biallelic MU-
TYH mutations have also been associated with early on-
set CRC and few or no polyps. Hyperplastic polyps are
present, even though adenomatous polyps are more largely
represented [1]. FAP-associated extra-colonic manifesta-
tions such as osteomas, desmoids, CHRPE and thyroid
cancer did not take place but a higher risk of ovarian,
bladder, skin, sebaceous gland tumors and breast cancer
was described [17].
3.2. Genetics
MAP accounts for about 18% of the APC-negative AFAP
families, is caused by MUTYH mutations. It is inherited
in a recessive manner and family history is less informa-
tive in the diagnosis of this syndrome. The MUTYH is a
base excision repair protein that provides defence against
oxidation-induced DNA damage by removing A mis-
paired with 8-oxo-7, 8-dihydro2’deoxyguanosine (8-
oxoG), the most stable deleterious products of oxidative
DNA damage. Hence, it prevents G:C to T:A transver-
sions caused by oxidative stress. Genetic testing for
MAP is suggested in AFAP individuals negative for
APC mutation. Identification and characterization of the
specific MUTYH mutation confirm the diagnosis and
allows genetic testing in family members. Biallelic MYH
mutations are associated with adenomatous colorectal
polyps and a very high risk of CRC. Nevertheless, mono-
allelic MUTYH mutations might act as low-penetrance
CRC susceptibility modifiers and/or cooperate with other
gene mutations. Parents and children of individuals with
MAP are rarely affected and siblings of individuals with
biallelic MUTYH mutations have a 25% possibility to be
affected and they should be informed about the risks [2].
The obligate heterozygote children of MAP patient and a
nonconsanguineous healthy partner have only a small
risk of developing MAP (about 1%). The CRC risk of
heterozygous carriers is still controversial. Recent sys-
tematic studies in large patient populations estimate the
relative risk at 1.5 to 2.1 in relation to the general popu-
lation [9].
3.3. Mutation-Negative Adenomatous Polyposis
In about 20% of families with FAP and in 70% of AFAP
families the cause of adenomatous polyposis remains un-
known and the specific pathogenic mutations have not
been identified. The absence of detectable mutations
could be explained by misdiagnoses, the existence of an
alternative gene inactivation mechanism that remains un-
discovered by routine screening methods or, alternatively,
by genetic heterogeneity. A monogenic or multifactorial
etiology is a possible explanation. In patients showing
attenuate FAP phenotype without extracolonic manifes-
tations and with uninformative family history, HNPCC
or other polyposis syndromes should be considered in the
differential diagnosis. On the other hand, an individual-
ized approach may often be necessary because mutations
in APC or MYH are sometimes associated with variable
phenotype and mutations have been reported in APC
causing an increment of CRC risk but not adenomatous
colorectal polyposis [9].
3.4. Phenotypic Heterogeneity of FAP Patients
from Southern Italy
Our knowledge points to various genotype/phenotype
correlations within familial adenomatous polyposis pa-
tients. All patients with a totally deleted APC gene and
most patients with point mutations within exon 15 had a
classical FAP phenotype with CHRPE [18]. We de-
scribed three families carrier of the full APC gene deletion,
one of whom showing intrafamilial phenotypic variability.
Among affected subjects colonic disease manifestations
were expressed at considerably different ages and the
number of polyps ranged from few in some patients to
hundreds of others; extracolonic manifestations, i.e. kid-
ney carcinoma and calcifying epithelioma, were present
in one of these patients. These data support the notion
that other genetic and/or environmental factors could
play an important role in the penetrance of the disease
[19]. Furthermore, in our study population, very severe
polyposis is associated with mutations that map in a re-
gion comprised from codon 1249 to codon 1330, but
phenotypic variability is often described. We reported a
severe case of FAP in a young child with very early on-
set of the disease. A 10-year-old female was evaluated
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M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58 53
for anemia and an 8-year-long history of recurrent he-
matochezia (initial disease presentation at the age of 2
years). Family history was negative for FAP, other poly-
posis syndromes, or colon cancer. Molecular diagnosis
performed in this proband revealed the presence of 1309
APC gene deletion that was not found in the proband’s
relatives and therefore represented a de novo mutation.
This mutation consists in a deletion of AAAGA bases
from sites 3927 to 3931 of the APC gene and it has been
found in about twenty percent of all FAP pedigrees typi-
cally associated with severe, early-onset disease and with
congenital hypertrophy of the retinal pigment epithelium
(CHRPE). This mutation is responsible for the rare cases
of polyposis that occur in the first decade of life. The
proband presented very early onset of disease although
she did not show a family history of FAP. Therefore, it is
important that a child with irondeficiency anemia and a
long history of rectal bleeding has an early and adequate
endoscopic investigation [20]. In another family we de-
scribed a mutation identified in exon 5 (595_596insG), a
region usually mutated in attenuated polyposis, associ-
ated with a particularly severe phenotype, without CH-
RPE [21]. Patient bearing this mutation was also affected
by desmoid tumours, mandibular osteomas, and tubular
adenomas with moderate dysplasia in the colon. Inter-
estingly, a patient bearing a different mutation in this re-
gion (591_592delAG) showed a classical pheno-type.
Two other families, bearing mutations 4621C > T
(Q1541X) and 4526_27insT, respectively, had similar
extracolonic manifestations, i.e. fundic gland polyps,
which are the most common gastric polyps, and cranial
osteomas. However, the patient with mutation 4621C > T
(Q1541X) had a classical FAP phenotype associated with
abdominal desmoid tumours, whereas the patient with
mutation 4526_27insT had attenuated polyposis with few
adenomatous polyps (about 10) in the colon, in contrast
to the genotype/phenotype correlation usually reported
for this mutation site. This finding lends weight to the
intra- and inter-familial variability observed in FAP fa-
milies [18].
Alterations of APC mRNA were also identified as
pathogenic for a subset of FAP cases in which no germ-
line APC or MYH mutations have been detected. About
15% of inherited human diseases involve splicing errors
caused by mutations in splice sites or in splicing control
sequences. We described a 62-year-old man without a
dominant family history of FAP and an attenuated FAP
phenotype with fewer colonic polyps (about 10). The fam-
ily history was unclear; in fact, a cousin died of colo-
rectal cancer at the age of 65 years, but his parents died
from causes other than colorectal cancer. This FAP pa-
tient had a missense mutation in exon 15, c.4909G- > A
(p.D1637N), which consists in a G to A transition at po-
sition 4909 and causes a substitution of the aspargine
1637 to aspartic acid. No other mutation was found.
Using the “ESEfinder” program, binding motifs in
known splicing enhancer proteins (SR proteins: SF2/ASF,
SC35, SRp40, and SRp55) were found in this region, in
both normal and mutated sequences. Remarkably, we
identified an increase of the SC35 binding motif affinity
in the mutated sequence (score 3.0) compared to the con-
trol sequence (score 2.5). An unusual feature of mutation
4909G- > A is that the change does not alter an authentic
splice site nor does it generate a cryptic splice site, rather,
the mutation probably activates an ESE control sequence
that indirectly activates a cryptic splice junction up-
stream of the mutated site within the same exon.
Moreover, our study on an Italian FAP population
confirm that MYH associated polyposis (MAP) geno-
type-phenotype correlations are very complex. Biallelic
MYH mutations can result in either classic or attenuated
polyposis, furthermore, patients with the same MYH bi-
allelic mutations can show different phenotypes. Finally,
in a relevant fraction of patients with colon polyposis, a
mutation was found in a single MYH allele (monoallelic
mutation) [22].
The hamartomatous polyposis syndromes are a hetero-
geneous group of disorders including less than 1% of all
hereditary colorectal cancers. They are characterized by
autosomal-dominant inheritance, development of gastro-
intestinal hamartomatous polyps and are associated with
GI and extraintestinal malignancy [23,24]. The hamarto-
matous polyposis syndromes include Peutz-Jeghers syn-
drome (PJS); PTEN hamartoma tumour syndrome (PH-
TS), comprehending Cowden syndrome (CS) and Banna-
yan-Riley-Ruvalcaba syndrome (BRRS); and juvenile
polyposis syndrome (JPS). Differential diagnosis are es-
sential for suitable patient management, because each of
these syndromes presents its own characteristic organ-
specific manifestations and each requires a precise sur-
veillance approach [25].
4.1. Peutz-Jeghers Syndrome: Clinical
Description, Extraintestinal
Manifestations and Genetics
Peutz-Jeghers syndrome (PJS) is an autosomal domi-
nantly inherited syndrome characterized by mucocuta-
noeus pigmentation, multiple hamartomatous polyps in
the gastrointestinal tract and an increased risk of cancer
at a young age. It is the most common form of hamar-
tomatous polyposis, with a reported prevalence of be-
tween 1 in 29,000 and 1 in 200,000 [26,27]. Inactivating
Copyright © 2013 SciRes. OPEN ACCESS
M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58
germ-line mutations in the tumour suppressor gene
STK11/LKB1 have been detected in approximately 80%
of patients [2]. The polyps, commonly found in the small
intestine but also in the stomach and colon, have a mus-
cular core, are histologically classified as hamartomas
and their numbers may range from 1 to a complete car-
peting of the gastrointestinal tract [2]. Abdominal pain,
intussusception, anemia, melena, hematochezia, hema-
temesis, and obstruction are the main PJS clinical mani-
festations. Pigmentation is seen around the lips (in over
95% of cases), in the buccal mucosa (about 80% of
cases), on the hands, feet, genitals, and around the nose
and eyes. Pigmentation is typically present in early child-
hood and starts to become dim usually after the start of
puberty [25]. Approximately one third of PJS patients
present a disease onset in the first decade of life, while
up to 60% by the second or third decade [28].
Extraintestinal polyps have been reported in the nose,
bronchi, renal pelvis, bladder, in the gallbladder and bile
ducts. PJS is also associated with various malignancies.
In addition to an elevated risk of gastrointestinal malign-
nancies, such as gastroesophageal, small bowel and co-
lorectal cancer, an increased risk of cancer at other sites,
particularly in breast, pancreas, ovary, uterus, cervix,
lung and testicle, have been reported. The extimated risk
of cancer is of 60% by 60 years of age and 85% by 70
years of age. The risk of developing cancer by 60 years
of age was estimated at about 31% for gastrointestinal
and breast cancer, 18% for gynecologic cancer, 7% for
pancreatic cancer and 13% for lung cancer [28].
Sex cord tumours and Sertoli cell tumours, both aris-
ing from the same embryonic tissue, are often described
in women and men affected by PJS [25].
The gene associated with PJS is a serine-threonine
kinase that is located on chromosome 19p13.3. Germ-
line mutations in LKB1/STK11 gene has been reported
in 80% of patients with PJS. In the remaining 20% of
PJS patients, defects in other genes or not yet identified
ways of LKB1 inactivation might be responsible for PJS.
Several putative candidate genes have been studied, in-
cluding genes encoding LKB1 interacting proteins; so far
a second PJS gene has not been identified. Common mu-
tations are frameshift and nonsense mutations in exons 1
- 6; however, large deletion mutations missed by direct
sequencing have been recently described using multiple
ligation probes, long range RCR and Real time PCR [28-
30]. LKB1 forms a complex with pseudokinase STRAD
and the scaffolding protein MO25, that activates at least
14 serine/threonine kinase by phosphorylation of the
“T-Loop” threonine localized in their kinase domain.
This implicates the involvement of LKB1 in several sig-
nalling pathways. The first identified physiological sub-
strate of LKB1 was AMPK (AMP-activated protein ki-
nase), which is a master regulator of cellular energy
charge. In addition to the involvement in energy metabo-
lism, LKB1 has the capacity to regulate multiple cellular
processes, such as cell cycle arrest, Wnt signalling, cell
polarity, transforming growth factor beta signalling, p53-
dependent apoptosis and chromatin remodelling [31].
We examined a population of 10 Italian PJS patiens
from Southern Italy, seting up a strategy to screen the
entire coding region of the LKB1 gene, both at DNA and
RNA level. We described an intra-exonic in-frame dele-
tion encompassing exons 2 and 4 and characterized the
breakpoints of this LKB1/STK11 intragenic deletion.
This rearrangement, that deletes about 7 kb of the LKB1
genomic region encompassing exons 2 and 3 is most
likely an Alu-Alu homologous recombination event. Two
26 bp core sequences of two Alu elements (both AluY
sequences), showing a 96% homology, are indeed local-
ized at the 5’ and 3’ end of the breakpoints, respectively.
This sequence, could itself act as a recombinase. Alu-
mediated homologous recombination is a mechanism
well documented so far, however it was the first evi-
dence that this mechanism is involved in the STK11/
LKB1 gene rearrangements. According to other literature
data, we identified the disease causing mutations in about
67% of PJS patients, suggesting that others gene inacti-
vating mechanisms might be responsible for PJS in our
mutation negative population subset [29].
4.2. PTEN Hamartoma Tumour Syndrome
The “PTEN hamartoma tumour syndrome” (PHTS) is in-
herited in an autosomal dominant manner and includes a
group of rare multiple hamartoma syndromes, such as
Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syn-
drome (BRRS), Proteus syndrome (PS), and Proteus-like
syndrome, that are caused by germline mutations within
the tumour suppressor gene “phosphatase and tensin ho-
molog deleted on chromosome ten” (PTEN). These syn-
dromes are characterized by multiple amartomatous pol-
yps in the gastrointestinal tract and by a greatly increased
risk of developing malignant tumours in many tissues.
Because of many of its phenotypic manifestations are
subtle and occur in the general population, its phenotypic
variability and incomplete penetrance, PHTS is likely to
be underdiagnosed [32].
4.3. Cowden Syndrome
CS is a rare autosomal dominant syndrome that occur in
1 in 200,000 individuals. This syndrome is characterized
by macrocephaly, mucocutaneous lesions (such as facial
trichilemmoma), acral keratosis, papillomatous papules
and glycogenic acanthosis of the esophagus, which in-
volves large benign glycogen-filled epithelial cells that
are gray to white in color. It is also associated with thy-
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M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58 55
roid, breast, and endometrial manifestations, including
cancer in all of these areas. Renal cancer has also been
associated with CS; the risk of developing gastrointesti-
nal carcinoma in CS is still unclear. The incidence of
gastrointestinal polyps in CS differs in the literature,
varying from 30% to 85%, reporting an incidence of gas-
trointestinal polyps in CS less than in BRRS [25]. The
specific pathogenic PTEN gene mutations are identified
in approximately 85% of individuals who meet the diag-
nostic criteria for CS and in about 65% of individuals
with a clinical diagnosis of BRRS. The most important
aspect of the management of an individual carrier of a
PTEN mutation is increased cancer surveillance because
of the most serious consequences of PHTS consist in the
increased risk of breast, thyroid, endometrial, and renal
cancer [31,32].
4.4. Bannayan-Riley-Ruvalcaba Syndrome
Clinical Presentation: The BRRS is a congenital disorder
characterized by macrocephaly, intestinal hamartomatous
polyposis, lipomas, and pigmented macules of the glans
penis. It is suggested that individuals with BRRS should
be considered at risk for malignancy, as with CS.
The incidence of gastrointestinal polyps in BRRS has
been reported to be 45%. The extraintestinal manifesta-
tions, consisting of macrocephaly, developmental delay,
accelerated growth of first metacarpal and first proximal
and middle phalanges, joint hyperflexibility, pectus ex-
cavatum, scoliosis, genital pigmentation, lipomas, he-
mangiomas, lipid storage myopathy, are the hallmarks of
this syndrome [33-36].
4.5. Cowden Syndrome and
Syndrome Genetics
CS and BRRS are allelic diseases with an autosomal do-
minant inheritance pattern and variable penetrance, in
which a mutation of the PTEN gene, located on chromo-
some 10q22-23, is found in 80% of CS patients and 60%
of BRRS patients [37,38]. Close to 100 different germ-
line mutations of PTEN have been reported to date en-
compassing point, nonsense, frame shift, splice site, mis-
sense, and deletion/insertion mutations. Most mutations
occur in exon 5, but mutations in all other exons, except
the first, have also been described. Around 10% of PTEN
mutations occur in the promoter region and the role of
epigenetic regulation is not well outlined.
Balanced translocations and deletions and mutations in
exons 6 and 7 occur preferentially in BRRS, while muta-
tions in all exons except 1, 4, and 9 have been found in
CS. Recently, differential expression of the PTEN gene
has been correlated with the different phenotypes of CS
and BRRS.
PTEN is a 9-exon tumour suppressor gene that en-
codes for a 403 amino acid tyrosine phosphatase protein
that dephosphorylates tyrosine, serine, and threonine. It
acts as a lipid phosphatase to negatively regulate the
PI3K/AKT/mTOR pathway [39]. Recently, nuclear com-
partmentalization of PTEN has been found as a key com-
ponent of its tumour-suppressive activity. PTEN is also
involved in regulating the cell cycle, apoptosis, and an-
giogenesis. Evidence exists indicating that PTEN is a
functionally haploinsufficient tumour suppressor gene.
A new study revealed that about 10% of CS and CSL
individuals, negative for germline PTEN mutations, har-
bor germline variants in SDHB and SDHD. These muta-
tions are associated with a greater risk of developing
breast, thyroid, and renal cell carcinomas consistent with
germline PTEN mutations and SDHB mutations obser-
vations in pheochromocytoma/PGL patients, who were
also found to have a risk of papillary thyroid cancer and
early-onset renal cancers [40].
4.6. An Overview of PHTS Patients from
Southern Italy
We performed mutational analysis of the PTEN gene in
three PHTS patients, setting up a combination of RT-
PCR reaction of the whole cDNA, PCR of genomic re-
gion, including the promoter region from bp 1398 to bp
+1, sequencing of the amplified fragments, Real Time
PCR and western blot techniques. The first PHTS patient
(PHTS1), affected by BRRS, had a missense mutation
named c.406TC in exon 5 of the PTEN gene. This mu-
tation, localized in the catalitic domain of PTEN protein,
determines the aminoacidic change of cysteine residue
136 into an arginine. The other two patients, (both af-
fected by CS), showed a significant decrease in the
PTEN mRNA expression when analysed by Real Time
quantitative RT-PCR.
PI3K-Akt signalling activation is related to β-catenin
phosphorylation at Ser 552 and its stabilization, nuclear
accumulation and transcriptional activation. Furthermore,
PI3K-Akt signalling activation results in the inactivation
of GSK-3β and reduces N-terminal β-catenin phosphory-
lation, which is associated with its degradation.
Thus, we provided the first evidence of β-catenin ac-
cumulation in non-neoplastic cells of PHTS patients,
caused by germ-line PTEN alteration without a “second
hit” of gene inactivation taking place. In light of these
data, we suggest that β-catenin could represent a good
candidate as a diagnostic marker for hereditary colorectal
diseases that determine β-catenin accumulation. This is
mainly noteworthy for PHTS syndrome, which is often
underdiagnosed. In addition, all PHTS patients analysed
showed alterations in the expression of TNFα, its recep-
tors and IL-10 [41].
Copyright © 2013 SciRes. OPEN ACCESS
M. De Rosa et al. / Open Journal of Genetics 3 (2013) 50-58
Differential diagnosis and identification of the polyposis
syndromes is essential for management and cancer pre-
vention for affected individuals, because of each poly-
posis syndrome has its own distinctive organ-specific
manifestation and each requires a different surveillance
strategy. Polyposis patients have a high lifetime risk of
gastrointestinal and extraintestinal carcinoma and their
first-degree relatives have a high risk of recurrence of the
syndrome. Differential diagnosis and identification of the
polyposis syndromes is essential for management and
cancer prevention for affected individuals, because of
each polyposis syndrome has its own distinctive organ-
specific manifestation and each requires a different sur-
veillance strategy. Polyposis patients have a high life-
time risk of gastrointestinal and extraintestinal carcinoma
and their first-degree relatives have a high risk of recur-
rence of the syndrome. Characterization of a causative
mutation in leukocyte DNA is essential for the different-
tial diagnosis among the various adenomatous polyposis
syndromes, assessment of the risk of recurrence (auto-
somal dominant versus autosomal recessive inheritance),
determination of familial cancer risks, based on gene-
specific cancer associations and predictive testing of
asymptomatic at risk individuals. The role of molecular
genetic findings in treatment decisions, on the other hand,
is limited because identification of a germline mutation
rarely allows any estimation of the likely course of the
disease. According to international literature data, we
suggest that next-generation sequencing is today the bet-
ter and more efficient technique for molecular diagnosis
of hereditary colorectal polyposis syndrome, hereditary
colorectal cancer and familial colorectal cancer. Indeed,
it allows to consider a number of different genes associ-
ated with colon cancer for differential diagnosis. Using
this solid technique, we are going to analyze a gene panel
including APC, MUTYH, PTEN, STK11, BMPR1A,
EPCAM and TP53. This approach could consent to de-
tect previously unidentified low frequency allelic vari-
ants including a novel candidate locus. Moreover, even if
no mutation is found, the patient with polyposis still
needs to be treated appropriately and clinical follow up
should be initiated even before mutation testing is com-
plete [40].
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