Original Article
Middle East Journal of Cancer; October
July 20152020
6(3):11(4): 493-501
New Variants in the CDH1 Gene in Iranian
Families with Hereditary Diffuse
Gastric Cancer
Majid Kheirollahi*, Maryam Saneipour**, Mohammad Amin Tabatabaiefar*,
Mehrdad Zeinalian*, Mohammad Minakari***, Abbas Moridnia**♦
*Pediatric Inherited Diseases Research Center, Research Institute for Primordial
Prevention of Non-communicable Disease and Department of Genetics and Molecular
Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
**Department of Genetics and Molecular Biology, School of Medicine, Dezful University of
Medical Sciences, Dezful, Iran
***Department of Internal Medicine, School of Medicine, Isfahan University of Medical
Sciences, Isfahan, Iran
Please cite this article as:
Kheirollahi M, Saneipour M,
Tabatabaiefar MA, Zeinalian
M, Minakari M, Moridnia A.
New variants in the CDH1 gene
in Iranian families with
hereditary diffuse gastric cancer.
Middle East J Cancer.
2020;11(4): 493-501. doi: 10.
30476/mejc.2020.81478.1016.
♦Corresponding Author:
Abbas Moridnia, PhD
Department of Genetics and
Molecular Biology, School of
Medicine, Dezful University of
Medical Sciences, Dezful,
Iran
Tel: +986142423791
Email: moridnia.a@dums.ac.ir
Abstract
Background: Hereditary diffuse gastric cancer (HDGC) is a hereditable form of
diffuse gastric cancer with very aggressive tumors, poor prognosis, and delayed
clinical signs.
Method: We assessed 17 probands identified with HDGC upon gastrectomy
according to the histopathological criteria confirmed by a pathologist and familial
history. We extracted DNA from peripheral blood and formalin fixed paraffin-embedded
tissues. DNA sequencing was done following PCR amplification of 16 exons and
exon/intron boundaries of the CDH1 gene and exon 2 of CTNNA1 gene. The Multiplex
Ligation-dependent Probe Amplification technique was performed on patients with
no pathogenic variants in sequencing.
Results: Totally, 17 probands comprising seven males and 10 females were
assessed. In three patients, we recognized the tumors in the early TNM stage (I, II),
while in 14 cases, tumors were observed in the late stages (III, IV). Overall, DNA
sequencing of the CDH1 gene identified 16 variants (seven exonic including five
new variants and nine intronic containing six new variants). Moreover, Multiplex
Ligation-dependent Probe Amplification detected one deletion in exon 1 of two
patients.
Conclusion: Our results showed that E-cadherin deficiency in HDGC was related
to CDH1 gene point mutations and large deletion with high heterogeneity, which
should be considered in the diagnosis and treatment of HDGC patients.
Keywords: CDH1 gene, Diffuse gastric cancer, Iranian families, Hereditary, Mutation
Received: April 23, 2019; Accepted: January 13, 2020
Majid Kheirollahi et al.
Introduction
Gastric cancer (GC) is the fourth common
cancer with 952,000 new cases and 723,000 deaths
during 2012 and the second cause of mortality
among all cancers.1,2 In addition, GC is estimated
to be the eleventh cause of all deaths and account
for 1.8% of all deaths by 2030.2 GC is the most
common cause of cancer-related mortality in Iran,
the second prevalent cancer in males (14%), and
the fourth in females (7%).2, 3 Most of GC cases
are sporadic, and familial aggregation could be
observed in approximately 10% of the cases.4, 5
Hereditary pattern is observed in a few cases (13%). 6 According to Lauren histological
classification, GC is divided into intestinal and
diffuse type of adenocarcinoma.7 Hereditary
diffuse gastric cancer (HDGC) is an autosomal
dominant inherited form of DGC, a highly
invasive tumor with a poor prognosis, high
penetrance, and infiltrating pattern. This causes
gastric wall thickening (Linitis plastica) without
forming a definite mass. Signet ring cell carcinoma
(SRCC) or isolated cell type carcinoma are
common histopathologic features of diffuse GC
(DGC).8
Mutations in the CDH1 gene is the most
prevalent cause of HDGC and sporadic DGC.9
CTNNA1 (encoding the alpha-E-catenin) is the
only identified gene involved in HDGC other
than CDH1 germline mutations. This gene has
been reported in a large HDGC pedigree as a 2
bp germline deletion in exon 2. 10 Germline
mutations in CTNNA1, BRCA2, STK11, SDHB,
PRSS1, ATM, MSR1, and PALB2 genes were
reported in HDGC patients.11 Furthermore, several
genes including LMTK3, RHOA, PIK3CA,
MED1, ARID1A, and MCTP22 were detected
in the HDGC patients with somatic mutations.10
More than 80% of the HDGC carriers for CDH1
mutations, whether male or female, might be
inflicted with GC until the age of 80. Moreover,
there is a 60% risk of lobular breast cancer until
Figure. 1 (a): Sequence electropherogram of exon 3 of the CDH1 gene. Arrow indicates the location of the base substitution
at c.181G>A ( p.61T>A). (b): Sequence electropherogram of exon 15 of the CDH1 gene. Arrow indicates the location of
the base substitution at c.2331C>G ( p.777D>E). 1 (c): Sequence electropherogram of exon 7 of the CDH1 gene. Arrow
indicates the location of the base deletion at c.889delA. (d): Sequence electropherogram of exon 9 of the CDH1 gene.
Arrow indicates the location of the base deletion at c.1177delA.
494
Middle East J Cancer 2020; 11(4): 493-501
CDH1 Gene and Hereditary Diffuse Gastric Cancer
Table 1. Epidemiological and clinicopathological features of HDGC patients
Sample ID
A
B
4
14
15
18
20
22
29
37
40
41
42
43
44
45
48
Tissue type
Blood
Blood
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
FFPE
Blood
Blood
FFPE
FFPE
Gender
Female
Female
Male
Male
Male
Female
Male
Male
Female
Female
Male
Female
Female
Male
Female
Female
Female
Age of diagnosis
31
34
49
36
61
37
78
31
70
30
51
57
27
41
29
37
72
the age of 80 in women with CDH1 germline
mutation.12
CDH1 gene is located on 16q22.1, including
16 exons encodingE-cadherin.13, 14 E-cadherin is
Stage
IV
IV
IIIA
IIIB
IV
IIIA
IIIC
IIIC
IIIC
IIIB
IV
IIIC
IIIA
IIIB
II
I
II
Histopathological type
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Signet ring cell carcinom
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
Signet ring cell carcinoma
a transmembrane protein that plays a pivotal role
in cell adhesion and tumor suppression.15 The
CDH1 promoter hypermethylation is the most
common epigenetic inactivation mechanism of
Figure. 2 (a): Sequence electropherogram of the exon 3 of the CDH1 gene. Arrow indicates the location of the base
substitution at c.348G>A (p.116L>L). (b): Sequence electropherogram of exon 13 of the CDH1 gene. Arrow indicates the
location of the base substitution at c.2076T>C ( p.692A>A). (c): Sequence electropherogram of exon 14 of the CDH1
gene. Arrow indicates the location of the base substitution at c.2292C>T (p.764D>D). (d): Sequence electropherogram of
exon 13 and the intron boundary of the CDH1 gene. Arrow indicates the location of the base deletion at c.1937-58delA.
Middle East J Cancer 2020; 11(4): 493-501
495
Majid Kheirollahi et al.
Table 2. Exonic and intronic variants in CDH1 gene among HDGC patients
Sample ID
14, 15, 20, 48.
20
A, B
B
14, 29, B, 15, 40,
41, 42, 46
B
Type of
Exon or exon/
tissue
intron boundary
FFPE
3
FFPE
3
Blood
7
Blood
9
FFPE/ Blood
13
Substitution
G>A
A>G
T>C
Deletion
Heterozygosity
Heterozygote*
Heterozygote*
A
Homozygote*
A
Homozygote*
- Heterozygote/ Homozygote
Blood
14
C>
-
Heterozygote
29
15
FFPE
FFPE
15
4
C>G
G>C
-
Heterozygote*
Heterozygote
15, 22, A, B, 40,
41, 43, 46
22
FFPE/ Blood
13
A
Homozygote*
FFPE
13
G>
-
Heterozygote*
22
FFPE
13
G>A
-
Heterozygote*
14, 15, 20, 22, 44,
FFPE
15
C>G
-
Heterozygote*
14, 15, 20, 22,
FFPE/ Blood
44, 48
14, 15, 20, 22, 44, 48 FFPE/ Blood
15
T>G
-
Heterozygote*
15
C>G
-
Heterozygote
40
FFPE
15
T>G
-
Heterozygote*
43, 46
FFPE/ Blood
15
G>A
-
Heterozygote
-
Amino acid
Chromosome location
L116L
T61A
Exonic
Exonic.
A692A
NM_004360.3:c.348G>A
NM_004360.3:c.181A>G
NM_004360.4:c.889delA
NM_004360.4:c.1177delA
NM_004360.:c.2076T>C
rs:1801552
D764D
NM_004360:c.2292C>T
rs: 61747636
D777E
NM_004360:c.2331C>G
NM_004360:c.531+10G>C
rs: 33963999
NM_004360.3:c.193758delA
NM_004360.4:
c.2164+48G>A
NM_004360.4:
c.2164+51G>A
NM_004360.4:c.229648C>G
NM_004360.4:c.229644T>G
NM_004360:c.229622C>G rs:763184960
NM_004360.3
:c.2439+105T>G
NM_004360.4:
c.2439+52G>A
rs:33965115
*New mutation, FFPE: Formalin fixed-paraffin embedded
the gene as the second hit in HDGC; however,
other secondary substitution or insertion/deletion
mutations have been reported with less
frequency.14 To date, the majority of the germline
mutations have been identified as single nucleotide
substitutions.16 On average, 5% of the familial
DGC cases are due to the large deletions up to
several exons of the CDH1 gene.17, 18 Large
deletions in CDH1 gene have been described as
a reason for cancer susceptibility in Japanese,19
Canadian, and European familial GC patients.20
In this study, we reported several new CDH1
variants and a large deletion in Iranian patients
with HDGC.
province, central Iran, and Alaa cancer control
center, a charity-based foundation for cancer
patients in Isfahan. Four samples belonged to
blood’s probands and 13 samples of probands
were formalin fixed-paraffin embedded (FFPE)
tumor tissues. We extracted the DNA of blood
samples by Prime Prep Genomic DNA Isolation
Kit (GeNet Bio, Korea). FFPE tumor samples
were cut to 5-l0µm thickness sections for DNA
extraction using SDS-proteinase K digestion,
phenol chloroform, and ethanol precipitation. All
patients participating in the study or their families
completed informed consent forms. The Review
Board of Isfahan University of Medical Sciences
approved this study with code number 394479.
Materials and Methods
Patients and sampling
We identified 17 probands with HDGC using
histological features and clinical criteria based
on IGCLC 21. A pathologist confirmed DGC.
We selected the samples from GC patients who,
from January 2011 to April 2016, referred to AlZahra Hospital, a referral hospital in Isfahan
496
DNA sequencing
We assessed the obtained DNA to sequence
CDH1 and CTNNA1 genes in all the samples.
Polymerase chain reaction (PCR) amplified the
DNA. Specific primers amplified all coding exons
and exon/intron boundary regions of the CDH1
gene (NM_004360.4) and exon 2 of CTNNA1
Middle East J Cancer 2020; 11(4): 493-501
CDH1 Gene and Hereditary Diffuse Gastric Cancer
Table 3. Effect of non-synonymous variants on protein function of CDH1 gene
Amino acid
subsitution
PolyPhen 2
T61A
Benign: 0.005
D777E.
SIFT
Tolerated: 0.78
Probably damaging: Tolerated: 1
0.985
I-Mutant v2.0
Decrease stability
DDG:
-0.99
Decrease stability
DDG:
-0.48
Mutation
taster
PROVEAN
Polymorphism.
Neutral
Disease causing.
Neutral
Mutation
assessor
PhD-SNP ConSurf
lowNeutral
FI score: 1.085
lowNeutral
FI score: 1.245.
1
7
Ranges of score variation are depicted below the program names. Categorical predictions based on the following cut-off values: Polyphen-2: Benign= 0-0.2, Possibly
damaging=0.2-0.85, Probably damaging=0.85-1; SIFT: Damaging if <=0.05, I-Mutant: Free Energy Change Value (DDG)<0= Decrease stability, DDG>0=Increase stability;
Mutation Taster: disease causing= probably deleterious, disease causing automatic = known to be deleterious, polymorphism= probably harmless, polymorphism automatic=
known to be harmless, PROVEAN: Deleterious if <= -2.5, Mutation assessor: Functional impact of a variant (Func. Ipmact)= predicted functional (high, medium), predicted
non-functional (low, neutral).;PhD-SNP: Neutral: Neutral polymorphism, Disease: Disease-related polymorphism; ConSurf: The conservation scale: Variable=1-3, Average=46, Conserved=7-9
gene (NM_001903.4). We sequenced the PCR
product of each reaction through the use of ABI
3130XL capillary sequencing platform (Applied
Biosystems/Life Technologies, Carlsbad, CA,
USA). The obtained sequences were analyzed
using Chromas software, version 2.31.
recognized the tumors at an early TNM stage (I,
II), and in 14 cases (82%), the tumors were
detected at late stages (III, IV). SRCC and “poorly
differentiated adenocarcinoma” were reported as
the histopathological type of the tumor in 13 (76.5%)
and 4 (23.5%) cases, respectively (Table 1).
In silico investigation of pathogenicity
We assessed the effect of non-synonymous
variants on protein function using bioinformatics
software tools, including Polyphen2, SIFT, IMutant, Mutation taster, Mutation assessor,
PROVEAN, ConSurf, and PhD-SNP. Human
Splice Finder (HSF) version 3 evaluated the effect
of intronic variants on the splicing site.
Sequence analysis
DNA sequencing of the amplified PCR
products exhibited eleven new variants (5 exonic
and 6 intronic) in the CDH1 gene of the samples
(Table 2). Two exonic variants were nonsynonymous (T61A and D777E), three were
synonymous (L116L, A692A and D764D), and
two were one-nucleotide deletion (c.889delA and
c.1177delA). No single nucleotide changes
occurred in exon 2 of CTNNA1. Using DNA
sequencing, we further found one base pair
deletion in CDH1 gene at c.1937-58delA in eight
samples. Interestingly, seven of these samples
also carried exonic variants, two of which were
predicted to be pathogenic. This could favor the
benign effect of the intronic variant.
Multiplex ligation-dependent probe amplification
(MLPA)
We examined samples with no identified
pathogenic point mutations to identify large
deletions/duplications in CDH1 and CTNNA1
genes using SALSA P083-C2 CDH1 MLPA kit
(MRC-Holland, Amsterdam, Netherlands). The
reactions were performed according to the
manufacturer’s instruction. Probe ratio (PR)
described deletions or duplications. A PR of less
than 0.7 presented a gene dosage reduction, and
a PR of more than 1.3 indicated an increase in
gene dosage.
Results
Clinicopathologic characteristics
Altogether, the mean age of the cases at
diagnosis was 45.4 years (49.6 in men and 42.4
in women) and seven of the 17 (41%) patients
were older than 45. In three patients (18%), we
Middle East J Cancer 2020; 11(4): 493-501
Amino acid substitutions
We detected two non-synonymous variants,
including a single base pair substitution, A to G
transition resulting in a single amino acid
substitution at codon 61 as p.61T>A (Figure 1a),
and a single base pair substitution C to G
transversion leading to an amino acid substitution
at codon 777 as p.777D>E (Figure 1b) (Table.
2). Moreover, we detected two deletions with
one-nucleotide at c.889delA (Figure 1c) and
c.1177delA (Figure 1d). The discovered
synonymous variants were: a single base pair
497
Majid Kheirollahi et al.
Figure 3. Coffalyser electropherogram of the CDH1 gene. Above electrophoretogram relates to normal controls and the
bottom belongs to the patients. Arrow indicates deletion in exon 1.
498
Middle East J Cancer 2020; 11(4): 493-501
CDH1 Gene and Hereditary Diffuse Gastric Cancer
Table 4. Intronic variants effect on splicing site
Sample ID
NM_004360.4:c.1937-58delA
NM_004360.4:c.2164+51G>A
NM_004360.4:c.2296-48C>G
NM_004360.4:c.2296-44T>G- c.2296-48C>G
NM_004360.4:c.2296-22C>G
NM_004360.4:c.2439+52G>A
NM_004360.3:c.2439+105G>T
Splice site type
Acceptor
Donor
Acceptor
Donor
Acceptor
Acceptor
Donor
Consensus value (0-100)
70.07
72.25
69.78
73.78
82.33
66.32
66.12
Consensus value: splice site if >= 65
substitution, G to A nucleotide transition resulting
in synonymous substitution at codon 116
(p.116L>L) (Figure 2a), a single base pair
substitution, T to C nucleotide transition leading
to a synonymous substitution at codon 692
(p.692A>A) (Figure 2b), and finally, a single
base pair substitution, C to T transition leading
to a synonymous substitution at codon 764
(p.764D>D) (Figure 2c) (Table. 2).
Effect of non-synonymous variants on protein
function
Bioinformatics analysis by PolyPhen2, IMutant, Mutation taster, Mutation assessor, and
ConSurf software tools suggested the p.777D>E
substitution can have pathogenicity effect on the
protein function (Table 3).
Intronic substitutions and splicing site-effects
Moreover, we identified certain likely benign
variants in intronic sites including a single base
pair deletion at c.1937-58delA (Figure 2d) and
several single base pair substitutions containing
the following: c.531+10G>C, (c.2164+48G>A,
c.2164+51G>Ac.2296-48C>G, c.2296-44T>G
c.2296-22C>G, c.2439+52G>A and finally
(.2439+105T>G. The evaluation of intronic
variants showed the potential effect of seven
different variants on the splicing site (Table 4).
MLPA results
Using the MLPA technique, we found one
large deletion in exon 1 (CDH1 probe 12651L19938) in two patients (Figure 3). This change
was confirmed by quantitative PCR by primers
of exon 1 CDH1 gene in patients. From the same
Middle East J Cancer 2020; 11(4): 493-501
patient, we obtained the normal sample as the
negative control for normalization. To analyze
the results, we utilized the ABI Step One Plus
(Applied Biosystems, Foster City, CA, USA)
instrument and the ΔΔCt method.
Discussion
Most GC cases are sporadic and in
approximately 10% of cases, a familial
aggregation is observed. Therefore, hereditary
GC encompasses just a minority of cases.4-6
Almost 15 to 50% of families presenting with
HDGC criteria (according to International Gastric
Cancer Linkage Consortium) presented germline
mutations in CDH1 gene.22 Until 2010, the rate
of CDH1 gene mutations in DGC was reported
25 to 50%;16 however, using updated criteria, the
rate of mutation was reduced down to 10-18%
in countries with low GC incidence.22, 23 The
HDGC incidence rate is unknown in Iran. In the
present study, we identified somatic and germline
variants in Iranian patients with HDGC in 15 of
17 (88.2%) cases. Regarding certain variants and
single nucleotide polymorphisms in CDH1 gene,
there is a correspondence between our findings
and other studies. For instance, substitutions at
position c.2076T>C (A692A), 24 c.2292C>T
(D764D), c.531+10G>C,25 and c.2439+52G>A
were previously described.26 Based on table 2,
other exonic and intronic variants marked with
an asterisk were novel in our study.
Corso et al. detected mutations in two Italian
patients with early onset DGC. In their study,
one of the mutations was missense p.Arg224Cys
and the other was a substitution -63C>A. Also,
they found five out of 21 tumors in early TNM
499
Majid Kheirollahi et al.
stage (I, II), and 15 out of 21 in the late stages
(III, IV).27 Until now, only one study has evaluated
CDH1 gene mutations in a single family with
HDGC in Iran, reporting a truncating mutation.28
We found certain substitutions, small and large
deletions in our samples located on exons 1, 3,
7, 9, 13, 14, and 15 of CDH1 gene. Bioinformatics
analysis suggested that the p.777D>E substitution
in exon 15 showed that this mutation would
negatively affect the protein function. Exon 1 of
CDH1 gene encodes the signal peptide domain
and exon 3 of this gene encodes the propeptide
of E-cadherin protein. The signal peptide domain
is necessary for the import of the protein into the
endoplasmic reticulum. Exons 7, 9, and 13 of
CDH1 gene encode the extracellular domain of
E-cadherin, essential for cell-cell adhesion;24 also,
changes in this domain can destroy the cell
adhesion. Exons 14 and 15 of CDH1 encode the
cytoplasmic domain of E-cadherin. Cytoplasmic
domain binds to β-catenin and plays a fundamental
role in tumor silencing.28 Approximately 5% of
CDH1 mutations in HDGC patients were large
deletions.17, 18 In the present study, we detected
one large deletion in exon 1 in two cases by the
MLPA technique. In 2009, Oliveira et al. identified
some large deletions in exons 1, 2, 14, 15, and
16 of CDH1 gene in HDGC families.18 In 2014,
a large genomic deletion (c.1566-?_1711+?del)
in exon 11 of the CDH1 gene in a patient with
no familial history of gastric cancer was reported;29
moreover, Molinaro et al. reported a deletion with
1642 bp length, with breakpoints in introns 6 and
8 of CDH1 gene (c.833-476_1138-463del).30
We found several intronic variants in CDH1
gene, including c.1937-58delA, c.2164+51G>A,
c.2296-48C>G, c.2296-44T>G, c.2296-22C>G,
c.2439+52G>A,
and
c.2439+105G>T.
Bioinformatics analysis by HSF showed that they
might generate new potential splice sites leading
to incorrect splicing. Further functional data is
required to reach a conclusion on the effects of
these variants.
In conclusion, our results showed that Ecadherin deficiency in HDGC is associated with
CDH1 gene point mutations and large deletions
with high heterogeneity. This should be considered
500
in the diagnosis and treatment of HDGC patients.
These results highlight the important roles of
CDH1 gene, development of molecular and
genetic testing by PCR sequencing, MLPA, and
high throughput techniques such as whole exome
sequencing and whole genome sequencing for
an early diagnosis and prevention of the potentially
lethal effects of HDGC in high risk individuals.
Acknowledgements
We sincerely thank the patients and the
professional staff of the pathology lab in Al-Zahra
Hospital (Isfahan, Iran) and Alaa Cancer Control
Center (Isfahan, Iran) for their cooperation in this
study.
Conflict of Interest
None declared.
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