1. Dr. Sherif Refaat , MSc, MD
Lecturer of medical Oncology, OCMU
Faculty of Medicine
Mansoura University
Is Angiotensin Converting Enzyme Insertion/Deletion
(rs1799752) Polymorphism Associated with Breast Cancer
Risk in Egyptian Population?
2. Background
o BC develops due to complex interactions between genetic and different risk factors.
o In Egyptian women, BC is a public health problem and is considered the most common cancer in Egyptian women and the
second largest cause of cancer death in Egyptian women.
o RAS system : regulates Na, Systemic Vascular Resistance , ECF volume and cardiovascular homeostasis
o ACE : cell surface zinc metalloenzyme dipeptidyle carboxypeptidase , it regulates tumor cell proliferation , invasion and
angiogenesis and there is over expression of ACE gene in many cancers.
o The ACE insertion/deletion (I/D) polymorphism is a nonsense and 287 bp Alu repetitive sequence of DNA in the intron 16 of
ACE gene, which represented by “Insertion” or “I”, and absence of the same denotes “Deletion” or “D”
o Thus, patients can be of three genotypes with regard to ACE, namely, II, ID and DD. Homozygotes for the D allele have the
greatest ACE plasma levels, followed by ID heterozygotes and homozygotes for the I allele.
Aim of the study
• to investigate in depth the role of the ACE I/D (rs1799752) gene polymorphism in breast cancer carcinogenesis in
Egyptian population.
3. Patients and Methods:
1- Three groups were recruited : 163 breast cancer patients (BC), 79 patients with benign breast diseases (BBD), 202
healthy controls (C).
2- Adequate tissue diagnosis and IHC and calculation of Nottingham prognostic index (NPI) for all patients
NPI= (0.2 x tumor size + node status+ grade)
3- DNA extraction and ACE (rs 1799752) gene I/D polymorphism genotyping by ARMS /PCR technique & 2nd PCR is
done for DD genotype “to avoid the common DD mistyping”.
4- statistical analysis.
.
.
4. Results:
1- Distribution of ACE I/D Genotypes (rs1799752) in
Different Studied Groups:
- No significant difference in frequencies of different
genotypes , different genetic models ( codominant ,
dominant, recessive ) and different alleles (I &D) in the
different studied groups when compared to controls or
when compared to each others (ID is the most common in
all groups)
- All the genetic models had the same OR (95 % CI) in all
groups with insignificant P value
Indicating lack of association of ACE I/D gene ploymorhism
to the development of breast cancer.
5. Results:
2-Distribution of ACE I/D Genotypes (rs1799752) in Different
Variant of BC Group:
- ID genotype→the most prevalent especially in :
• stage T2,
• N0,
• M0,
• +VE ER & PR ,
• -VE HER-2 ,
• NPI 3.4-5.4 (MPI) ,
• Right MRM.
6. Results:
3- Association of ACE I/D Genotypes (rs1799752) in
Response to Hormonal and HER-2 Status of BC Group:
- ER, PR :no significant association with with the different
genetic models of ACE I/D gene
- HER-2 and operation side : significant association with co
dominant ( II vs ID and II vs DD) and dominant models (II vs
ID +DD) with negative HER-2 and left MRM
- No significant differences were noted btween different
IHC patterns “Luminal , HER-2 enriched, TNBC “ when
compared to each others EXCEPT Co-dominant model (II vs
ID) & dominant model ( II vs ID + DD)in TNBC when
compared to luminal A .
7. 4- Distribution of ACE I/D (rs1799752)
Genotype According to NPI in BC Group :
- No significant difference in NPI with
different ER, PR status , but significant
increase in NPI in HER-2 +ve patients.
- No significant difference in different ACE
genotypes in each NPI groups .
5- Distribution of ACE I/D (rs1799752)
GENOTYPE ACCORDING to METASTASIS in
BC Group:
ID genotype is the most prevalent genotype
Bone mets was the most common.
8. Discussion:
- RAS stimulation : directly and indirectly stimulates angiogenesis (may be related to cancer development )
ACE gene I/D polymorphism was found in many types of cancer
- Analysis of ACE I/D polymorphism : showed the same frequencies of different genotypes , alleles as well as different genetic
models ( most predominant was ID 75% in all groups) indicating lack of association to breast cancer risk
- Previous studies showed similar results while others suggested that it is linked to increased BC risk “ so larger samples and more
ethnic groups should be included in future studies”.
- Our study showed that ID genotype was the most predominant with different BC variants while Brasilians found that DD
genotype is the most predominant “but may be because they didn’t perform 2nd PCR to differentiate the mistyping of of DD
genotype.
- No association of ACE I/D gene polymorphism to ER, PR but significant association of the codominant and dominant models to
HER-2 –ve , and when TNBC is compared to Luminal A , confirming the association of ID genotype with aggressiveness of BC.
- NPI : significant difference in NPI in response to HER-2 in ID genotype “confirming again association of ID with aggressiveness”.,
but no previous studies showed the same results.
- Metastasis : most metastatic patients were of ID genotype.
9. Conclusion:
.
- The study demonstrated no association in BC group in response to DD genotype or D allele of ACE I/D (rs1799752)
polymorphism when compared to either BBD or control group.
- The ID genotype was significantly correlated with the aggressiveness of BC, suggesting its role in the pathogenesis of
BC.
- This study confirm also that ID genotype have association with NPI, Her2/neu expression marker and metastatic
distribution in BC patient.
- ACE I/D (rs1799752) polymorphism ID genotype have strong association to breast cancer carcinogenesis, poor
prognosis and metastasis. It may be used as practical biomarker to guide the BC carcinogenesis and risk process. This
may explain the high incidence of breast cancer in Egyptian population as it possesses the highest frequency for ACE
I/D (rs1799752) genotypes .