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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 3  |  Page : 121-130

Expression of tissue PSA in breast cancer is associated with less aggressive disease and lower chance of tumor relapse


1 Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, UAE
2 College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
3 Woman’s Breast Health Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada
4 Iraqi Board for Medical Specialization, Iraq

Date of Submission08-Mar-2022
Date of Decision04-Apr-2022
Date of Acceptance13-Apr-2022
Date of Web Publication27-Jun-2022

Correspondence Address:
Ibrahim Yaseen Hachim
Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah
UAE
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/abhs.abhs_18_22

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  Abstract 

Background: Human kallikrein 3 (hK3), also known as Prostatic specific antigen (PSA), was considered as one of the most useful markers for the detection as well as management of prostate cancer. While PSA was thought to be a prostatic tissue-specific protein, many reports suggest the presence of extraprostatic PSA in different tissues, including the breast. Few reports showed PSA immunoreactivity in breast cancer tissues and suggest a favorable prognostic role of PSA in breast cancer. However, most of those studies were not conclusive or restricted to small scale studies limiting their clinical significance. Methods: We used a bioinformatical approach to investigate the association between tissue PSA expression levels and different clinicopathological parameters in breast cancer using different publicly available databases. Further validation was done using our patient cohort of 40 surgical breast samples obtained from patients attending Al Kadhemyia Teaching Hospital – Iraq. Results: Using a cohort of 593 breast lesion samples extracted from the TCGA database using the ONCOMINE database, our results showed no significant upregulation of PSA mRNA levels in breast cancer samples compared to healthy tissue (P = 0.1). The same trend was also observed in our patient cohort with positive immunoreactivity in 50% (5 samples) of benign lesions compared to 36.66% (11 samples) in breast cancer samples. In addition, investigating the correlation between mRNA PSA expression and different clinicopathological parameters using the Breast Cancer Gene-Expression Miner v4.0 database and ONCOMINE databases, revealed a significant association between PSA expression and tumor grade (P = 0.0001), breast cancer subtype (P < 0.0001), in addition to early-stage disease presented as smaller tumor size and absence of LN involvement. The same trend confirmed with our patient cohort. Moreover, our analysis using KM plotter (4000 breast cancer samples) showed a significant association between higher PSA mRNA levels and favorable patient outcomes presented as prolonged relapse-free survival (RFS) (P < 0.0001). Conclusions: Our results clearly demonstrate the possibility of using tissue mRNA and protein levels of PSA as a marker to identify patients with a favorable outcome and lower risk of tumor recurrence. Our results also highlight the need for more efforts to investigate the biological role of PSA in breast cancer.

Keywords: Biomarkers, breast cancer, PSA


How to cite this article:
Hachim IY, Hachim MY, López-Ozuna VM, Al-Hadithi RH. Expression of tissue PSA in breast cancer is associated with less aggressive disease and lower chance of tumor relapse. Adv Biomed Health Sci 2022;1:121-30

How to cite this URL:
Hachim IY, Hachim MY, López-Ozuna VM, Al-Hadithi RH. Expression of tissue PSA in breast cancer is associated with less aggressive disease and lower chance of tumor relapse. Adv Biomed Health Sci [serial online] 2022 [cited 2022 Dec 3];1:121-30. Available from: http://www.abhsjournal.net/text.asp?2022/1/3/121/348431




  Background Top


The human kallikreins are a big family that consists of 15 secreted serine proteases. Each member of this family responsible for encoding a serine protease that is translated as pre-proenzymes with a trypsin-like or chymotrypsin-like activity [1]. One of the most well-known members of this family is kallikrein 3 (KLK3), which is considered as one of the most important tumor markers used in clinical practice [2]. Indeed, KLK3, which is also known as the prostate-specific antigen (PSA) is widely used for prostatic cancer detection, patient stratification as well as follow up [2]. While PSA was thought to be a prostatic tissue-specific protein, more recent reports demonstrated the presence of PSA immunoreactivity in many other tissues [3]. This includes hormonally regulated females tissue, including the breast. Indeed, one study highlights the presence of detectable PSA concentration in >50% of female sera. Moreover, PSA was also detectable in around 70% of breast cancer cytosolic extracts [4]. Breast PSA was found in 73% of tumor extracts, in the milk of lactating women and in nipple aspirates. The PSA expression in female breast tissue was found to be regulated by other steroid hormones including androgen and progestin, but not estrogens [5]. For that reason it was suggested that PSA can be used as a marker of endogenous hormone balance between androgens, progesterone, and estrogens [6]. Several functions was suggested for PSA in breast tissue including the modulation of growth factors as well as translational/post-transcriptional protein regulator. In addition, it was found that PSA stimulates oestradiol conversion to oestrone and the hydrolysis of fibronectin, insulin chains as well as extracellular matrix laminin. Other properties of PSA includes the enzymatical digestion of insulin-like growth factor binding proteins, parathyroid hormone-related protein bioactivity regulation as well as the digestion of plasminogen and the release of angiostatin-like fragments [7,8].

In addition to normal tissues, reports also found PSA to be also expressed with a hormone-dependent manner in a number of human breast cancer cell lines [5,9]. Moreover, the total and free serum PSA was found to be higher in patients with breast cancer compared to benign lesions [10],[11],[12]. Tissue PSA was also found to be expressed in a group of tumors, including colon, ovarian, liver, kidney, as well as breast cancer [13]. The tissue PSA was suggested as a potential prognostic marker in breast cancer [14]. Interestingly, while some reports showed that PSA expression to be associated with favorable clinicopathological parameters including smaller size and positive hormonal status, [6, 14, 15] other report showed that PSA expression might be a marker of poor patient outcome, in addition to poor response to tamoxifen therapy in a patient with recurrent breast cancer [16].

Those controversies that was observed in the different reports might be attributed to the fact that most of those studies were restricted to small scale studies, which might affect their clinical significance. For that reason, here, we used a combined approach that consists of in silico approach to investigates the gene expression levels of tissue PSA in thousands of breast cancer samples using a group of publicly available databases. Our results provide evidence that tissue PSA to be a marker of less aggressive phenotype and less advanced disease. Moreover, we also showed that higher expression levels of tissue PSA to be associate with a lower chance of tumor recurrence. We next verified ours in silico obtained finding using our patient’s cohort consist of 40 breast lesion samples using immunohistochemistry.


  Materials and methods Top


In silico analysis

Different dataset of the large publicly available ONCOMINE database was used [17]. Indeed, this database is regarded as the largest cancer microarray database. It contains 65 gene expression dataset that allows the researchers to investigate the association between gene expression levels and different parameters. This includes the Ramaswamy multi-cancer database (218 samples), TCGA (593 samples) as well as Curtis (2000 samples) and Hartiz dataset (508). The different datasets of the ONCOMINE database were used to investigate the gene expression levels of PSA in different cancers as well as normal versus breast cancer samples. In addition, we also used this database to investigate the association between tissue gene expression levels of PSA and different clinicopathological parameters, including tumor size and stage.

We also used The Breast Cancer Gene-Expression Miner v4.0 database, which is another publicly available database.[6] This database allows us to investigate the association between tissue PSA gene expression levels and different clinicopathological and molecular parameters in around 5000 breast cancer samples.

Besides, we used KM plotter database [18] (http://kmplot.com/analysis/) that includes another 5000 patients samples to investigate the association between PSA expression levels and patient outcomes presented as relapse-free survival (RFS).

Patients cohort

Forty surgical breast biopsies from females attending the surgical department of Al Kadhymiah Teaching Hospital for the period from April 2004 to April 2005 were included.

The biopsies include cases of benign lesions (fibroadenoma and fibrocystic disease) and malignant lesions (in situ ductal carcinoma, invasive ductal carcinoma, in situ lobular carcinoma, invasive lobular carcinoma). Clinical information regarding age, tumor size, and lymph node involvement were obtained from the available histological reports [Supplemental Table 1]].
Supplemental Table 1: The clinicopathological features of our patient’s cohort

Click here to view


For each biopsy, one representative section was stained with H and E, and two other slides were stained immunohistochemically for PSA. H and E stained sections were examined to define the type of tumor, histological grading, vascular invasion, and lymphocytic infiltration.

Immunohistochemistry procedure

We used the Universal DAKO Labeled Streptavidin Biotin for immunohistochemistry visualization. In summary, the slides were deparaffinized and rehydrated using a serial dilution of alcohol (95%,80%, 70% alcohol). Next, the endogenous peroxidase was blocked by incubating sections with peroxidase blocking solution (3%H2O2) for 10 minutes at room temperature. After that, sections were incubated in a humid chamber after covering the tissue with sufficient amount of ready to use universal block solution (Power BlockTM Universal Blocking Reagent, Biogenix, HK083-50K) for 10 minutes, then drained and blotted without washing. Stock monoclonal antibody was diluted properly (1/100 for PSA- Mouse Anti-PSA Phosphatase, MU013-UC, Biogenix) then 100 µl was added to each slide. After that, the slides were left in a humid chamber and kept in the refrigerator with 4Co overnight. Then the slides were rinsed in washing buffer (PBS,0.02M phosphate-buffered saline) for 2 minutes twice and carefully drained and blotted. The secondary biotinylated antibodies (dilution 1/100) were added in an amount that covers the slides sections, then incubated for 30 minutes. After that, drops of the conjugate were added, and the slides were left in a humid chamber for 30 minutes at incubator with shaking, the temperature was kept on 37Co. Then the slides were rinsed in washing buffer for 2 minutes twice and carefully drained and blotted. After that, cases stained with DAB or Alkaline phosphatase and slides were observed under a light microscope.

Immunohistochemistry scoring

The staining intensity was classified into four categories using the semiquantitative method. Cases with no immunoreactivity were scored 0, with weak stain were classified as +1, moderate staining were considered +2, and strong immunoreactivity were considered +3. Due to the low number of cases, both 0 and +1 stain were combined as negative, and +2 and+3 were combined and considered positive.

Statistical analysis

For graphs with a box plot that was obtained from ONCOMINE database, the band inside the box represents the median, while the top and bottom of the boxes represent the 25th percentile and 75th percentile. P-value was automatically calculated using a t-test. T-tests were conducted both as two-sided for differential expression analysis and one-sided for specific overexpression analysis. Regarding data obtained from the breast cancer miner database, the data was presented as box and whisker plots. In addition, and to investigate the association between KLK3 gene expression levels and tumor grade, molecular subtype, and age, a Welch’s test as well as Dunnett-Tukey-Kramer’s tests were used.

For our patient’s cohort, data analysis was done using the chi-square test. P-value of ≤ 0.05 was used as the level of significance using the SPSS (Statistical Package for the Social Science; SPSS Inc, Chicago, Illinois, version 21)

Descriptive statistics for the clinical features of the patients were done using the range, mean, and standard deviation (SD).


  Results Top


PSA mRNA expression levels are comparable in normal versus malignant breast cancer samples

Due to the fact that most of the previous reports evaluating PSA levels in prostatic cancer and only limited studies investigating its expression in breast cancer, we initially investigated the tissue mRNA expression of PSA in breast cancer samples compared to prostatic cancer samples using the Ramaswamy Multi-cancer dataset of the ONCOMINE database [[Figure 1] A left panel]. As expected, while tissue PSA mRNA levels were highest in samples obtained from patients with prostatic cancer, breast carcinoma samples showed significant lower levels of the tissue PSA. The median expression of cases with prostatic carcinoma was 8.683 (range 8.581to 9.148) compared to -0.874 in breast cancer cases. (range -5.426 to 3.931) [[Figure 1] A right panel].
Figure 1: The association between PSA (KLK3) gene expression levels and different clinicopathological parameters using different publicly available databases. A) The mRNA expression of PSA (KLK3) in breast cancer compared to prostatic cancer using the Ramaswamy multi-cancer dataset of the ONCOMINE database (left panel).The expression levels of KLK3 in breast cancer samples compared to breast cancer samples (Maximum, median, minimum, 25th percentile, as well as 75th percentile)(right panel). B) The mRNA expression of PSA (KLK3) in normal tissue compared to breast cancer patients’ samples using TCGA dataset of ONCOMINE database. The expression levels of KLK3 in breast cancer samples compared to normal tissue (Maximum, median, minimum, 25th percentile as well as 75th percentile)(right panel). C) PSA (KLK3) mRNA levels and their association with tumor grade using bc-GenExMiner 4.0 database. Data presented as box and whisker plots. A Welch’s test, as well as Dunnett-Tukey-Kramer’s tests, were used to investigate the level of significance between the different groups. D) PSA (KLK3) mRNA levels and their association with breast cancer molecular subtypes (RMSPC classification) using bc-GenExMiner 4.0 database. Data presented as box and whisker plots. A Welch’s test, as well as Dunnett-Tukey-Kramer’s tests, were used to investigate the level of significance between the different groups. E) PSA (KLK3) mRNA levels and their association with patients age using the bc-GenExMiner 4.0 database. Data presented as box and whisker plots. A Welch’s test, as well as Dunnett-Tukey-Kramer’s tests, were used to investigate the level of significance between the different groups.

Click here to view


Next, we investigated the expression levels of tissue PSA in normal breast tissue compared to breast cancer samples using 593 breast samples extracted from the TCGA database using the ONCOMINE database. Our results showed no significant difference of tissue PSA expression in breast cancer samples compared to normal tissue (P = 0.1) [[Figure 1] B left panel]. Indeed, the median expression of normal tissues was 0.456 (range -2.57 to 7.63) compared to 0.799 in samples from breast cancer samples (range -2.123 to 3.65) [[Figure 1] B right panel].

PSA mRNA expression is significantly associated with more differentiated tumors and less aggressive breast cancer subtypes

We also evaluated the association between tissue PSA mRNA expression and tumor grade in 7000 breast cancer samples using the breast cancer miner database. Our results showed that PSA expression is significantly associated with more differentiated tumors compared to poorly differentiated tumors (P = 0.0001) [Figure 1C]. Next, we investigated the expression levels of tissue PSA in different breast cancer subtypes. Our results showed tissue PSA mRNA levels to be highest in the more differentiated and less aggressive luminal A breast cancer subtype and least in other more aggressive molecular subtypes, including luminal B, HER-2, and basal-like breast cancer subtypes [Figure 1D]. Moreover, our results also showed PSA mRNA to be associated with the younger age group (<40) and age group (41–69) compared to the elder age group (≥70) (P = 0.0158) [Figure 1E].

PSA mRNA expression is downregulated in the more advanced breast cancer samples compared to early carcinomas

Next, we investigated the expression levels of tissue PSA DNA copy number in association with tumor stage using Curtis 2 Database (1992 patients) [Figure 2]A. Our data showed that PSA expression levels to be reduced during tumor progression. Indeed PSA DNA copy numbers were highest in early stages (stage 0, I, and II) compared to more advanced stage III and IV. Similarly, data from the Hatzis database that investigated the mRNA levels, also showed tissue PSA mRNA levels to be downregulated in more advanced stages (IIIB and III C) compared to early stage tumors [Figure 2]B.
Figure 2: The association between PSA (KLK3) gene expression levels and tumor progression. (A) The PSA (KLK3) gene copy number in different tumor stages using Curtis dataset of ONCOMINE database. (B) The PSA (KLK3) mRNA expression level in different tumor stages using Hatzis dataset of ONCOMINE database. (C) PSA (KLK3) mRNA levels and their association with LN involvement using bc-GenExMiner 4.0 database. (D) The PSA (KLK3) mRNA expression level in different tumor sizes using the Hatzis dataset of ONCOMINE database.

Click here to view


Next, we investigate the association between tumor size and LN involvement using a cohort of more than 7000 breast cancer samples. Our results showed tissue PSA mRNA expression to be significantly downregulated in tumors with LN involvement compared LN negative tumors (P = 0.008) [Figure 2]C. The same trend was also observed with tumor size, when tumors with larger tumor size (T2, T3and4) showed lower PSA tissue mRNA expression compared w to small tumors (<2 cm) [Figure 2]D.

PSA mRNA expression is a marker of a favorable outcome in breast cancer patients’ samples

To further evaluate the prognostic value of tissue PSA mRNA expression, next, we evaluated the association between PSA m RNA levels and patient outcome presented as relapse-free survival (RFS) using 3409 patients’ sample from the KM plotter database. Interestingly, patients with higher PSA mRNA expression showed better outcomes presented as prolonged RFS compared with patients with lower PSA levels, which showed shortened RFS [Figure 3]A and [Supplemental Figure 1]. Moreover, further stratification of patients into molecular subtypes also revealed that, while it does not reach to statistical significant, patients with higher PSA mRNA expression showed a trend of prolonged RFS in all breast cancer molecular subtypes [Figure 3B]-[E].
Figure 3: The association between PSA (KLK3) gene expression levels and patient outcome presented as relapse-free survival (RFS) using KM plotter database. (A) The PSA (KLK3) gene expression level and its association with patient outcome in all patients samples. (B-E) The PSA (KLK3) gene expression level and its association with patient outcome in different breast cancer subtypes.

Click here to view
Supplemental Figure 1: PSA (KLK3) gene expression levels in different clinical subgroups and its association with patient outcome presented as relapse-free survival (RFS) using KM plotter database. (A) The PSA (KLK3) gene expression level and its association with patient outcome in LN negative and LN positive patients samples. (B) The PSA (KLK3) gene expression level and its association with patient outcome in different grade.

Click here to view


Tissue PSA protein levels are downregulated in breast cancer samples compared to normal/benign breast lesions

To validate our results obtained through our bioinformatical approach, we next evaluated the protein expression levels of tissue PSA in a cohort of 40 surgical breast biopsies obtained from our own patient cohort [Figure 4]. Our results showed that tissue PSA expression to be lower in breast cancer samples (36.6%) compared to benign/normal samples (50%) [Table 1]. The localization of tissue PSA was cytoplasmic and mainly in the luminal layer in both benign and malignant samples [Figure 4].
Figure 4: The immunohistochemical expression of PSA in benign breast lesion as well as breast cancer samples (A) Benign breast lesion (fibrocystic disease) with positive immunohistochemistry staining (DAP stain) for PSA (brown cytoplasmic staining) X400. (B)Invasive lobular carcinoma with negative immunohistochemical staining for PSA X400. (C) Invasive lobular carcinoma showed positive immunohistochemical staining (alkaline phosphatase stain) for PSA (red cytoplasmic staining) X400. (D) Invasive ductal carcinoma showed positive immunohistochemical staining (alkaline phosphatase stain) for PSA (red cytoplasmic staining) X400.

Click here to view
Table 1: PSA expression and its association with different clinic-pathological parameters.

Click here to view


Moreover, our results also showed minimal difference in the tissue PSA protein expression in the lobular breast cancer (42.85%) compared to the ductal carcinomas (34.78%). In addition, positive PSA expression was double (57.15%) in younger age group (<40) compared to 30% in patients older than 55 years [Table 1].

PSA protein expression is associated with more differentiated tumors and less advance disease

Our results also showed that tissue PSA expression was higher in grade I-II (44%) compared to only 25% in the poorly differentiated grade III. Moreover, our results also showed that PSA protein expression to be higher (47.3%) in smaller size tumor (<5) compared to 33.3% in the larger tumor sizes. Furthermore, our results also showed PSA levels to be more expressed in the LN negative tumors (46.1%) compared to LN positive tumors (29.5%) [Table 1].


  Discussion Top


The prognostic role of tissue PSA in breast cancer is not fully established. This can be attributed to the variability of the techniques and methods used to investigate PSA expression. In addition to the fact that most of those reports were small to mid-scale reports that might affect the clinical value of those reports [19],[20],[21]. For that reason, here, we used a combined approach to investigate the prognostic value of tissue PSA protein and gene expression levels in breast cancer. Indeed, the use of around 5000 breast cancer samples from the different publicly available databases made this study one of the largest studies to investigate the prognostic role of tissue PSA in breast cancer and its possible use as a potential biomarker in the future.

Our results demonstrate that there was no upregulation of PSA mRNA expression levels in breast cancer samples compared to normal. Moreover, our results also showed that PSA levels in breast cancer is the least compared to other cancers in the body. These results were further confirmed in our patient cohort that showed PSA protein expression to be downregulated in breast cancer samples compared to benign. Our results here are similar to previous reports that showed PSA as well as other kallikreins to be downregulated in breast cancer samples [21],[22],[23],[24].

Our results showed a significant association between tissue PSA expression and less aggressive phenotype. Indeed, tissue PSA mRNA levels, as well as protein levels, were found to be associated with more differentiated tumors compared to less differentiated tumors. The association between PSA tissue expression and low-grade tumors was previously reported in a group of reports [25],[26],[27].

According to our knowledge, this is the first study that investigates the association between tissue PSA expression and different breast cancer subtype. As expected, our results showed higher level of tissue PSA expression in the least aggressive luminal A subtype, usually characterized by ER and/or PR positivity. This result goes with the previous literature that shows a possible correlation between PSA expression and both ER and PR [20, 28, 29]. The association was found to be stronger between PSA and progesterone expression [9]. The association between PSA and hormone receptors was also confirmed at the molecular levels. In luminal breast cancer cell lines, PSA production was found to be regulated by a group of hormones, including progesterone, androgens, mineral corticoids as well as glucocorticoids [5]. The strong association and regulation of KLK3 gene by androgen receptor highlight the possible use of PSA as a marker of AR signaling or AR dependency. Moreover, the wide use of PSA in other cancers and the familiarity of pathologists in the clinical practice of PSA scoring highlight the possible use of tissue PSA as a simple and clinically relevant predictive marker for AR-targeting therapy response in breast cancer.

Moreover, our results also showed that higher tissue mRNA as well as protein PSA levels to be associated with smaller tumor size and early tumor stage and LN negative tumors. Those findings are also in agreement with other reports that showed PSA expression to be inversely correlated with larger tumor size, tumor stage, as well as LN involvement [25]. Similarly, Sauter et al. also showed PSA expression in nipple aspirates to be associated with a lower risk of breast cancer and its expression to be reduced with more advanced disease including higher stage, larger tumor size, and LN positivity.

Our results are in disagreement with Mohammadizadeh et al. study [30] that showed no significant association between PSA expression and all the prognostic parameter in patients with invasive breast carcinoma. This might be attributed to the difference in sample size as in Mohammadizadeh et al. study, the patient cohort consists of 100 patients, while in our study we used a combined approach that includes patients cohort as well as information from publicly available databases that includes thousands of breast cancer samples.

The association between higher PSA levels and prolonged patients’ survival, as well as lower chance of tumor relapse clearly demonstrated the ability of the use of tissue PSA expression as a prognostic biomarker in breast cancer patients. Many explanations were proposed to explain the favorable prognostic role of PSA in breast cancer. Indeed, PSA was found to reduce breast cancer cell lines growth through the conversion of estradiol to the less potent estrone [31]. Another explanation is that the presence of PSA in breast cancer tissue might reflect the existence of a complete hormone receptor pathway, usually associated with better prognosis [32]. In addition, it was also found that PSA might have anti-angiogenic properties though the suppression of the endothelial cell response to some angiogenic factors including fibroblast growth factor-2 and vascular endothelial growth factor [33].


  Conclusion Top


In conclusion, our results showed tissue PSA as a marker of a less aggressive phenotype. In addition, PSA expression levels was found to be associated with less advanced disease shown as early stage, negative LN involvement and smaller tumor size. Moreover, higher PSA expression levels was found to be significantly associated with lower cancer of tumor relapse. All this together highlight the possible use of tissue PSA levels as a potential marker of favorable prognosis and it might help to identify a group of patients with lower risk of tumor relapse.

Study limitations

Further studies are needed to investigate the biological role of PSA in breast cancer as well as other cancers which might revealed a novel roles and mechanisms through which PSA might exert its functions.

Author contributions

Conceptualization, I.Y.H. and R.H.M.A; Methodology, I.Y.H, V.M.L.-O; Software, M.Y.H; Validation, I.Y.H., M.Y.H. and V.M.L.-O; Formal analysis, I.Y.H., M.Y.H..; Investigation, I.Y.H., M.Y.H. and V.M.L.-O.; Resources, I.Y.H. and R.H.M.A; Data curation, I.Y.H., M.Y.H. and V.M.L.-O; writing—original draft preparation, I.Y.H.; Writing—review and editing, I.Y.H., M.Y.H. and V.M.L.-O.; Visualization, I.Y.H., M.Y.H. and V.M.L.-O.; Supervision, I.Y.H. and R.H.M.A; Project administration, I.Y.H..; Funding acquisition, I.Y.H

Ethical statement

We obtained Approval from College of Medicine-Al Nahrain University for the cases obtained from Al Kadhymiah Teaching Hospital. The in silico portion of the study is exempted from Ethical approval since we don’t use any human or animal subjects.

Financial support and sponsorship

The work did not require funding grant.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

All the original contributions presented in this manuscript are included in the article.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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