O R I G I N A L P A P E R
ABO blood groups in relation to breast carcinoma incidence and associated prognostic factors in Moroccan women
S. Zouine1,2• F. Marnissi3•N. Otmani4•M. Bennani Othmani4•M. El Wafi1,2 • K. Kojok5• Y. Zaid5•N. Tahiri Jouti6•N. Habti1,2
Received: 7 May 2016 / Accepted: 23 May 2016 ÓSpringer Science+Business Media New York 2016
Abstract The association between blood groups ABO and different types of diseases was established in several previous studies. Our aim was to seek the possible asso- ciation between the ABO blood group and breast cancer- associated prognostic factors. The Chi-squared analytic test was used to compare phenotypic ABO distribution among Moroccan blood donors and 442 cases of women suffering from breast carcinoma with archived files in Maternity Ward of University Hospital C.H.U Ibn Rochd between 2008 and 2011. High incidence of breast carci- noma was observed in blood type B patients (p\0.05).
Blood type B was associated with breast carcinomas overexpressing human epidermal growth factor receptor HER2 (p\0.05) and high risk of cancer at age over 70 years (p\0.001). Blood type A was associated with high risk of cancer among women younger than 35 years
old. Blood type A and AB were associated with high incidence of lymph node metastasis (p\0.05). Multi- variate analysis has shown correlation between O blood type and estrogen receptor-positive tumor. Patients with blood group A, B, and AB were more likely to develop aggressive breast carcinoma. Further follow-up studies are necessary to clarify the role of ABH antigens in the progression of breast carcinoma.
Keywords ABO blood groupBreast carcinomaAge at diagnosisHuman epidermal growth factor receptor 2 Lymph node metastasisEstrogen receptor
Abbreviations
CHU Centre Hospitalier Universitaire ER Estrogen receptor
& S. Zouine
soukaina.zouine@gmail.com F. Marnissi
faridamarnissi@hotmail.fr N. Otmani
nada.oudidi@gmail.com M. Bennani Othmani bennanim2000@gmail.com M. El Wafi
mariam.benabdeljalil@gmail.com K. Kojok
kevinkojok@outlook.com Y. Zaid
younes.zaid@umontreal.ca N. Tahiri Jouti
nadiatahiri19@gmail.com N. Habti
norhabti@yahoo.fr
1 Laboratory of Biotechnology and Experimental Medicine, Faculty of Medicine and Pharmacy Casablanca, Hassan II University of Casablanca, 19 Rue Tarik Ibnou Ziad, B.P. 9154, 20000 Casablanca, Morocco
2 Laboratory of Hematology, Cellular and Genetic
Engineering, Faculty of Medicine and Pharmacy Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
3 Pathology Department, University Hospital Ibn Rochd Casablanca, Casablanca, Morocco
4 Laboratory of Medical Informatics, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
5 Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montreal, QC, Canada
6 Pathology Laboratory, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
DOI 10.1007/s12032-016-0784-2
HER2 Human epidermal growth factor receptor 2 PR Progesterone receptor
SBR Scraff Bloom and Richardson histological grading
SICAM-1 Soluble intercellular adhesion molecule-1 SNP Single nucleotide polymorphism
TNF-a Tumor necrosis factor-alpha VWF Von Willebrand factor
Introduction
Blood group antigens were originally identified on red blood cells in 1900 by Karl Landsteiner. Later, through the use of monoclonal antibodies, these antigens were also found on the surface of other cells such as endothelial and epithelial cells and in various body fluids and secretions. It became clear that the ABO system belongs to the tissue system, hence the name ‘‘histo-blood group system.’’ The blood group antigens are an extra-cytoplasmic saccharide portion which confers them specificity of the cell [1]. These antigens linked to sphingolipids form glycolipids that are found on the surface of red blood cells and epithelial cells of all organs. When linked to polypeptide chains, they emerge as free glycoproteins found in a plethora of liquid secretions (saliva, tears, breast milk, etc) [2]. The synthesis of ABH molecules involves the ABO gene encoding glycosyltrans- ferases specific to the substrate [3,4]. ABO gene spans over 18 kb of genomic DNA. It is located on 9q34 region, in which the genetic modification is common to several can- cers derived from epithelial cells [5–7].
Since 1950, numerous studies have reported a relation- ship between the distribution of ABO blood group and risk and poor prognosis of cancer. The explanation would be disorders of the mechanisms related to cell signaling, intercellular adhesion, and inflammation [8–10].
The distribution of ABO blood groups varies in different geographical and ethnic groups. In Morocco, we have reported that the frequencies of blood types are: O=46.05 %;
A=33.89 %; B=15.08 %; and AB=4.33 % [11].
Breast cancer is a heterogeneous malignant tumor, most commonly diagnosed among women. Indeed, it is the leading cause of cancer death with over 400,000 deaths annually worldwide [12,13].
The aim of this study is to seek the association between the ABO blood groups, breast cancer incidence, and dif- ferent breast cancer-associated prognostic factors.
Ethical statement
The study was evaluated and approved by the Ethic Committee for Biomedical Research of Rabat (CERBR) of
the Faculty of Sciences, Rabat-University Mohammed V (No. Fsr-umv-1214-93). Patient’s data were collected anonymously according to declaration of Helsinki.
Materials and methods
The retrospective study included 954 patients who were diagnosed with breast diseases between 2008 and 2011.
The clinical and histopathological data were collected anonymously from Department of Pathology University Hospital C.H.U. Ibn Rochd in Casablanca. These data included age at diagnosis, subtypes of breast cancer, tumor size, histological grade according to modified Scraff Bloom and Richardson grading, estrogen and progesterone recep- tor status, HER2, and lymph node metastasis status. The ABO blood group was collected from Department of Maternity C.H.U Ibn Rochd. The criteria for inclusion in the study were mainly the ABO blood group and the malignancy of the tumor.
The comparison of the ABO phenotypic distribution among blood donors and women suffering from breast carcinoma was performed by a bivariate analysis, using the conventional parametric test Chi-squared and Statistical Package for the Social Sciences software (SPSS version 17.0). A multivariate logistic regression analysis was employed to estimate the impact of non-O blood group (combined group A, B, and AB) versus blood group O, on breast carcinoma and its prognostic factors. Odds ratios with 95 % of confidence intervals were calculated.
Results
Among 954 cases, only 442 met our criteria for inclusion in the study. Table 1 shows the clinical and anatomopatho- logical characteristics of 442 patients. 85.33 % of carci- nomas were infiltrating ductal and 6.25 % infiltrating lobular and 2.16 % were in situ ductal type. The remaining were mixed carcinomas, medullary, mucinous, and meta- plastic. The average age was 49.29 years.
The frequency of blood group B in the population affected by breast carcinoma (19.91 %) was greater than in blood donor population (15.08 %). This difference is sta- tistically significant (p\0.05) (Table 2). The percentage of young patients (B35 years old) is greater among blood group A patients than among patients with blood groups O, B, or AB (p\0.05). The percentage of old patients (C70 years old) is higher among B blood group patients than among other blood groups patients (p\0.001) (Fig.1). No difference was observed between histological tumor grade SBR and ABO blood group. The frequency of breast carcinoma overexpressing HER2 is higher in
patients with blood group B compared with patients blood type A and AB taking together, and blood group O (p\0.05) (Fig.2). Blood type A and AB are more likely to develop lymph node metastasis than blood type B and blood type O. A statistically significant association between blood type A and AB and the presence of involved nodes was noted (p\0.05) (Fig.3). No association was observed between ABO blood group and the number of involved nodes. The distribution of ABO blood group is independent of tumor size, status of estrogen and proges- terone receptors, and incidence of carcinomas triple nega- tive. In multivariate models, O blood group was associated with estrogen receptor-positive tumors (p\0.05; OR 3.104; 95 % CI 1.011–9.533). No statistically significant
associations were observed between non-O blood group versus O blood group and other prognostic factors.
Discussion
Our study showed a high frequency of blood group B in the population of patients with breast carcinoma compared to the population of blood donors. The frequency of blood group O, A, and AB was statistically not different in the two populations. Our results are consistent with several studies that have reported a strong association between blood group B and the risk of various cancers, including pancreatic, ovarian, breast cancer, and others [14–16].
Table 1 Anatomopathological features of 442 patients according to ABO blood groups Patient characteristics Blood group
O A B AB
Age (years) 48.34 (28–76) 48.62 (22–91) 52.74 (29–90) 48.56 (33–66)
Histological type
Infiltrating ductal carcinoma 167 (80.68 %) 110 (83.97 %) 66 (75.00 %) 12 (75.00 %)
Infiltrating lobular carcinoma 10 (4.83 %) 6 (4.58 %) 7 (7.95 %) 3 (18.75 %)
Others 30 (14.49 %) 15 (11.45 %) 15 (17.05 %) 1 (6.25 %)
Tumor size
B2 cm 34 (16.43 %) 29 (22.14 %) 11 (12.50 %) 2 (12.50 %)
[2 cm 110 (53.14 %) 54 (41.22 %) 45 (51.14 %) 10 (62.50 %)
Missing 63 (30.43 %) 48 (36.64 %) 32 (36.36 %) 4 (25.00 %)
Tumor grade
SBR I 22 (10.63 %) 12 (9.16 %) 10 (11.36 %) 2 (12.50 %)
SBR II 78 (37.68 %) 65 (49.62 %) 32 (36.36 %) 9 (56.25 %)
SBR III 70 (33.82 %) 30 (22.90 %) 28 (31.82 %) 2 (12.50 %)
Missing 37 (17.87 %) 24 (18.32 %) 18 (20.46 %) 3 (18.75 %)
Status HER2?
Positive 24 (11.59 %) 9 (6.87 %) 16 (18.18 %) 0 (0.00 %)
Negative 93 (44.93 %) 57 (43.51 %) 34 (38.64 %) 6 (37.50 %)
Missing 90 (43.48 %) 65 (49.62 %) 38 (43.18 %) 10 (62.50 %)
Status RE
Positive 87 (42.03 %) 42 (32.06 %) 33 (37.50 %) 9 (56.25 %)
Negative 34 (16.42 %) 25 (19.08 %) 17 (19.32 %) 2 (12.50 %)
Missing 86 (41.55 %) 64 (48.86 %) 38 (43.18 %) 5 (31.25 %)
Status RP
Positive 56 (27.05 %) 37 (28.24 %) 25 (28.41 %) 7 (43.75 %)
Negative 65 (31.40 %) 30 (22.90 %) 25 (28.41 %) 4 (25.00 %)
Missing 86 (41.55 %) 64 (48.86 %) 38 (43.18 %) 5 (31.25 %)
Lymph node status
Positive 73 (35.27 %) 51 (38.93 %) 28 (31.82 %) 10 (62.50 %)
Negative 27 (13.04 %) 7 (5.34 %) 10 (11.36 %) 1 (6.25 %)
Missing 107 (51.69 %) 73 (55.73 %) 50 (56.82 %) 5 (31.25 %)
Total 207 (46.83 %) 131 (29.64 %) 88 (19.91 %) 16 (3.62 %)
Other studies have suggested that individuals with blood group A has a significantly higher risk of developing cancer and that individuals with non-O blood group
showed a significant increased risk of overall cancer with a low survival rate [17–31]. However, some works in dif- ferent people and ethnic groups have reported that there is no correlation between ABO blood group and cancer [32–40]. We also report a high incidence of breast carci- noma among very young women with blood group A and among the blood group B patients aged over 70 years.
Unlike the cohort conducted by Klimant et al. [41]
reporting no difference between the distribution of ABO blood group and HER2 status, the analysis of our results revealed an association between blood type B and HER2 overexpression. The HER2 tumor is characterized by high rates of cell division, invasiveness, a greater metastatic potential, and a strong aggression [42]. Blood group B patients would develop more aggressive malignancy than patients with non-B blood group. This hypothesis is sup- ported by the results of Holdsworth et al. [43] showing a high risk of death among breast cancer patients with blood group B or AB. The analysis of the frequency of occur- rence of lymph node metastasis—another prognostic fac- tor—showed higher frequency among the blood group A and AB patients. An in vitro study has suggested that the expression of A antigen on the tumor cell facilitates to the latter to escape immune control [44]. Multivariate analysis failed to show any marked differences in frequency of breast carcinoma or associated prognostic factors among blood group non-O versus blood group O. However, this analysis showed correlation between O blood type and tumors expressing estrogen receptor. Breast carcinomas expressing the estrogen receptor have a good prognosis with a low proliferation index [45].
Plausible biological mechanisms explaining the link between cancer and ABO blood group are still unknown.
Some researchers have suggested that blood group antigens may influence the systemic inflammatory response that is closely related to carcinogenesis by regulating the serum levels of several circulating adhesion molecules and inflammation [46]. Tumor necrosis factor-a (TNF-a) is a key mediator of apoptosis. At low serum levels, it acts as an angiogenic factor and facilitates the development of cancer [47]. This marker of inflammation is found in low levels in serum of blood group A or B patients [48]. The soluble intercellular adhesion molecule-1 (sICAM-1) con- stitutively expressed blocks the cellular interaction to Table 2 Distribution of ABO
blood group among breast carcinoma patients and blood donors
Blood group Breast carcinoma patients % (n=442)
Blood donors % (n=344,954)
Odds ratio
O 46.83 46.05 0.77
A 29.64 33.89 0.66
B 19.91 15.08 1
AB 3.62 4.33 0.63
Fig. 1 ABO blood groups and age at diagnosis
Fig. 2 ABO blood groups and HER2 status
Fig. 3 ABO blood groups and lymph node status
prevent leukocyte recognition of the tumor cell, thus enabling the latter to escape the immune system control [49]. The plasma concentration of this molecule was associated with multiple SNPs variations within the ICAM gene and SNPs in the ABO locus [50, 51]. The Von Willebrand factor (VWF), plasma glycoprotein that acts as an adhesive molecule, bonds between platelets and endothelial cells and plays a critical role in angiogenesis [52–54]. Indeed, it was detected at high levels in the serum of blood type non-O patients suffering from cancer [55].
To sum up, compared to blood group O, patients with blood group A, B, and AB were more likely to develop aggressive breast carcinoma. Further follow-up studies are necessary to clarify the role of ABH antigens in the pro- gression of breast carcinoma.
Acknowledgments We are extremely grateful to Pr S. Zamiati who has facilitated us access to Pathology Department and Pr M. Matar who has facilitated us access to Maternity Ward L 9 C.H.U Ibn Rochd Casablanca. We thank all the team of Pathology Department C.H.U Ibn Rochd in Casablanca: Pr S. Benayad; residents; secretary; and technicians for their kind helping and encouragement.
Author contributions SZ, FM, MEW, NTJ, and NH participated in the design of the study. SZ and NH interpreted results and wrote the paper. NO and MBO performed the statistical analysis. All authors have read and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest The authors declare having no conflict of interests.
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