Review The prognostic value of ABO blood group in cancer patients Massimo Franchini1, Giancarlo M. Liumbruno2, Giuseppe Lippi3 Department of Haematology and Transfusion Medicine, "Carlo Poma" Hospital, Mantua; 2Italian National Blood Centre, National Institute of Health, Rome; 3Section of Clinical Biochemistry, University of Verona, Verona, Italy 1
Sr l
Search methods
We systematically reviewed the scientific literature for published studies evaluating the association between ABO blood group antigens and outcome in patients with various types of cancers. The MEDLINE® electronic database was searched without temporal limits using English language restriction. The Medical Subject Heading and keywords used were the following: "ABO blood group", "cancer", "survival", "prognosis", "outcome", "disease progression" and "life-expectancy". We also hand-searched the reference lists of the most relevant items to identify further eligible studies not captured in the initial literature search. Search terms were also applied to abstracts from the latest international congresses on cancer.
Se rv
The antigens of the ABO system are expressed on red blood cell membranes as well as on the surface of several other normal and pathological cells and tissues. Following the first clinical observations more than 60 years ago, the role of ABO blood group in cancer biology has been intensely studied by several investigators, and it is now widely recognised that ABO antigens are associated with the risk of developing several types of tumours, namely pancreatic and gastric cancers. However, whether this association also affects the clinical outcome of cancer patients is less certain. In this narrative review, based on literature data, we discuss the role of ABO blood types as prognostic biomarkers in different types of cancers. The current knowledge of the underlying pathogenic mechanisms of the association is also analysed.
cardiovascular, infectious and neoplastic diseases, as well as in several other human disorders7-12. More specifically, although a number of studies have found evidence of an association between ABO blood group antigens and various types of cancers13,14, so far there is limited understanding of the prognostic value in cancer patients. Moreover, the underlying molecular mechanisms are largely unknown. The relationship between ABO blood groups and survival from cancer is addressed in this review through analysis of the pathogenic mechanisms and the published clinical data.
iz i
Abstract
Keywords: ABO blood group, cancer, prognosis, outcome, survival.
TI
Introduction
©
SI M
The ABO blood group is by far the most important among human blood group systems1. The ABO gene is located on chromosome 9q34 and encodes two alleles (i.e., A and B) for specific glycosyltransferases which catalyse the covalent linkage of N-acetylgalactosamine or D-galactose to a common precursor side chain (i.e., the H determinant), which is finally converted into A or B antigen2-4. Unlike A and B alleles, the O variant encodes a non-functional glycosyltransferase, thus leaving the H antigen virtually unmodified in this instance4. The ABO blood group antigens are defined by carbohydrate moieties on the extracellular surface of red blood cell membranes5. However, along with their expression on erythrocytes, these antigens are also highly expressed on the surface of a large number of human cells and tissues, including epithelia, sensory neurons, platelets and the vascular endothelia6. The term histo-blood group ABO is often used to reflect the ubiquitous distribution of ABO antigens. It is biologically plausible that the clinical significance of the ABO system could expand beyond immunohaematology, transfusion and transplantation medicine. Indeed, there is growing evidence from the recent scientific literature of an important involvement of the ABO blood group system in the development of
Pathogenic mechanisms
The underlying mechanisms by which the ABO blood group or the closely linked genetic variants of the ABO locus may interplay with cancer development and progression are still poorly understood and remain the matter of research 9. One plausible hypothesis encompasses a dysregulation of the enzymatic activity of the ABO glycosyltransferases, which are specifically involved in the processes of intercellular adhesion and cellular membrane signalling as well as in the immune response to the host15-17. The alteration of these surface molecules may promote the process of malignancy18, through a mechanism analogous to the well-known role played by the ABO glycosyltransferases in modulating the circulating plasma levels of von Willebrand factor and the consequent increased risk of venous thromboembolism19,20. This association is particularly
Blood Transfus 2016; 14: 434-40 DOI 10.2450/2015.0164-15 434
All rights reserved - For personal use only No other use without premission
© SIMTI Servizi Srl
ABO and cancer
ICAM levels in patients with non-O blood groups may promote metastatic spread of tumours. In support of this hypothesis, a number of studies showed decreased survival in non-O blood type cancer patients and a favourable prognosis in those carrying O blood type31,32. Figure 1 summarises the mechanisms involved in the association between ABO antigens and cancer risk.
Epidemiological and clinical data
A number of epidemiological studies have assessed the relationship between ABO blood group antigens and survival in patients with various types of cancers (Table I)14.
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Sr l
Pancreatic cancer As far as regards pancreatic cancer, Amundadottir and colleagues identified the contribution of genetic variations in the ABO locus of 9q34 to pancreatic carcinogenesis in a two-stage genome-wide association study33, and their results were then replicated by Rizzato and collaborators34. Furthermore, the lower incidence of pancreatic cancer among patients with blood group O observed in some studies35-37 has raised the question as to whether ABO blood group status may correlate with the outcome of patients who develop this type
©
SI M
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intriguing, also considering that von Willebrand factor was recently found to be an important modulator of angiogenesis and apoptosis, which, in turn, are processes involved in tumorigenesis21. Alterations in the host inflammatory state due to ABO blood group antigens provide a further potential mechanism by which blood type may influence the progression and spread of malignancy22. Recent studies reported an association between polymorphisms at the ABO gene locus and circulating levels of tumour necrosis factor-alpha23, soluble intercellular adhesion molecule (ICAM)-124,25, E-selectin26,27 and P-selectin25. All these adhesion molecules are important mediators of chronic inflammation and immune cell recruitment. They may, therefore, provide a biological basis for the postulated influence of ABO on cancer survival, by directly linking ABO blood group and tumour initiation and spread9. The expression of soluble ICAM-1, which inhibits lymphocyte attachment to endothelial cells by binding to the ICAM ligands on circulating cells, is significantly reduced in patients with non-O blood group (particularly blood group A) compared to the expression in those with blood group O28,29. Since some cancer cells use similar mechanisms for adhesion to endothelial cells and subsequent metastatisation30, the decreased soluble
Figure 1 - Mechanisms of the association between ABO antigens and cancer.
VWF: von Willebrand factor.
Blood Transfus 2016; 14: 434-40 DOI 10.2450/2015.0164-15 All rights reserved - For personal use only No other use without premission
435
436
627 patients undergoing resection for pancreatic cancer
488 patients with pancreatic cancer
900 patients undergoing surgery for renal cell carcinoma
556 patients undergoing surgery for renal cell carcinoma
3,172 patients undergoing surgery for renal cell carcinoma
494 patients with superficial bladder cancer
931 patients with non-muscle invasive bladder cancer
261 patients with bladder cancer
538 patients with bladder cancer
7,906 patients with bladder cancer undergoing radical cystectomy
Prospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Rahbari, 201231
Wang, 201240
Kaffenberger, 201232
de Martino, 201442
Lee, 201543
Orihuela, 198744
Klatte, 201445
Raitanen, 199346
Yamada, 199347
Klatte, 201449
Ouyang, 201351
All rights reserved - For personal use only No other use without premission
511 patients with with esophageal squamous cell carcinoma
474 patients with gastric adenocarcinoma/404 controls
1,555 patients with surgically resected colon cancer
1,001 patients with invasive breast cancer
3,107 patients with breast cancer
426 patients undergoing surgery for breast cancer
468 patients with triple-negative breast cancer
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Sun, 201462
Qiu, 201166
Cao, 201468
Holdsworth, 198570
Gates, 201173
Klimant, 201174
Yu, 201275
OS: overall survival; HR: hazard ratio; CI: confidence interval.
284 patients with esophageal squamous cell carcinoma
Retrospective
After adjusting for age, disease stage and treatment, no significant differences were observed in 5-year OS and disease-free survival Compared to women with blood type O, there was no significant difference in breast-cancer specific mortality for blood types A, B, or AB
No association between blood type and breast-cancer specific mortality was found
Patients with B and AB blood types had a poorer OS than those with O and A blood groups (p=0.015)
Patients with AB blood type had a better mean OS than those with non-AB blood type (113.9 months vs 106.1 months; p
Sr l
Search methods
We systematically reviewed the scientific literature for published studies evaluating the association between ABO blood group antigens and outcome in patients with various types of cancers. The MEDLINE® electronic database was searched without temporal limits using English language restriction. The Medical Subject Heading and keywords used were the following: "ABO blood group", "cancer", "survival", "prognosis", "outcome", "disease progression" and "life-expectancy". We also hand-searched the reference lists of the most relevant items to identify further eligible studies not captured in the initial literature search. Search terms were also applied to abstracts from the latest international congresses on cancer.
Se rv
The antigens of the ABO system are expressed on red blood cell membranes as well as on the surface of several other normal and pathological cells and tissues. Following the first clinical observations more than 60 years ago, the role of ABO blood group in cancer biology has been intensely studied by several investigators, and it is now widely recognised that ABO antigens are associated with the risk of developing several types of tumours, namely pancreatic and gastric cancers. However, whether this association also affects the clinical outcome of cancer patients is less certain. In this narrative review, based on literature data, we discuss the role of ABO blood types as prognostic biomarkers in different types of cancers. The current knowledge of the underlying pathogenic mechanisms of the association is also analysed.
cardiovascular, infectious and neoplastic diseases, as well as in several other human disorders7-12. More specifically, although a number of studies have found evidence of an association between ABO blood group antigens and various types of cancers13,14, so far there is limited understanding of the prognostic value in cancer patients. Moreover, the underlying molecular mechanisms are largely unknown. The relationship between ABO blood groups and survival from cancer is addressed in this review through analysis of the pathogenic mechanisms and the published clinical data.
iz i
Abstract
Keywords: ABO blood group, cancer, prognosis, outcome, survival.
TI
Introduction
©
SI M
The ABO blood group is by far the most important among human blood group systems1. The ABO gene is located on chromosome 9q34 and encodes two alleles (i.e., A and B) for specific glycosyltransferases which catalyse the covalent linkage of N-acetylgalactosamine or D-galactose to a common precursor side chain (i.e., the H determinant), which is finally converted into A or B antigen2-4. Unlike A and B alleles, the O variant encodes a non-functional glycosyltransferase, thus leaving the H antigen virtually unmodified in this instance4. The ABO blood group antigens are defined by carbohydrate moieties on the extracellular surface of red blood cell membranes5. However, along with their expression on erythrocytes, these antigens are also highly expressed on the surface of a large number of human cells and tissues, including epithelia, sensory neurons, platelets and the vascular endothelia6. The term histo-blood group ABO is often used to reflect the ubiquitous distribution of ABO antigens. It is biologically plausible that the clinical significance of the ABO system could expand beyond immunohaematology, transfusion and transplantation medicine. Indeed, there is growing evidence from the recent scientific literature of an important involvement of the ABO blood group system in the development of
Pathogenic mechanisms
The underlying mechanisms by which the ABO blood group or the closely linked genetic variants of the ABO locus may interplay with cancer development and progression are still poorly understood and remain the matter of research 9. One plausible hypothesis encompasses a dysregulation of the enzymatic activity of the ABO glycosyltransferases, which are specifically involved in the processes of intercellular adhesion and cellular membrane signalling as well as in the immune response to the host15-17. The alteration of these surface molecules may promote the process of malignancy18, through a mechanism analogous to the well-known role played by the ABO glycosyltransferases in modulating the circulating plasma levels of von Willebrand factor and the consequent increased risk of venous thromboembolism19,20. This association is particularly
Blood Transfus 2016; 14: 434-40 DOI 10.2450/2015.0164-15 434
All rights reserved - For personal use only No other use without premission
© SIMTI Servizi Srl
ABO and cancer
ICAM levels in patients with non-O blood groups may promote metastatic spread of tumours. In support of this hypothesis, a number of studies showed decreased survival in non-O blood type cancer patients and a favourable prognosis in those carrying O blood type31,32. Figure 1 summarises the mechanisms involved in the association between ABO antigens and cancer risk.
Epidemiological and clinical data
A number of epidemiological studies have assessed the relationship between ABO blood group antigens and survival in patients with various types of cancers (Table I)14.
iz i
Sr l
Pancreatic cancer As far as regards pancreatic cancer, Amundadottir and colleagues identified the contribution of genetic variations in the ABO locus of 9q34 to pancreatic carcinogenesis in a two-stage genome-wide association study33, and their results were then replicated by Rizzato and collaborators34. Furthermore, the lower incidence of pancreatic cancer among patients with blood group O observed in some studies35-37 has raised the question as to whether ABO blood group status may correlate with the outcome of patients who develop this type
©
SI M
TI
Se rv
intriguing, also considering that von Willebrand factor was recently found to be an important modulator of angiogenesis and apoptosis, which, in turn, are processes involved in tumorigenesis21. Alterations in the host inflammatory state due to ABO blood group antigens provide a further potential mechanism by which blood type may influence the progression and spread of malignancy22. Recent studies reported an association between polymorphisms at the ABO gene locus and circulating levels of tumour necrosis factor-alpha23, soluble intercellular adhesion molecule (ICAM)-124,25, E-selectin26,27 and P-selectin25. All these adhesion molecules are important mediators of chronic inflammation and immune cell recruitment. They may, therefore, provide a biological basis for the postulated influence of ABO on cancer survival, by directly linking ABO blood group and tumour initiation and spread9. The expression of soluble ICAM-1, which inhibits lymphocyte attachment to endothelial cells by binding to the ICAM ligands on circulating cells, is significantly reduced in patients with non-O blood group (particularly blood group A) compared to the expression in those with blood group O28,29. Since some cancer cells use similar mechanisms for adhesion to endothelial cells and subsequent metastatisation30, the decreased soluble
Figure 1 - Mechanisms of the association between ABO antigens and cancer.
VWF: von Willebrand factor.
Blood Transfus 2016; 14: 434-40 DOI 10.2450/2015.0164-15 All rights reserved - For personal use only No other use without premission
435
436
627 patients undergoing resection for pancreatic cancer
488 patients with pancreatic cancer
900 patients undergoing surgery for renal cell carcinoma
556 patients undergoing surgery for renal cell carcinoma
3,172 patients undergoing surgery for renal cell carcinoma
494 patients with superficial bladder cancer
931 patients with non-muscle invasive bladder cancer
261 patients with bladder cancer
538 patients with bladder cancer
7,906 patients with bladder cancer undergoing radical cystectomy
Prospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Rahbari, 201231
Wang, 201240
Kaffenberger, 201232
de Martino, 201442
Lee, 201543
Orihuela, 198744
Klatte, 201445
Raitanen, 199346
Yamada, 199347
Klatte, 201449
Ouyang, 201351
All rights reserved - For personal use only No other use without premission
511 patients with with esophageal squamous cell carcinoma
474 patients with gastric adenocarcinoma/404 controls
1,555 patients with surgically resected colon cancer
1,001 patients with invasive breast cancer
3,107 patients with breast cancer
426 patients undergoing surgery for breast cancer
468 patients with triple-negative breast cancer
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Sun, 201462
Qiu, 201166
Cao, 201468
Holdsworth, 198570
Gates, 201173
Klimant, 201174
Yu, 201275
OS: overall survival; HR: hazard ratio; CI: confidence interval.
284 patients with esophageal squamous cell carcinoma
Retrospective
After adjusting for age, disease stage and treatment, no significant differences were observed in 5-year OS and disease-free survival Compared to women with blood type O, there was no significant difference in breast-cancer specific mortality for blood types A, B, or AB
No association between blood type and breast-cancer specific mortality was found
Patients with B and AB blood types had a poorer OS than those with O and A blood groups (p=0.015)
Patients with AB blood type had a better mean OS than those with non-AB blood type (113.9 months vs 106.1 months; p
