ABO blood group and skin cancers

Abstract

Beside the role of ABO group in immunohaematology, there is accumulating evidence that the ABO blood group also plays a key role in various human disorders. The interest in blood groups and their association with disease stems from the awareness that blood group antigens are incredibly important components in the process of cell maturation and control. Studies have indicated a link between cancer and the ABO blood group. The appearance or disappearance of blood type antigens is now considered a hallmark of malignancy in many common cancers. Several tumour markers are in fact known blood group antigens. The aim of this review is to describe the history and possible functions of the ABO group and then summarize the association between blood groups and skin cancers.

Keywords

ABO blood group cancer skin

1 Introduction

According to the International Blood Transfusion Association, 38 blood group systems representing more than 300 antigens have been discovered [1]. The most antigenic of these are the ABO and Rh (D) antigens, expressed in a codominant manner [2]. ABO blood group system was discovered in 1900 by Karl Landsteiner. This blood group system contains three antigens (i.e. A, B and H) and is the most researched and clinically important blood group system [3]. The gene for ABO is located on chromosome 9 at 9p34.1-q34.2 containing 7 exons, with three main allelic forms A, B and O [4]. Serological ABO typing is performed using the anti-A and anti-B antisera of polyclonal or monoclonal origin, which can distinguish the four phenotypes (A, B, AB and O) [4, 5]. Blood group classification refers to the antigens present or absent on the surface of erythrocytes, determining an individual’s blood type. Individuals with blood type A have antigen A present but absent antigen B on their erythrocytes whereas those with blood type B have antigen B but no antigen A. People with blood type AB have both antigens A and B present in the surface of erythrocytes. In contrast, individuals with blood type O have neither antigens A nor B expressed on their erythrocytes [7]. The antigens of the ABO blood group are oligosaccharides on the extracellular surface of erythrocyte cell membrane: The A phenotype is defined by the sugar N-acetylgalactosamine (GalNAc) and B by galactose (Gal). These sugars are transferred to a precursor antigen known as the H antigen controlled by a single gene, ABO.

The second most important blood group system after ABO is the Rhesus system. The erythrocyte surface of an individual may or may not express Rh factor or immunogenic D antigen. Accordingly, the condition is defined as Rh positive (D antigen present) or Rh negative (D antigen absent) [3]. When both systems are combined, a total of eight blood groups/phenotypes are achieved [8 –10].

Erythrocyte cell antigens have various functions such as structural integrity of the membrane, cell movement, tissue differentiation, inflammation, transport of molecules from membranes and adhesion [11 –13]. ABO antigens along with their expression on red blood cells are also highly expressed on the surface of a variety of human cells and tissues, sensory neurons, platelets, and the vascular endothelium [14]. In the skin, blood group antigens are expressed in stratum corneum, stratum granulosum, stratum spinosum, acrosirringium and in the hair follicle regions [15]. In normal skin, A antigen is found in the granular layer of the epidermis, in the sebaceous and sudoriferous gland canals, and in the part of hair follicle root sheath passing through the granular layer [16]. B antigen and H antigen type 2 chain is detected in the granular layer, on cell membranes and in the cytoplasm [17].

2 ABO system and its link to disease

The frequency of A and B blood groups differs among the population of the world. The ABO blood group is a useful and valuable resource because the inheritance of blood groups is not affected by any environmental factors during life [18]. The distribution of blood groups varies across various ethnic, geographic, and socioeconomic groups [19]. It is well-established that human gene frequencies for the ABO blood groups vary in a society, thereby leading to a risk factor for many diseases [19, 20]. The simultaneous disintegration of genes (genetic imbalance) or the hypothesis of antigenic expression and antibody production may be a mechanism for explaining relationships between blood types and many different diseases [2 , 23].

There are proven relationships between ABO blood group and diseases for haemolytic transfusion reactions due to the transfusion of ABO-incompatible blood, transplantation of ABO-incompatible cells/tissues/organs that may, without immunosuppression, result in acute rejection, and haemolytic disease of the foetus and newborn resulting from ABO incompatibility between mother and baby, which is a relatively common event but is nearly always mild and only rarely causes severe anaemia [24].

Beside its role in immunohaematology, there is accumulating evidence that the ABO blood group also plays a key role in various human disorders. Some studies have shown increased related risks and severity of some diseases. For example, the association between ABO groups with several malignancies, hypercholesterolaemia, thrombosis, myocardial infarction, duodenal ulcer, infections, and autoimmune diseases is reported [6 , 26]. Meta-analyses have detected associations between increased risk of coronary heart disease, and venous thromboembolism and the non-O blood types [26, 27]. On the other hand, duodenal ulcer has been reported more frequently in blood group O [6, 29].

The relationship between blood groups and susceptibility to various infectious diseases has also been reported [6 , 30]. In dermatophytosis, Young and Roth observing antigenic similarities between T. rubrum, T. mentagrophytes and E. floccosum cell wall glycoproteins and A1 and A2 human erythrocyte isoantigens, suggested that a possible cross reactivity would turn individual with blood group A more susceptible to chronic dermatophyte infections and resistant to the treatment than the individuals lacking of the antigen [30]. While several studies suggest a potential selective advantage of the O allele influencing the susceptibility to several different pathogens responsible for diseases such as severe malaria [31], H. pylori infections [32] and severe forms of cholera [33]. The positive selective pressure could have been caused by the absence of the A and B antigens (that can be used as receptors by infectious agents) and by the presence of anti-A and anti-B antibodies.

Many early studies have shown association of particular cancers with specific ABO groups [9 , 35]. Studies prior to 1950 are not that reliable due to the lack of appreciation of the large numbers needed for a study to be informative, the inadequate controls used, and the lack of awareness of the wide variations of ABO frequencies occurring over relatively limited areas even in populations considered ethnically homogeneous [6]. The first convincing study relating to ABO blood group and gastric cancer can be traced back to 1953 [34]. Aird et al. discovered a statistically significant association between blood type A and risk of gastric cancer [34]. This finding has stimulated an immense amount of research that examined the relationship between ABO blood type and risk of cancer, other chronic diseases, and infectious diseases.

More recent observations have demonstrated a significant prevalence of malignancies such as stomach, pancreas, breast, ovary, and salivary glands in blood type A individuals compared to O blood group [8 , 35–38]. Blood group A was found to elevate the risk of cancer and may play a role in its development [39, 40]. In contrast, Zhang et al. (2014) reported increased risk with blood group B compared to non-B group in oesophageal cancers [41]. In later studies evaluating the association between ABO blood group and colon cancer, no differences in blood group frequencies were detected between cases and controls [42]. The inconsistencies in previous cancer results could possibly be attributed to poor study design that included inappropriate control selection, residual confounding from population heterogeneity, as well as low statistical power [38].

3 Skin cancer

Skin cancer is the most common type of cancer in humans and represents approximately half of all cancers in the United States. Each year more than 1 million cases of skin cancer are diagnosed, with about 11,590 deaths from skin cancer in 2009 [43]. The etiopathogenesis of skin cancers is still unknown. Risk factors of skin cancer include ultraviolet (UV) light exposure, chemical carcinogens, exposure to ionizing radiation, age, male gender, genetic susceptibly and constitutional factors, for instance hair colour, number of moles, skin colour, and skin reaction to sun exposures [43 –49]. There are three types of skin cancer: melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) originating from three major types of cells in the epidermis.

Non-melanoma skin cancers (NMSCs) is a term most frequently referring to BCC and SCC, represent the most common malignant neoplasms of all skin tumours, accounting for 80% and 20% respectively [50]. Although NMSCs are the most common malignant tumours diagnosed, they account for less than 0.1% of cancer-related deaths [44]. In spite of the growing awareness of the harmful effects of UV radiation as the major risk factor in the pathogenesis of these tumours, the incidence of NMSCs has been globally increasing over the years, thus becoming an ever-greater public health problem [51, 52]. It is presumed to be influenced by a number of factors, such as damage to the ozone layer, which loses its protective role to filter for UV rays, prolonged life expectancy, earlier tumour detection through popularization of sun protection, the use of tanning salons, modified clothing, and an increasing number of organ transplantations. The latter is associated with long-term immunosuppressant therapy, which in turn entails the occurrence of malignant tumours, SCC being most common in this group of patients with an aggressive prognosis [51 –53]. These findings suggest that immunosuppression might play a role in the underlying etiology of skin cancers. On the other hand, no increased incidence of BCC in patients with compromised immune systems was reported, whereas the incidence of SCC was higher in patients with mutations in the Tp53 gene [46, 54]. Individuals with fair skin are at an increased risk of developing BCC. The incidence of the disease increases with the increase in age; increasing trend is observed in favor of SCC in individuals at the age of≥65 [2, 46].

Derived from abnormal melanocytes, malignant melanoma is the most dangerous primary malignant skin tumour, responsible for more than 75% of skin cancer deaths [55]. Each year, nearly 20,000 cases of cutaneous malignant melanoma are diagnosed in China [56]. The incidence of this disease is less frequent in black people [35]. Since this type of cancer has high invasiveness, patient mortality is high and five-year survival rates of patients with metastatic disease is less than 20% [55, 57]. The development of melanoma appears to be related to multiple risk factors such as skin and hair colour as well as family history of melanoma [45, 47]. However, the most significant factors associated with the development of this type of tumour remain to be identified.

The huge interest in blood groups and their association with disease stems from the developing awareness that blood group antigens are incredibly important components in the process of cell maturation and control. The appearance or disappearance of blood type antigens is now considered a hallmark of malignancy in many common cancers [58]. Several tumour markers are in fact known blood group antigens such as CA19-9. It is widely accepted that there is a relationship between blood group A and gastric [34], pancreatic [59], ovarian [39], laryngeal and hypopharyngeal [60], salivary gland [61], breast [37], testicular [62] and bone cancers [63]. Although it has been reported that several forms of cancer are associated with subtypes of ABO blood groups, the exact mechanism of this association remains to be elucidated [10 , 64,65]. The aim of this review is to summarize the association between blood groups and skin cancers.

Table 1
Table1

First author, year ref Study design Disease Patient/Control Main results

Karakousis, 1986, USA [35] Retrospective Malignant Melanoma 168/white Americans No significant association between ABO (P = 0.23), Rh(P = 0.74) blood groups &malignant melanoma.

(High frequency of patients with O blood group 49.4% compared to various series in general white population 42.2– 47%).

Cihan, 2013, Turkey [20] Retrospective Non-melanoma skin cancer 255/25701 Statistically significant association (P < 0.001) between Non-melanoma skin cancer and ABO/Rh blood groups (High incidence of A blood group Rh Negative (no. 29/11.4%) compared to control group (no. 1299/5.1%))

25701: Healthy volunteer blood donation center

255 patients:

– 54 Squamous Cell Carcinoma (SCC)

– 201 Basal Cell Carcinoma (BCC).

Celic, 2019, Croatia [71] Non-melanoma skin cancer 515/438 AB blood group patients (no. 70/13.6%) compared to control group (no. 33/7.5%) was significantly associated with an increase risk of non-melanoma skin cancer compared to the non AB blood group (MOR = 2.28; 95% CI = 1.41– 3.69).

438: Subject treated for other skin disease.

515 patients:

– 148 SCC.

– 367 BCC.

Walter,1979, USA [67] Malignant melanoma 191/same geographical area USA healthy controls The incidence of O blood group in melanoma patients higher than control.

Tursen, 2005, Turkey [2] Retrospective study Skin cancer 98/419 No significant association between skin cancer and ABO/Rh blood groups. (Patients with blood group A (45%) were higher than in controls (35%)).

419 Healthy blood donors.

98 Patients:

– 23 SSC

– 42 BCC

– 33 in situ SCC.

Iodice, 2010, Italy [9] Case-control Skin cancer (Melanoma, non-melanoma) 760/14,599 No statistically significant association between ABO blood group and skin cancer (melanoma 463/14896 (P = 0.10) and Non-melanoma 297/15062 (P = 0.37)

14,599 Other forms of cancer.

760 Patients:

– 463 Melanoma

– 297 Non-melanoma.

Vincenzo, 2011, Italy [44] Retrospective study Malignant melanoma 445/38321 Patients from the blood laboratory of the same hospital. (O)Rh negative blood group (patients 9.5% and control group 7.1%) was associated with statistically significant increase risk of developing malignant melanoma (odds ratio = 1.4).

Ikonopisov,1974, Bulgaria [66] Melanoma and squamous cell carcinoma 414 Melanoma/ Bulgarian general Population – Significant association between ABO blood group and melanoma (High frequency of O blood group in melanoma patients (42.8%) compared to general population in Bulgaria (32.1%)). (P < 0.01)

862 SCC/ Bulgarian general Population – No significant association between ABO blood group and SCC patients compared to control. (P > 0.05)

Jorgensen, 1972, Germany [68] Melanoma 164/694 Germany general normal population No significant association between ABO (P∼0.3)/Rh blood group (P = 0.2) and melanoma patients. (High frequency of O blood group in patients group (no. 74/45.12%) compared to control group (no. 273/39.33%)).

Chang, 2014, China [56] Case-control Malignant melanoma 482/3068 Healthy control admitted for a checkup at the same hospital. Statistically significant association (P = 0.001) between ABO blood group and malignant melanoma (blood type A was associated with higher incidence of malignant melanoma (no. 178/36.9%) compared to control group (no. 859/28%))

OR = 1.575; 95% CI = 1.208– 2.053

Xie, 2010, USA [11] Non prospective cohort study ^95,470 US participants ^70650 female nurses ^*24820 male health professional Skin cancer (Melanoma, Non-Melanoma) – 685 Melanoma patients. Non- melanoma patients: 1533 SCC. 19860 BCC. – Non-O blood group (A, B, and AB combined) significantly association with decrease risk of non-melanoma skin cancer. (Non-O in SCC 53% and Non-O in control 57.2%) 14% decrease risk of developing SCC (multivariable HR:0.86; 95% CI:0.78,0.95), and (Non-O in BCC 55.9% and Non-O in control 57.2%) 4% decrease risk of developing BCC (multivariable HR: 0.96; 95% CI:0.93, 0.99).

– Non-O blood group was not significantly associated with decrease risk of melanoma multivariable HR:0.91; 95% CI:0.78, 1.05).

– No association findings between Rh factor and risk of any type of skin cancer.

Koul, 2018, India [26] Retrospective non-randomized cross sectional study Skin and melanoma cancer 58/ The most common blood group is AB (32.7%) and Rh + ve (66.6%).

Mansour, 2014, Egypt [40] Retrospective hospital-based case control study Skin cancer 45/1200 1200: Healthy controls (volunteers, medical students, blood donors, paramedical and health workers). Blood group A (42.2%) significantly associated with increase the risk for skin cancer (OR = 1.19, 95% CI = 0.99– 1.47).

Huang, 2017, China [69] Prospective cohort study of 355,797 Chinese person and 3973 incident cancer cases Bone, connective tissue and skin cancers 69/ ABO blood group not associated with risk of skin cancer.

Vasan, 2016, Sweden &Denmark [38] Prospective cohort study of 1.6 million blood donors and 119,584 incident cancer cases Skin cancer (Melanoma4433, non-melanoma 8232) ABO blood group not associated with risk of (Melanoma, non-melanoma) skin cancer. P > 0.05

First author, year ref	Study design	Disease	Patient/Control	Main results
Karakousis, 1986, USA [35]	Retrospective	Malignant Melanoma	168/white Americans	No significant association between ABO (P = 0.23), Rh(P = 0.74) blood groups &malignant melanoma.
				(High frequency of patients with O blood group 49.4% compared to various series in general white population 42.2– 47%).
Cihan, 2013, Turkey [20]	Retrospective	Non-melanoma skin cancer	255/25701	Statistically significant association (P < 0.001) between Non-melanoma skin cancer and ABO/Rh blood groups (High incidence of A blood group Rh Negative (no. 29/11.4%) compared to control group (no. 1299/5.1%))
			25701: Healthy volunteer blood donation center
			255 patients:
			– 54 Squamous Cell Carcinoma (SCC)
			– 201 Basal Cell Carcinoma (BCC).
Celic, 2019, Croatia [71]		Non-melanoma skin cancer	515/438	AB blood group patients (no. 70/13.6%) compared to control group (no. 33/7.5%) was significantly associated with an increase risk of non-melanoma skin cancer compared to the non AB blood group (MOR = 2.28; 95% CI = 1.41– 3.69).
			438: Subject treated for other skin disease.
			515 patients:
			– 148 SCC.
			– 367 BCC.
Walter,1979, USA [67]		Malignant melanoma	191/same geographical area USA healthy controls	The incidence of O blood group in melanoma patients higher than control.
Tursen, 2005, Turkey [2]	Retrospective study	Skin cancer	98/419	No significant association between skin cancer and ABO/Rh blood groups. (Patients with blood group A (45%) were higher than in controls (35%)).
			419 Healthy blood donors.
			98 Patients:
			– 23 SSC
			– 42 BCC
			– 33 in situ SCC.
Iodice, 2010, Italy [9]	Case-control	Skin cancer (Melanoma, non-melanoma)	760/14,599	No statistically significant association between ABO blood group and skin cancer (melanoma 463/14896 (P = 0.10) and Non-melanoma 297/15062 (P = 0.37)
			14,599 Other forms of cancer.
			760 Patients:
			– 463 Melanoma
			– 297 Non-melanoma.
Vincenzo, 2011, Italy [44]	Retrospective study	Malignant melanoma	445/38321 Patients from the blood laboratory of the same hospital.	(O)Rh negative blood group (patients 9.5% and control group 7.1%) was associated with statistically significant increase risk of developing malignant melanoma (odds ratio = 1.4).
Ikonopisov,1974, Bulgaria [66]		Melanoma and squamous cell carcinoma	414 Melanoma/ Bulgarian general Population	– Significant association between ABO blood group and melanoma (High frequency of O blood group in melanoma patients (42.8%) compared to general population in Bulgaria (32.1%)). (P < 0.01)
			862 SCC/ Bulgarian general Population	– No significant association between ABO blood group and SCC patients compared to control. (P > 0.05)
Jorgensen, 1972, Germany [68]		Melanoma	164/694 Germany general normal population	No significant association between ABO (P∼0.3)/Rh blood group (P = 0.2) and melanoma patients. (High frequency of O blood group in patients group (no. 74/45.12%) compared to control group (no. 273/39.33%)).
Chang, 2014, China [56]	Case-control	Malignant melanoma	482/3068 Healthy control admitted for a checkup at the same hospital.	Statistically significant association (P = 0.001) between ABO blood group and malignant melanoma (blood type A was associated with higher incidence of malignant melanoma (no. 178/36.9%) compared to control group (no. 859/28%))
				OR = 1.575; 95% CI = 1.208– 2.053
Xie, 2010, USA [11]	Non prospective cohort study ^95,470 US participants ^70650 female nurses ^*24820 male health professional	Skin cancer (Melanoma, Non-Melanoma)	– 685 Melanoma patients. Non- melanoma patients: 1533 SCC. 19860 BCC.	– Non-O blood group (A, B, and AB combined) significantly association with decrease risk of non-melanoma skin cancer. (Non-O in SCC 53% and Non-O in control 57.2%) 14% decrease risk of developing SCC (multivariable HR:0.86; 95% CI:0.78,0.95), and (Non-O in BCC 55.9% and Non-O in control 57.2%) 4% decrease risk of developing BCC (multivariable HR: 0.96; 95% CI:0.93, 0.99).
				– Non-O blood group was not significantly associated with decrease risk of melanoma multivariable HR:0.91; 95% CI:0.78, 1.05).
				– No association findings between Rh factor and risk of any type of skin cancer.
Koul, 2018, India [26]	Retrospective non-randomized cross sectional study	Skin and melanoma cancer	58/	The most common blood group is AB (32.7%) and Rh + ve (66.6%).
Mansour, 2014, Egypt [40]	Retrospective hospital-based case control study	Skin cancer	45/1200 1200: Healthy controls (volunteers, medical students, blood donors, paramedical and health workers).	Blood group A (42.2%) significantly associated with increase the risk for skin cancer (OR = 1.19, 95% CI = 0.99– 1.47).
Huang, 2017, China [69]	Prospective cohort study of 355,797 Chinese person and 3973 incident cancer cases	Bone, connective tissue and skin cancers	69/	ABO blood group not associated with risk of skin cancer.
Vasan, 2016, Sweden &Denmark [38]	Prospective cohort study of 1.6 million blood donors and 119,584 incident cancer cases	Skin cancer (Melanoma4433, non-melanoma 8232)		ABO blood group not associated with risk of (Melanoma, non-melanoma) skin cancer. P > 0.05

4 Results

Early studies indicated cancer of the skin to be strongly associated with blood type O. However, unlike gastric and pancreatic cancer, the correlation between skin cancer and ABO blood group remains controversial. Blood type O has been found to have the highest frequency of malignant melanoma. In a study investigating the possible relationship between the ABO and cutaneous malignant melanoma, Ikonopisov and Tsanov (1974) found statistically significant association (P < 0.01) between ABO blood group and malignant melanoma (High frequency of O blood group in melanoma patients (42.8%) compared to general population in Bulgaria (32.1%)) [66]. In another study involving 168 patients with malignant melanoma, Karakousis et al. (1986) revealed that a higher number of patients with O blood group 49.4% had malignant melanoma compared to various series in general white population 42.2–47%. However, the results did not indicate statistical significance (P = 0.23) [35]. Similarly in other studies a higher frequency of blood group O among melanoma patients has been observed compared to the general population [67, 68].

Several more recent studies document the relationship between the risk of cutaneous melanoma and ABO blood groups, but data from these are inconsistent. Mansour et al. (2014) reported that blood group A was associated with a statistically significant higher risk for skin cancer (OR = 1.19, 95% CI = 0.99–1.47) [40]. However, the contrasting results of the study conducted by Iodice et al. (2010) through a case-control analysis, who performed ABO phenotyping in patients with skin cancer (melanoma = 463 and Non-melanoma = 297) did not find statistically significant differences (P = 0.10) ( P = 0.37) respectively in the non-O versus O blood type [9]. In 2016, a large cohort of blood donors from the Scandinavian Donations and Transfusions-2 database (known as the “SCANDAT2” database) involved more than 1.6 million donors and transfused patients who were followed from 1968 in Sweden and 1981 in Denmark until December 31, 2012. This study showed that the ABO blood group was not associated (P > 0.05) with an increased risk of Melanoma and NMSC [38]. A recent prospective cohort study in Chinese population also suggested that ABO blood groups were not associated with the risk of skin cancers [69].

Studies supporting the notion that ABO blood group is associated with skins cancers are numerous. Chang et al. (2014) observed that blood type A was associated with a higher incidence of cutaneous malignant melanoma, compared with those with blood group O (OR = 1.575; 95% CI = 1.208–2.053, p = 0.001) [56]. In a 2010 prospective cohort study of 95,470 US participants derived from the Nurses’ Health Study and the Health Professionals Follow-up Study, 685 participants developed melanoma during the study follow-up period (mean time was 27.1 years for females; 16.9 years for males) [11]. There was no statistically significant decreased risk of developing melanoma across Non-O blood group, compared to participants with blood group O (multivariable HR:0.91; 95% CI:0.78–1.05). On the other hand, Vincenzo et al. (2011) reported (445 patients with a histological diagnosis of malignant melanoma and 38,321 controls) a statistically significant increased risk for developing cutaneous malignant melanoma in individuals with O Rh-negative group (odds ratio = 1.4) [44]. Possible reasons for this discrepancy may include differences in participants. The participants in Chang et al. (2014) study were Chinese, participants of two prior studies were Caucasian, living in United States [11] or Italy [44]. Racial differences may exist and living latitudes may be associated with ultraviolet radiation exposure. Furthermore, some studies did not adjust for age and other possible confounders [56].

Cihan et al. (2013) reported Statistically significant association (P < 0.001) between Non-melanoma skin cancer and ABO/Rh blood groups with high incidence of A blood group Rh Negative (no. 29/11.4%) compared to control group (no. 1299/5.1%) [20]. These findings were consistent with an earlier case-control study conducted in Turkey reported by Tursen et al. (2005) who had investigated the possible relationship between the blood groups and Non-melanoma skin cancer in 98 histologically confirmed skin cancer patients (23 SCC, 42 BCC, and 33 in situ SCC) and 419 healthy controls. The author reported that a higher number of patients with skin cancer had A blood group, while a lower number of patients had O blood group. However, the findings were not statistically significance (skin cancer cases were more likely than controls to be in blood groups A, AB and B than O “odds ratios ranged from 1.5 to 3.77”) [2].

Data from large prospective cohort studies indicate that the ABO blood group is associated with the risk of developing skin cancer [15]. Xie et al. (2010) reveal that non-O blood group was significantly associated with a decreased risk of non-melanoma skin cancer overall. Compared to participants with blood group O, participants with non-O blood group had a 14% decreased risk of developing SCC and a 4% decreased risk of developing BCC than the O blood group. Their study included Caucasians, however, without data on their origin, which is important information considering the ethnic heterogeneity of the USA population and the fact that the frequency of human genes of the ABO system varies among different populations and ethnic groups [15, 29]. One study evaluating normal penile skin compared to squamous cell carcinoma showed less A antigen expression in SCC compared to the surrounding normal skin [20], which is consistent with Xie et al. (2010) finding that A blood type was less common in SCC cases (multivariable HR: 0.86; 95% CI: 0.77–0.96) [15]. The opposing association of the non-O blood group with skin cancer compared to that with pancreatic [70], gastric [34], and ovarian [39] cancers suggests unique carcinogenic mechanisms of skin cancer.

There are several possible reasons for the observed differences between the results Xie et al. (2010) [15] and the results of other studies [2, 13]. First, the participants in [15] are white residing in the US, while the population in [2, 13] was from Turkey. The association between ABO blood group and the risk of skin cancer may vary among different races or ethnicities. Second, results from the [2, 13] were based on a relatively small sample size, and confidence intervals were wide. Another strength of [15] study is the large study population and the high follow-up rate.

Celic et al., (2019) found that AB blood group was significantly associated with an increase risk of non-melanoma skin cancer compared to the non AB blood group (MOR = 2.28; 95% CI = 1.41–3.69) [71]. It is presumed that the concurrent presence of A and B antigens in the skin epithelium increases the probability of NMSCs development. The association of AB phenotype and NMSCs recorded in our study could be explained by the greater resistance to apoptosis of epithelial cells expressing A or B antigens as compared with the cells that express exclusively H antigens [72]. These findings were consistent with data of the previous retrospective non-randomized cross sectional study conducted in India reported by Koul et al., (2018) founded that a higher number of patients with skin and melanoma cancer had AB blood group (32.7%) [26].

Consistent to Celic et al., (2019) results on the association of NMSCs and the AB blood group versus non AB blood groups, other authors also confirmed the association of AB blood group and particular types of carcinoma [71]. A study conducted in the population of southeast China demonstrated the association of nasopharyngeal carcinoma with the A blood group and the AB blood group versus the O blood group [73]. A study by Ben et al. in a Chinese population confirmed the association of pancreatic carcinoma with the A blood group and the AB blood group versus the O blood group [74]. A study conducted in Taiwan confirmed the association of all carcinomas (lungs, liver, pancreas, oesophagus, stomach, colon and prostate) in men with AB blood group as compared with the O blood group [75].

However, there are a limited number of studies investigating the relationship between Rh factor and different forms of cancer [13]. Cihan (2013) observed that the incidence of non-melanoma skin cancer was higher in patients with A Rh negative [20]. Vincenoz et al. (2011) also found that increase risk of developing malignant melanoma in O Rh negative patients [44]. However, no relationship between the Rh factor and skin cancer was reported [2 , 68].

5 Discussion

Epidemiological investigations supporting the relationship between ABO blood group and cancer risk have been consistently observed mostly for gastric and pancreatic cancer [36, 59]. However, as the ABO antigens are present not only on blood cells but also on various epithelial cells, blood group antigens are expected to constitute important aspects in many human tumours [76, 77]. ABO blood group genes are mapped at 9q in which genetic alterations are common in many cancers [78]. Alteration of ABO/Lewis-related antigens is associated with the malignant transformation of some tumours [24 , 79]. On the other hand, changes in ABO blood group antigen expression may be effected by the genetic change of tumours [46]. It is possible that the observed associations are not due to the blood group antigens themselves, but to the effects of genes closely associated with them [2]. Several mechanisms, including inflammation, immune-surveillance for malignant cells, intercellular adhesion, and membrane signaling have been proposed to explain the observed association between ABO blood groups and cancer risk [70]. Alterations in surface glycoconjugates may lead to modifications in intercellular adhesion, membrane signaling, and immunosurveillance, which could have important implications for the development of cancer [7, 80].

In regards to skin cancer, several biological mechanisms could associate ABO blood group with its development [15]. Alteration in the expression of blood group antigens on epithelial cells may affect tumour formation with modified glycosyl transferase specificity [15, 70]. An alternative explanation is that ABO blood group may be indirectly associated with skin cancer. It is possible that the ABO gene was in linkage disequilibrium with other genes involved in skin carcinogenesis [15]. In tumours, changes in glycosylation are found in both glycolipids and glycoproteins [19, 80]. Most studies have dealt with alteration of carbohydrates at the cell surface. However, several recent studies have shown that altered glycosylation plays a major role in most aspects of the malignant phenotype, including signal transduction and apoptosis. These studies have recently been reviewed [81, 82].

In most human carcinomas, including oral carcinoma, a significant event is decreased expression of histo-blood-group antigens A and B, due to relative down-regulation of the glycosyltransferase necessary for their biosynthesis [83]. Decreased expression of A and B antigens on the cells of the carcinomas of the stomach, proximal colon, pancreas, larynx, lungs, endometrium, ovary, prostate, urinary bladder, kidney, breast and oral cavity have been reported [19 , 84]. Molecular genetic studies have shown that loss of ABO gene and/or hypermethylation of its gene promoter are events that lead to loss of A transferase in many cancers, with hypermethylation considered as a tumour specific event [85]. Other regulatory factors independent of the ABO promoter may be critical in transcriptional regulation of the ABO gene [86]. Cell motility and migration is enhanced in malignant oral cancer due to loss of ABO blood group antigen expression, and the loss of these antigens correlates with higher metastatic potential, and thus poorer prognosis [83]. Glycosylation can lead to conformational changes in proteins that not only directly stimulate cell growth and survival, but also facilitate tumour-induced immunomodulation and eventual metastasis [87, 88].

Several tumour markers are the known product of certain blood type precursors/antigens. Many of these tumour antigens resemble A antigen, which may explain the striking number of associations with blood type A and AB [6]. Detection of A antigen in tumour cells from non-A individuals indicates ABO antigens as cancer risk factors. There are blood group A-like antigens present at a biochemical level which are usually inaccessible to the immune system [89]. Hence the growth of such tumours tends to be stimulated by low level of immunity [90]. As the tumour grows, type A person who cannot make anti-A antibodies, will be more likely than an blood type O person to tolerate the cancer, but less likely than an O person to attack his own tissues [58]. Indeed, Hakomori has suggested that if the immune surveillance theory is correct and we recognize tumour antigens as foreign, leading to attack of the tumour, then the “A-like” properties of tumour antigens may not be recognized by group A patients as foreign as readily as group O patients [91]. This could explain the suggested increase of group A over O in many malignancies.

In an attempt at identifying genes associated with risk of developing pancreatic cancer, an association was found relating to the ABO blood group. Genotyping of over 500 thousand SNPs in 1896 patients with pancreatic cancer and 1939 controls revealed a significant association between SNP rs505922, mapped within the first intron of ABO [92]. The finding was consistent with earlier epidemiologic evidence suggesting that people with blood groups A and B are at increased risk of pancreatic cancer than those with group O. The recent studies highlighting an association between ABO blood group and pancreatic cancer have reignited interest in this field [9 , 70].

The alleles for the ABO gene located on chromosome 9q34 encode three glycosyltransferases to form the antigenic structures of the ABO blood groups. Blood group antigens are present on key receptors, which differ according to the cancer type, and control cell proliferation, resistance to apoptosis and adhesion, such as receptors for integrins, cadherins, epidermal growth factor and CD44 [74]. Furthermore, blood group antigens could influence two markers of inflammation–soluble intercellular adhesion molecule-1 (ICAM-1) and tumour necrosis factor-α (TNF-α) in plasma [93, 94]. ICAM-1 contributes to inflammatory responses within the blood vessel wall by augmenting atherosclerotic plaque formation and increasing endothelial cell activation. TNF-α can stimulate cell proliferation and differentiation under certain conditions. Some reports indicate that ICAM-1 and TNF-α are related to melanoma [95, 96]. The influence of ABO antigens on plasma markers of inflammation (sICAM1, TNF-α and E-selectin) suggests a possible link between chronic inflammatory states and cancer, and raising the possibility that blood group antigens may alter the systemic inflammatory response [93, 94].

Despite the multitude of studies attempting to correlate ABO phenotype with cancer risk, the link between expression of histoblood group antigens and tumourigenesis was unclear for most tumour types evaluated. The associations do not explain how antigen expression may alter tumour susceptibility neither. Thus, functional studies to determine whether ABO antigens have a function and if so, how that function may contribute to tumourigenesis is clearly needed.

Declaration of conflicting interests

The author(s) declare that they have no financial interest and personal relationships with other people or organizations that could in appropriately influence (bias) their work.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

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