Inclusion criteria
(1) Newly diagnosed, biopsy-proven of WHO type III (Shanmugaratnam & Sobin, 1991), non-metastatic NPC
patients without anticancer treatment before being hospitalized at the Sun Yat-sen University Cancer Center;
(2) Patients born in southern China;
(3) Patients had a complete pretreatment evaluation including patient history, physical examination, hematology
and biochemistry profiles, magnetic resonance imaging (MRI) of the nasopharynx and neck, chest radiography,
abdominal sonography and a whole-body bone scan using single-photon emission computed tomography;
(4) Patients had complete records about cigarette smoking status at diagnosis, alcohol drinking status at diagnosis,
pretreatment titer of serum immunoglobulin A against EBV viral capsid antigen (VCA-IgA) and ABO blood type.
Potential mechanisms
A previous study in gastric cancer (Beckman & Angqvist, 1987) demonstrated that blood type O provided a
protective effect by preventing the growth and spread of tumors, thus blood type A patients had shorter survival
than blood type O patients. Underlying molecular and pathogenic differences may play more important roles in
the effect of ABO blood groups on survival. Firstly, the ABO blood group alleles on chromosome 9q34.1 encode
specific A and B glycosyltransferases which then alter a protein backbone – the H antigen – to create the A and B
cell surface antigens. (Reid & Mohandas, 2004) Due to a frameshift mutation, the O allele encodes a
non-functional glycosyltransferase, and the H antigen is thereby unaltered in individuals with blood type O. Blood
group antigens are expressed on the surface of red blood cells and numerous other tissues throughout the body,
including the epithelial cells of head and neck (Adam et al, 2012; Yazer, 2005). Modified expression of blood group
antigens on the surface of cancer cells may alter their cell motility, sensitivity to apoptosis, and immune escape,
with important implications on malignant progression (Le Pendu et al, 2001). It is well known that loss of the
expression of the histo-blood group A/B antigens is a frequent event in tumors (Dabelsteen, 1996; Mandel et al,
1992; Sanchez-Mora et al, 2007), and that the incidence of this loss can be as high as 84% in oral squamous cell
carcinoma (Gao et al, 2004). Previous studies have shown that loss of the histo-blood group A and B antigens is
associated with a poor prognosis in cancers of the lung, urinary bladder, and head and neck (Malmstrom et al,
1988; Moldvay et al, 2000; Wolf et al, 1990). Unfortunately, the expression of blood type A antigens was not
examined in the tumor tissues in this study, and there are no reports on the incidence of the loss of expression of
the histo-blood group A antigen in NPC. However, the prognostic impact of the ABO blood groups in NPC via this
mechanism should not be neglected. Secondly, a recent study showed an association between ABO blood group
status and the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) (Pare et al, 2008), and the
serum sICAM-1 concentration is related to distant metastasis in NPC (Yu et al, 2004). Therefore, sICAM-1 may
further explain the association between the ABO blood groups and survival in NPC. Notably, the sICAM-1
concentration is significantly lower in patients with blood type A or B, particularly blood type A, than those with
blood type O (Pare et al, 2008). It is known that sICAM-1 may function as an immunosuppressive agent by
blocking lymphocyte function–associated antigen 1 (LFA-1) on T lymphocytes, then rendering it less available for
binding to ICAM-1 expressed on the surface of cancer cells, which would allow cancer cells to avoid
ICAM-1/LFA-1–mediated tumor cell cytotoxicity (Becker et al, 1991). Thus the lower concentration of sICAM-1 in
patients with blood type A, compared to those with blood type O, may partially explain the poorer survival of
patients with blood type A in NPC. Further basic research is required to fully elucidate the potential mechanisms
by which blood type A is associated with poorer survival in NPC.
Study limitations
The following limitations of this study deserve comment. Firstly, like other retrospective studies in NPC, the
treatment regimens were not totally consistent with the latest NCCN guidelines, for example, the number of
patients with Stage I and II disease was not equal to the number of patients who received RT alone. This is mainly
due to the fact that most patients were initially staged according to the sixth edition of the AJCC/UICC Staging
System or the Chinese 1992 Staging System for NPC before making treatment decisions, whereas we restaged the
patients according to the seventh edition of the AJCC/UICC Staging System during the retrospective analysis.
Additionally, during the period of time when the patients were treated, many patients were encouraged to
participate in randomized trials, which also resulted in heterogeneous treatment strategies. However, we analyzed
the association of the blood groups with survival in the IMRT and CRT cohorts individually, and undertook
subgroup analyses on the basis of the patients’ basic characteristics, especially the type of chemotherapy
regimens used. Therefore, the significant conclusions were little influenced by the heterogeneity of radiation
techniques and chemotherapy regimens. Secondly, we were unable to collect adequate information regarding the
patients’ pretreatment plasma EBV DNA copy number, which has been demonstrated to strongly predict survival
in NPC (Lin et al, 2004; Lo et al, 2000). However, we performed multivariate analysis and stratified analysis
according to the pretreatment serum EBV VCA-IgA antibody titer, another significant prognostic factor for survival
in NPC (Ling et al, 2009), though the plasma EBV DNA copy number has been shown to be superior to the serum
EBV VCA-IgA antibody titer for making prognostic predictions in NPC (Twu et al, 2007). Studies based on the
plasma EBV DNA copy number are being planned. Thirdly, we could not collect information on treatment delay –
the time from cancer diagnosis and begin of radiotherapy. Fourthly, we excluded patients with missing data, such
as data on smoking status at diagnosis, alcohol drinking status at diagnosis and pretreatment titer of VCA-IgA, and
patients with unknown ABO blood type. This may result in information bias. Finally, 233/2117 (11.0%) patients for
the entire population, 59/577 (10.2%) and 174/1540 (11.3%) patients with blood type A and non-A blood types
were lost to follow up, respectively.
References
Adam SI, Wilson KM, Overholser SM, Khabbaz E, Moreno K, Patil YJ (2012) Are laryngeal squamous cell carcinoma
incidence and patient mortality a function of ABO blood grouping? A retrospective study. J Laryngol Otol 126(2): 180-4
Becker JC, Dummer R, Hartmann AA, Burg G, Schmidt RE (1991) Shedding of ICAM-1 from human melanoma cell lines
induced by IFN-gamma and tumor necrosis factor-alpha. Functional consequences on cell-mediated cytotoxicity. J
Immunol 147(12): 4398-401
Beckman L, Angqvist KA (1987) On the mechanism behind the association between ABO blood groups and gastric
carcinoma. Hum Hered 37(3): 140-3
Dabelsteen E (1996) Cell surface carbohydrates as prognostic markers in human carcinomas. J Pathol 179(4): 358-69
Gao S, Worm J, Guldberg P, Eiberg H, Krogdahl A, Liu CJ, Reibel J, Dabelsteen E (2004) Genetic and epigenetic alterations
of the blood group ABO gene in oral squamous cell carcinoma. Int J Cancer 109(2): 230-7
Le Pendu J, Marionneau S, Cailleau-Thomas A, Rocher J, Le Moullac-Vaidye B, Clement M (2001) ABH and Lewis
histo-blood group antigens in cancer. APMIS 109(1): 9-31
Malmstrom PU, Busch C, Norlen BJ, Andersson B (1988) Expression of ABH blood group isoantigen as a prognostic factor
in transitional cell bladder carcinoma. Scand J Urol Nephrol 22(4): 265-70
Mandel U, Langkilde NC, Orntoft TF, Therkildsen MH, Karkov J, Reibel J, White T, Clausen H, Dabelsteen E (1992)
Expression of histo-blood-group-A/B-gene-defined glycosyltransferases in normal and malignant epithelia: correlation
with A/B-carbohydrate expression. Int J Cancer 52(1): 7-12
Moldvay J, Scheid P, Wild P, Nabil K, Siat J, Borrelly J, Marie B, Farre G, Labib T, Pottier G, Sesboue R, Bronner C, Vignaud
JM, Martinet Y, Martinet N (2000) Predictive survival markers in patients with surgically resected non-small cell lung
carcinoma. Clin Cancer Res 6(3): 1125-34
Pare G, Chasman DI, Kellogg M, Zee RY, Rifai N, Badola S, Miletich JP, Ridker PM (2008) Novel association of ABO
histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS
Genet 4(7): e1000118
Reid ME, Mohandas N (2004) Red blood cell blood group antigens: structure and function. Semin Hematol 41(2): 93-117
Sanchez-Mora N, Cebollero Presmanes M, Monroy V, Herranz Aladro M, Alvarez-Fernandez E (2007) Expression of
histo-blood group antigens in bronchial squamous metaplasia. Eur Respir J 29(2): 268-72
Shanmugaratnam K, Sobin LH (1991) International histological classification of tumours, 2nd edn: WHO
Wolf GT, Carey TE, Schmaltz SP, McClatchey KD, Poore J, Glaser L, Hayashida DJ, Hsu S (1990) Altered antigen expression
predicts outcome in squamous cell carcinoma of the head and neck. J Natl Cancer Inst 82(19): 1566-72
Yazer MH (2005) What a difference 2 nucleotides make: a short review of ABO genetics. Transfus Med Rev 19(3): 200-9
Yu Y, Dong W, Zhou X, Li S (2004) The significance of serum soluble intercellular adhesion molecule 1 and transforming
growth factor alpha in patients with nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 130(10): 1205-8