Evaluation of ABO blood group as a prognosticmarker in renal cell carcinoma (RCC)Michela de Martino, Matthias Waldert, Andrea Haitel*, Georg Schatzl,Shahrokh F. Shariat and Tobias KlatteDepartments of Urology and *Clinical Pathology, Medical University of Vienna, Vienna, Austria

Objective• To evaluate ABO blood group as a prognostic marker in

patients with renal cell carcinoma (RCC).

Patients and Methods• This retrospective study included 556 consecutive patients

who underwent surgery for RCC at a single institution.• The associations of ABO blood group with clinical and

pathological variables were assessed using Kruskal–Wallisand chi-squared tests.

• The impact on overall survival (OS) and RCC-specificsurvival (RCC-SS) was analysed using univariable andmultivariable Cox proportional hazards regression models.

Results• Blood group O was associated with the absence of lymph

node metastases (P = 0.034) and the presence of bilateralRCC (P = 0.017).

• No associations with age, gender, body mass index, Charlsoncomorbidity index, T stage, M stage, grade and histologicalsubtype were observed.

• In univariable and multivariable survival analysis,ABO blood group was not associated with OS andRCC-SS.

Conclusions• In the present study, ABO blood group was not linked with

RCC prognosis.• Blood group O may be associated with the absence of

lymph node metastases and the presence of bilateralRCC.

• External validation in larger cohorts is necessary.

KeywordsABO, blood group, blood type, prognosis

IntroductionRenal cell carcinoma is the third leading tumour type of thegenitourinary tract with >60 000 new cases being diagnosed inthe USA annually [1]. Tobacco use, obesity, and arterialhypertension are modifiable risk factors for the disease [2],and a familial history in a first-degree relative increases thelifetime risk 1.6-fold [3]. RCC is also associated with severalgenetic syndromes such as von Hippel–Lindau disease,hereditary papillary RCC, and Birt–Hogg–Dubé’s syndrome[4]. Surgery is the mainstay of therapy for RCC, and TNMstage and grade are its most established prognostic factors[5–8].

ABO blood group is a potential inherited marker of cancersusceptibility and progression. Studies show that blood groupis associated with the risk of various solid malignancies[9–11], and may also serve as a prognostic marker [12,13]. InRCC, a study conducted several decades ago suggested arelationship between blood group antigens and the risk ofdeveloping the disease [14], whereas other studies havereported no association [15–17]. Kaffenberger et al. [18]

recently showed, in a cohort of 900 patients with RCC withoutdistant metastases, that blood group O was associated withbetter overall survival (OS). Thus, data suggest a possible roleof ABO blood group in the progression of RCC. The aim ofthe present study was to verify this blood group status as aprognostic marker.

Materials and MethodsStudy Design

The cohort of the present retrospective study consisted of556 consecutive white patients, who underwent radical orpartial nephrectomy for RCC of all subtypes and all stages atour institution between January 2002 and December 2012.Patients with familial RCC and hereditary RCC wereexcluded.

Patient data were collected prospectively in the institutionalkidney cancer database. The database was analysedretrospectively after obtaining institutional review boardapproval (protocol registration number 1958/2012). Clinical,

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pathological, laboratory and follow-up information wasgathered. Clinical data included ABO blood group, age,gender, self-reported history of smoking and body mass index(BMI). Comorbidity status was graded using the Charlsoncomorbidity index (CCI). Pathological data comprisedhistological subtype, according to the WHO classification [19],TNM stage, according to the 2010 criteria [20], and Fuhrmangrade [21]. All surgical specimens were examined by an experturological pathologist (A.H.). N stage was assigned fromradiological and pathological data. Patients with clinicallypositive nodes, defined as the presence of at least one node>10 mm in size in the retroperitoneal lymphatic area atpreoperative imaging, underwent a node dissection. In patientswith negative nodes on imaging, the node dissection wasperformed at the surgeon’s discretion. The positive nodesreported in the present study were all confirmedpathologically. No adjuvant therapy was administered.Postoperative surveillance was performed according toestablished guidelines [5].

Statistical Analysis

The continuous variables age and BMI were found to benon-normally distributed (Kolmogorov–Smirnov P > 0.3).These variables are therefore presented as median values withinterquartile ranges (IQRs).

Because of the low numbers of patients in several stratums,ABO blood group was evaluated as O and non-O, aspreviously suggested [18]. Univariable associations withclinical and pathological factors (age, gender, BMI, smokinghistory, CCI, TNM stage, grade, bilaterality and subtype) wereanalysed using Kruskal–Wallis and chi-squared tests, asappropriate. Significant univariable predictor variables weretested in multivariable logistic regression models.

The Kaplan–Meier product limit method was used to estimatefunctions for OS and RCC-specific survival (RCC-SS).Follow-up information was available for 442 of the 556 RCCpatients (79.5%). The survival times were calculated from thedate of surgery to the date of last follow-up, death or deathfrom RCC, respectively. Differences in Kaplan–Meier curveswere assessed using log-rank tests. Univariable andmultivariable Cox proportional hazards regression modelswere used to evaluate the relationship of OS and RCC-SS withABO blood group and clinical and pathological variables. Toreduce the risk of over-fitting in multivariable Cox models,only factors that were significantly (P < 0.05) associated withsurvival in univariable analysis were included for multivariablemodelling with ABO blood group. Multivariable Cox modelswere bootstrap-corrected to account for dichotomization bias(200 resamples). All statistical testing was two-sided and a Pvalue <0.05 was considered to indicate statistical significance.The statistical package STATA 11.2 (Stata Corp., College Station,TX, USA) was used for all analyses.

ResultsAssociation with Clinical and Pathological Factors

Results are shown in Table 1. Blood group O was associatedwith a significantly lower risk of lymph node metastases (1.0%vs 4.0%, P = 0.034). Of the 16 patients with positive nodes, 14(87.5%) had a non-O blood group. In multivariable logisticregression analysis, non-O blood group (odds ratio [OR] 5.79,95% CI 1.22–27.51, P = 0.027), M stage (OR 5.29, 95% CI1.64–17.12, P = 0.005), and grade (hazard ratio [HR] 22.32,95% CI 2.69–185.42, P = 0.004) were independent predictorsof lymph node metastases.

Furthermore, blood group O increased the risk of bilateralRCC (OR 2.45, 95% CI 1.15–5.24, P = 0.017). Of 29 (58.6%)patients with bilateral RCC, 17 had blood group O, comparedwith 193 of 527 (36.6%) patients with unilateral disease. Inmultivariable analysis, blood group O was an independentpredictor of bilateral disease (OR 0.42, 95% CI 0.19–0.87, P =0.023), while age, gender, T stage, N stage, M stage and gradewere not.

No associations of ABO blood group with age, gender, BMI,smoking history, CCI, T stage, M stage, grade or subtype wereobserved (Table 1).

Association with Survival

The median (IQR) follow-up was 39 (45) months. There were93 overall deaths, of which 61 (66%) were attributable toRCC. The 5-year OS and RCC-SS rates (±SE) were 75 (±3) %and 83 (±2) %, respectively, with no difference betweenpatients with blood group O and non-O (P = 0.33 andP = 0.99, respectively). Similarly, if blood groups wereanalysed unstratified as O, A, B, and AB, no differences in theKaplan–Meier functions were seen (every P value >0.4; Fig. 1).Similar results were obtained when the cohort was stratifiedinto non-metastatic (P = 0.14 and P = 0.75) and metastaticdisease (P = 0.91 and P = 0.91). In non-metastatic disease,there was also no association with recurrence-free survival(P = 0.81). In univariable and multivariable Cox modelspredicting OS and RCC-SS, ABO blood group was not asignificant prognostic factor (Table 2).

DiscussionIn the present study, we analysed the association of ABOblood group with clinicopathological factors and prognosis ofpatients with RCC. Blood group O was associated with theabsence of lymph node metastases and the presence ofbilateral RCC, but was not linked to survival.

The primary goal of our study was to validate ABO bloodgroup as a prognostic factor. Recently, Kaffenberger et al. [18]found in a cohort of 900 patients without distant metastasesthat blood group O was associated with improved OS. The

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3-year OS rates were 75% for patients with blood group O and68% for those with blood group non-O. In the multivariableanalysis, patients with blood group non-O had a 1.68-foldgreater risk of death from all causes. In addition, a

nonsignificant trend (P = 0.065) was observed for RCC-SS. Inthe present study, we could not demonstrate a survivaldifference between patients with blood group O and non-O.There are several possible explanations for the discrepancy

Table 1 Associations of ABO blood group with clinical and pathological variables in 556 patientswith RCC.

Variable All patients,N = 556

Blood group P

O, n = 210 Non-O, n = 346

Median (IQR) age, years 64 (55–72) 63 (56–70) 65 (54–73) 0.47Male, n (%) 367 (49.2) 140 (66.7) 227 (65.6) 0.80Median (IQR) BMI 27.0 (24.1–30.1) 27.1 (24.2–30.4) 26.9 (23.9–29.8) 0.32Pack years, n (%) 0.77

0 358 (64.4) 139 (66.2) 219 (63.3)1–40 108 (19.4) 38 (18.1) 70 (20.2)>40 90 (16.2) 33 (15.7) 57 (16.5)

CCI >1, n (%) 239 (43.0) 85 (40.5) 154 (44.5) 0.35pT stage, n (%) 0.69

T1–2 309 (55.6) 119 (56.7) 190 (54.9)T3–4 247 (44.4) 91 (43.3) 156 (45.1)

pN stage, n (%) 0.034pNx/N0 540 (97.1) 208 (99.0) 332 (96.0)pN+ 16 (2.9) 2 (1.0) 14 (4.0)

M stage, n (%) 0.65M0 484 (87.1) 181 (86.2) 303 (87.6)M1 72 (12.9) 29 (13.8) 43 (12.4)

Fuhrman grade, n (%) 0.741–2 399 (71.8) 149 (71.0) 250 (72.3)3–4 157 (28.2) 61 (29.0) 96 (27.7)

Laterality, n (%) 0.017Unilateral 527 (94.8) 193 (91.9) 334 (96.5)Bilateral 29 (5.2) 17 (8.1) 12 (3.5)

Subtype, n (%) 0.48Clear-cell 394 (70.9) 154 (73.3) 240 (69.4)Papillary 107 (19.2) 35 (16.7) 72 (20.8)Chromophobe 55 (9.9) 21 (10.0) 34 (9.8)

Blood group O was associated with the absence of lymph node metastases and the presence of bilateral RCC.

0.0

0.2

0.4

0.6

0.8

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0 12

OABABNon-O

Numbers at risk

A B

134148

6025

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4722

181

66642915

108

5340141367

77913820

149

24Months from surgery

p = n.s.

Prob

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ty o

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ival

36 48 600.0

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p = n.s.Prob

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-spe

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ival

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OABABNon-O

Numbers at risk134148

6025

233

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66642915

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5340141367

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Fig. 1 Kaplan–Meier curves for (A), OS and

(B), RCC-SS according to ABO blood group.

There was no significant difference for any

comparison. Non-O blood groups are also

summarized (dashed curve). The numbers of

patients at risk are indicated.

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between the two studies. First, the inclusion criteria differed.We included patients of all stages, whereas Kaffenberger et al.[18] excluded patients with distant metastases. This differencein inclusion criteria, however, should have been balanced withmultivariable modelling. Second, the distribution of bloodgroups differs among countries and races and thus among theinstitutions, which subsequently affects statistical power.Finally, a significant association may have been blurred by thelower number of patients (n = 556) and the relatively lownumber of events (n = 93), so that the present study may havebeen underpowered to detect a significant difference. The βerror may have been a limitation of the present study, i.e. thatthe null hypothesis (no survival difference) is false, but is notrejected; however, it is also possible that a significantdifference would not have been detected with more patientsand events. To the best of our knowledge, no other dataregarding the prognostic impact of ABO blood group in RCCare available. Further studies are necessary.

Our data suggest that blood group O is associated with alower risk of lymph node metastases. As the number ofpatients with positive nodes was small (n = 16) and themajority of these patients presented with concomitantdistant metastases, this did not translate into a survivaldifference in either univariable or multivariable analyses.Data suggest that different routes of metastatic spread(lymphatic vs haematogenous spread) are the result ofunique biological propensities [22]. One could thushypothesize that blood group O may be protective withregard to lymphatic, but not haematogenous spread. Ourfinding is in contrast to the study by Kaffenberger et al. [18],who reported no association with lymph node involvement.This may, in part, be attributed to selection bias, as theseauthors excluded patients with distant metastasis. We didnot exclude patients with distant metastases; these patientsaccounted for the majority of those with metastatic lymph

nodes. The results of the present study further suggest thatblood group O is associated with bilateral RCC. To thebest of our knowledge, this is the first study showing thisrelationship. Reflecting the overall low incidence of positivenodes and bilateral disease, our data are derived from a smallnumber of patients. The present study generates hypotheses,and external validation in larger datasets is necessary.

The mechanisms through which blood group may influencecancer risk and progression are largely unknown. The ABOgene is located on chromosome 9q34 and is encoding forglycosyl-transferases, which catalyse the transfer of sugars tothe H antigen to form the blood group antigen [23]. The Oallele encodes a non-functional glycosyl-transferase and the Hantigen, which leaves the H antigen unaltered. ABO bloodgroup antigens are expressed on red blood cells and severalother normal and tumour tissues, including the kidney andseveral RCC cell lines [24,25]. Blood group antigens maycontribute by modifying cell adhesion, membrane signalling,and immune surveillance, which may in turn affect cancerdevelopment and progression [26]. These processes may inpart be influenced by TNF-α, as polymorphisms at the ABOgene locus are linked with TNF-α serum levels [27].

The best data on the impact of ABO blood group on cancerrisk and survival come from studies on pancreatic cancer. Twolarge, independent, prospective cohort studies showed that therisk of pancreatic cancer is increased 1.32–1.72-fold if anon-O blood group is present [11]. Moreover, it has beenshown that a non-O blood group decreases the risk of skincancer [28] and that the B antigen increases the incidence ofovarian cancer [29], while other studies have not shown anassociation of blood group with cancer risk [16,30]. A fewstudies have investigated the role of blood group as aprognostic marker in malignancies other than RCC, withvarying results [12,13,18,30].

Table 2 Univariable and bootstrap-corrected multivariable Cox models predicting OS and RCC-SS.

Variable OS RCC-SS

Univariable Multivariable Univariable Multivariable

HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P

Age >65 years 1.88 1.24–2.85 0.003 2.33 1.50–3.60 <0.001 1.64 0.98–2.73 0.06Male vs female 1.25 0.80–1.95 0.33 1.25 0.72–2.17 0.43BMI 0.99 0.95–1.03 0.71 1.02 0.98–1.07 0.33CCI >1 1.58 1.05–2.38 0.028 1.16 0.76–1.78 0.49 1.57 0.95–2.61 0.08T3–4 vs T1- 2.86 1.86–4.39 <0.001 1.63 0.99–2.66 0.052 7.42 3.76–14.63 <0.001 3.08 1.44–6.60 0.004N+ vs Nx/0 9.23 4.88–17.46 <0.001 4.04 1.97–8.29 <0.001 14.95 7.69–29.07 <0.001 3.63 1.76–7.46 <0.001M1 vs M0 8.11 5.30–12.39 <0.001 5.99 3.70–9.70 <0.001 18.83 10.96–32.37 <0.001 10.20 5.53–18.82 <0.001Grade 3/4 vs 1/2 3.05 2.02–4.60 <0.001 1.85 1.16–2.96 0.010 5.25 3.09–8.95 <0.001 2.23 1.21–4.10 0.010Non-clear-cell vs clear-cell 0.96 0.61–1.50 0.84 0.75 0.41–1.36 0.34Bilateral vs unilateral 0.88 0.41–1.91 0.75 0.81 0.29–2.24 0.69Blood group non-O vs O 0.82 0.54–1.23 0.33 0.72 0.48–1.10 0.13 1.00 0.60–1.67 0.99 0.86 0.51–1.45 0.56

In all analyses, ABO blood group was not an independent prognostic factor.

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The present study has several limitations. Its design wasretrospective and we analysed a relatively small cohort ofpatients with a short follow-up. Some hypotheses, e.g. thatblood group O is associated with the absence of lymph nodemetastases and the presence of bilateral RCC, are generatedfrom sub-analyses of small cohorts and should be confirmedwith larger datasets. The study did not confirm the previouslyreported association of ABO blood group with OS [18], butour analysis may have been underpowered to detect asignificant difference. Since the study population and inclusioncriteria differed considerably, the two studies should beinterpreted as complementary, not oppositional. We suggestthat there is a different impact of ABO blood group onsurvival, although our conclusions are limited.

In conclusion, the present study showed ABO blood groupwas not associated with RCC prognosis. Blood group O was,however, associated with the absence of lymph nodemetastasis and the presence of bilateral RCC. Externalvalidation of these findings on larger well-defined cohorts isnecessary.

Conflict of InterestNone declared.

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Correspondence: Tobias Klatte, Department of Urology,Medical University of Vienna, Vienna General Hospital,Währinger Gürtel 18-20, A-1090 Vienna, Austria.

e-mail: tobias.klatte@gmx.de

Abbreviations: BMI, body mass index; CCI, Charlsoncomorbidity index; OS, overall survival; RCC-SS, RCC-specificsurvival; OR, odds ratio; HR, hazard ratio; IQR, interquartilerange.

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