ABO blood type correlates with survival in hepatocellular carcinoma following hepatectomy
Scientific RepoRts |
ABO blood type correlates with survival in hepatocellular carcinoma following hepatectomy
OPEN Published: xx xx xxxx ABO blood types are associated with the prognosis of several malignancies. However, the role of the ABO blood type in hepatocellular carcinoma (HCC) remains elusive. Here, we evaluated the prognostic role of the ABO blood group in 691 HCC patients after hepatectomy by Cox regression analysis. A prognostic nomogram was generated to predict the 3 and 5-year overall survival (OS). A total of 262 HCC patients (37.9%) had blood group O, 199 (28.8%) had blood group A, 165 (23.9%) had blood group B, and 65 (9.4%) had blood group AB. The median OS was 55 months in patients with blood group O, 39 months for blood group A, 34 months for blood group B, and 34 months for blood group AB patients (P = 0.001, log-rank test). There were significant differences in OS between patients with blood groups O and A [hazard ratio (HR) = 1.416; 95% CI, 1.101-1.820; P = 0.007], blood group B (HR = 1.736; 95% CI, 1.333-2.262; P < 0.001), blood group AB (HR = 1.739; 95% CI, 1.210-2.499; P = 0.003) and non-O blood groups (HR = 1.485; 95% CI, 1.204-1.830; P < 0.001). Our constructed nomogram (c-index = 0.687) predicted the prognosis more accurately than the TNM stage alone(c-index = 0.601). In conclusion, non-O blood groups are poor prognostic indicators for HCC following hepatectomy. Our findings justify further external validation in larger cohorts.
Variable, no (%)
Place of residence
HBV + HCV
Serum AFP level
AJCC TNM Stage
Over cohort O
691 262 (37.9)
In this study, we retrospectively evaluated the correlation of ABO blood type with prognosis in patients
receiving hepatic resection as an initial treatment for HCC in a Chinese population. The results of this study
showed that non-O blood groups (A, B, and AB) are poor prognostic indicators for HCC patients, suggesting
that ABO blood typing status might represent a refined approach to prognostic stratification and individualized
Demographic data. A final total of 691 patients (564 males and 127 females) who received hepatic resection
were included and completed follow-up. As shown in Table?1, the basic characteristics of patients were stratified
by ABO blood type. The median age of participants was 54 years[interquartile range (IQR),25?75 years)]. The
ABO blood types were as follows: O in 262 (37.9%) patients, A in 199 (28.8%) patients, B in 165 (23.9%) patients,
and AB in 65 (9.4%) patients. Patient baseline characteristics were similar across the blood groups except for the
AFP level, which was higher in individuals with blood group O(P = 0.014).
Correlation of ABO blood type with survival. Overall, 392 patients died and 299 survived after a median
follow-up of 36 months (IQR, 25?75 months). As shown in Figure?1A, the blood group correlated significantly
with OS (P = 0.001). The 1-year survival rate was 85.2%, the 3-year survival rate was 52.9%, and 5-year survival
rate was 38.7%. The median OS times were 55 months (95% CI, 42.69?67.31 months) for blood group O, 39
months (95% CI, 32.20?45.80 months) for blood group A, 34 months (95% CI, 26.58?41.42 months) for blood
group B, and 34 months (95% CI, 24.09?43.91 months) for blood group AB. The 1-, 3- and 5-year OS rates were
markedly higher in HCC patients with blood group O than patients with other blood groups (Table?2). OS was
similar in patients with A/B/AB blood groups (P = 0.226).Therefore, we divided the entire cohort into two
subgroups [blood group O versus non-O blood groups (A, B, and AB)]. The median OS for patients with blood group
O was 55 months (95% CI, 42.69?67.30 months) and non-O blood groups was 36 months (95% CI, 31.18?40.81
months). As seen in Figure?1B and Table?2, OS was significantly higher in patients with blood type O blood
compared with non-O blood types (P < 0.001). Our findings indicated that blood group AB correlated positively with
AFP levels. Thus, we further examined the interaction between blood type and AFP level as a predictor of
prognosis. As shown in Figure?2, OS differed between patients with non-O and O blood groups subdivided by AFP level.
Of note, ABO blood group correlated significantly with OS in HCC patients with high AFP levels (AFP> 400 ng/
ml, P = 0.018), but not in HCC patients with low AFP levels (P = 0.072).
Univariate analysis revealed that age (P = 0.044), serum AFP levels (P = 0.008), tumor size (P = 0.001),
stage (P < 0.001), differentiation (P < 0.001), and ABO blood group (P = 0.001) were prognostic indicators
for overall outcome. Further multivariate analysis identified age, tumor TNM stage and tumor
differentiation as significant prognostic factors for OS. In particular, the ABO blood type was a prognostic indicator
for OS. The hazard ratio (HR) of patients with blood type A was 1.416 (95% CI, 1.101?1.820, P = 0.007), the
HR of patients with blood type B was 1.736 (95% CI, 1.333?2.262, P < 0.001), and the HR of patients with
blood type AB was 1.739 (95% CI, 1.210?2.499, P = 0.006), when compared with blood group O. Patients
with non-O blood groups had a worse survival (HR = 1.485; 95% CI, 1.204?1.830; P < 0.001). These analyses
are presented in Table?3.
Prognostic nomogram for OS. As shown in Figure?3, we used a nomogram to predict the probability of
death in individual HCC patients within 3 or 5 years after hepatectomy. Independent prognostic factors (age,
tumor stage, differentiation and blood type) were incorporated into the nomogram. Calibration curves are
shown in Figure?4, and these were similar to the ideal model. The Harrell?s c-index for OS was 0.687, higher
than that for the TMN stage alone (0.601), This indicated that the nomogram was able to predict the prognosis
ABO blood type was recently shown to affect the risk of multiple cancers18, 19, including HCC16, 17. Based on these
reports, we hypothesized that the ABO blood group is associated with survival in HCC patients.
In the current study, ABO blood group was associated with OS in a large cohort of HCC patients following
hepatectomy. The prognosis and overall outcome were worse in HCC patients with non-O blood type compared with
blood group O. Interestingly, the ABO blood type did not correlate with OS in HCC patients with low AFP levels.
The correlation between blood type and oncologic outcome of HCC has not been investigated so far. Our results
are consistent with previous studies in patients with pancreatic cancer20, renal cancer and bladder cancer21, 22.
These studies indicated a better prognosis in patients with blood type O compared with non-O blood groups.
Prognostic nomograms can evaluate the prognosis in individual patients23. In this study, we developed a novel
nomogram incorporating ABO blood type and other prognostic factors. Our proposed nomogram was more
discriminative than the TNM stage in predicting the prognosis of HCC after liver resection. In addition, our
nomogram (model) might facilitate accurate prognostic stratification and the selection of optimal therapies. The
serum blood type can easily be determined in all HCC patients and understanding the influence of blood group
on tumor biology or therapeutic response may accelerate the development of individualized therapy for HCC.
The mechanisms by which ABO blood type influences HCC patient outcomes remains to be fully elucidated.
However, several plausible hypotheses may explain the correlation. The ABO gene contains two alleles (A and B)
that encode glycosyltransferases that catalyze the transfer of nucleotide donor sugars to the H antigen, which is
then converted into ABO blood group antigens24. Aberrant glycosylation is a hallmark of cancer progression25.
Terada and colleagues26 reported that ABO antigens are usually expressed in HCC tissue but not in normal liver
and chronic hepatitis tissue. This suggests that alterations in glycosyltransferase are involved in HCC
carcinogenesis and may explained how blood group affects OS in HCC patients. A correlation has also been reported between
ABO blood group and liver disease. Poujol-Robert et al. revealed that individuals with non-O blood groups had
an increased risk of liver fibrosis following HCV infection27. Moreover, Li et al. reported that non-O blood groups
may increase the risk of HCC. Furthermore, a link between ABO and important cytokines has been shown, which
may promote the development of HCC28. Recent studies have revealed single nucleotide polymorphisms in the
ABO locus that correlate with circulating levels of tumor necrosis factor-alpha (TNF-a) and intercellular adhesion
molecule-1(ICAM-1)29, 30. TNF-a is a multifunctional inflammatory cytokine involved in hepatocarcinogenesis.
ICAM-1 regulates the immune response, which is implicated in the antigen-presenting mechanism31. Serum
soluble ICAM-1(sICAM-1) has been associated with occurrence and prognosis of HCC32. Interestingly, a recent
genomic study demonstrated that sICAM-1 levels are linked to ABO gene variants33. Patients with non-O blood
groups express low levels of sICAM-1, compared with blood group O34, and reduced sICAM-1 levels may
promote tumor metastasis in these patients35. These biological mechanisms may explain the favorable survival of
HCC patients with blood type O. The mechanism underlying the interaction between blood type and AFP level is
currently not well understood and should be further explored.
There were limitations to the present study. The major disadvantage of this analysis was its retrospective
nature. The study was not representative of the general population and the possibility of selection bias cannot
be ruled out. The ABO blood group was analyzed in relation to race, but all participants were Chinese; therefore
these findings cannot reliably be extrapolated to other populations. The Eastern Cooperative Oncology Group
scores were was not assessed because these data were not available. Furthermore, unidentified confounders may
have biased our results. All participants had received a hepatectomy. Therefore, the findings cannot be used to
predict associations between blood group and survival of patients with advanced HCC.
In summary, we have shown that ABO blood type is associated with the prognosis of Chinese HCC patients after
hepatic resection. OS is reduced in patients with non-O blood types (blood group A, B, and AB) compared with
blood type O. Further studies are necessary to confirm these findings and to elucidate the underlying mechanisms.
Patients and Methods
Ethics statements and patients. The Institutional Review Board (IRB) of the First Affiliated Hospital of
Xi?an Jiaotong University approved this study. The methods were performed in accordance with approved ethical
guidelines. Informed consent was obtained from all eligible patients. After obtaining IRB approval, we
retrospectively reviewed the medical records of patients who underwent hepatectomy at the First Affiliated Hospital
of Xi?an Jiaotong University between 2008 and 2013. The exclusion criteria were as follows: previous anti-cancer
treatment prior to surgical resection, vascular invasion, portal vein tumor thrombus or extra-hepatic spread, a
class C Child-Pugh score of liver function, death within 30 days after surgery and poor data integrity. A total of
691 HCC patients were enrolled in the final analysis.
Clinical variables. Factors potentially related to survival were collected, including age, gender, place of
residence, liver cirrhosis, tumor size, differentiation, stage, Child-Pugh grades and hepatitis status. Pre-operative serum
AFP levels were also included in analysis. Information about alcohol consumption and tobacco use was obtained
from the patients. All tumor-related factors were determined by pathological examination of HCC tissue.
Study endpoints and survival data. Outcome data were collected by telephone survey until October 2014
or until patient death. Overall survival (OS) was defined as the time from start of surgery to death from any cause
or the last follow-up date. Patients alive at the time of last follow-up were defined as censored data.
Statistical analysis. Categorical variables were compared using the Chi-square test or Fisher exact test.
The cumulative OS was estimated according to the Kaplan-Meier method and tested using the log-rank test. The
prognostic value of each factor was determined according to the Cox proportional hazards regression model.
Significant prognostic indicators of endpoints in univariate analysis were included in the multivariate analysis.
A nomogram was formulated based on the results of the multivariable analysis. Harrell?s c-index and
calibration curve were used to assess the performance of the nomogram36. These activities were calculated using
bootstrapping with 1000 repetitions. The prognostic nomogram were constructed and analyzed by R 3.3.1 with rms
packages (http://www.r-project.org). Other statistical analyses were performed using SPSS23.0 software (IBM
Corporation, Armonk, NY, USA). Statistical significance was set at P < 0.05.
This study was supported by the National Natural Science Foundation of China (81372581) and the Science and
Technology Project of Xi?an[SF1324(
H.G., K.-J.N. and L.-N.L. conceived the study. Q.L., M.-J.L., J.-Y.G., T.W. and L.-N.L. collected clinical data and
performed data analysis. G.-Q.W., X.L., Z.-P.R., and T.T. contributed to the analysis and interpretation of data.
T.W, L.-N.L. and X.-A.M. co-wrote and revise the manuscript. All authors reviewed the manuscript.
Competing Interests: The authors declare that they have no competing interests.
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1. Ferlay , J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 . International journal of cancer 136 , E359 -386, doi:10.1002/ijc.29210 ( 2015 ).
2. El-Serag , H. B. & Rudolph , K. L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis . Gastroenterology 132 , 2557 - 2576 , doi:10.1053/j.gastro. 2007 . 04 .061 ( 2007 ).
3. Davis , G. L. , Alter , M. J. , El-Serag , H. , Poynard , T. & Jennings , L. W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression . Gastroenterology 138 , 513 - 521 , 521 . e511 - 516 , doi:10.1053/j.gastro. 2009 . 09 .067 ( 2010 ).
4. El-Serag , H. B. Hepatocellular carcinoma . The New England journal of medicine 365 , 1118 - 1127 , doi:10.1056/NEJMra1001683 ( 2011 ).
5. Roayaie , S. et al. The role of hepatic resection in the treatment of hepatocellular cancer . Hepatology (Baltimore , Md.) 62 , 440 - 451 , doi:10.1002/hep.27745 ( 2015 ).
6. DeSantis , C. E. et al. Cancer treatment and survivorship statistics . CA: a cancer journal for clinicians 64 , 252 - 271 , doi:10.3322/ caac.21235 ( 2014 ).
7. Altekruse , S. F. , McGlynn , K. A. & Reichman , M. E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005 . Journal of clinical oncology: official journal of the American Society of Clinical Oncology 27 , 1485 - 1491 , doi:10.1200/JCO. 2008 . 20 .7753 ( 2009 ).
8. Park , B. K. et al. Long-term outcome of chronic hepatitis B based on histological grade and stage . Journal of gastroenterology and hepatology 22 , 383 - 388 , doi:10.1111/j.1440- 1746 . 2007 . 04857 . x ( 2007 ).
9. Kelley , R. K. & Venook , A. P. Novel therapeutics in hepatocellular carcinoma: how can we make progress? American Society of Clinical Oncology educational book/ASCO . American Society of Clinical Oncology. Meeting. doi: 10 .1200/EdBook_AM. 2013 . 33 . e137 ( 2013 ).
10. Tandon , P. & Garcia-Tsao , G. Prognostic indicators in hepatocellular carcinoma: a systematic review of 72 studies. Liver inte r n ati on al : of f i c i al j our n al of th e Inte r n ati on al Ass o c i ati on for th e Stu dy of th e Liv e r 2 9 , 5 0 2 - 5 1 0 , doi:10.1111/j.1478- 3231 . 2008 . 01957 .x ( 2009 ).
11. Franchini , M. , Favaloro , E. J. , Targher , G. & Lippi , G. ABO blood group, hypercoagulability, and cardiovascular and cancer risk . Critical reviews in clinical laboratory sciences 49 , 137 - 149 , doi:10.3109/10408363. 2012 . 708647 ( 2012 ).
12. Xu , Y. Q. , Jiang , T. W. , Cui , Y. H. , Zhao , Y. L. & Qiu , L. Q. Prognostic value of ABO blood group in patients with gastric cancer . The Journal of surgical research 201 , 188 - 195 , doi:10.1016/j.jss. 2015 . 10 .039 ( 2016 ).
13. Hanprasertpong , J. , Jiamset , I. & Atjimakul , T. Prognostic value of ABO blood group in patients with early stage cervical cancer treated with radical hysterectomy with pelvic node dissection . Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 37 , 7421 - 7430 , doi:10.1007/s13277-015-4626- 1 ( 2016 ).
14. Zhou , J. et al. Prognostic Impact of ABO Blood Group on the Survival in Patients with Ovarian Cancer . Journal of Cancer 6 , 970 - 975 , doi:10.7150/jca.12471 ( 2015 ).
15. Gates , M. A . et al. ABO blood group and breast cancer incidence and survival . International journal of cancer 130 , 2129 - 2137 , doi:10.1002/ijc.26220 ( 2012 ).
16. Iavarone , M. et al. Risk of hepatocellular carcinoma in relation to ABO blood type . Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 48 , 94 - 96 , doi:10.1016/j.dld. 2015 . 10 .011 ( 2016 ).
17. Shim , H. J. et al. Association between ABO genotype and risk of hepatocellular carcinoma in Koreans . Asian Pacific journal of cancer prevention: APJCP 16 , 2771 - 2775 ( 2015 ).
18. Hsiao , L. T. , Liu , N. J. , You , S. L. & Hwang , L. C. ABO blood group and the risk of cancer among middle-aged people in Taiwan . Asia-Pacific journal of clinical oncology 11 , e31 - 36 , doi:10.1111/ajco.12253 ( 2015 ).
19. Li , B. , Tan , B. , Chen , C. , Zhao , L. & Qin , L. Association between the ABO blood group and risk of common cancers . Journal of evidence-based medicine 7 , 79 - 83 , doi:10.1111/jebm.12098 ( 2014 ).
20. Rahbari , N. N. et al. AB0 blood group and prognosis in patients with pancreatic cancer . BMC cancer 12 , 319, doi:10.1186/ 1471 -2407- 12- 319 ( 2012 ).
21. Kaffenberger , S. D. et al. ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma . BJU international 110 , E641 -646, doi:10.1111/j. 1464 - 410X . 2012 . 11366 . x ( 2012 ).
22. Gershman , B. et al. The association of ABO blood type with disease recurrence and mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy . Urologic oncology 34, 4.e1-9 , doi:10.1016/j.urolonc. 2015 . 07 .023 ( 2016 ).
23. Yang , H. I. et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection . Journal of clinical oncology: official journal of the American Society of Clinical Oncology 28 , 2437 - 2444 , doi:10.1200/jco. 2009 . 27 .4456 ( 2010 ).
24. Wolpin , B. M. et al. ABO blood group and the risk of pancreatic cancer . Journal of the National Cancer Institute 101 , 424 - 431 , doi:10.1093/jnci/djp020 ( 2009 ).
25. Hakomori , S. Glycosylation defining cancer malignancy: new wine in an old bottle . Proceedings of the National Academy of Sciences of the United States of America 99 , 10231 - 10233 , doi:10.1073/pnas.172380699 ( 2002 ).
26. Terada , T. & Nakanuma , Y. Expression of ABH blood group antigens, receptors of Ulex europaeus agglutinin I, and factor VIIIrelated antigen on sinusoidal endothelial cells in adenomatous hyperplasia in human cirrhotic livers . Human pathology 22 , 486 - 493 ( 1991 ).
27. Poujol-Robert , A. , Boelle , P. Y. , Wendum , D. , Poupon , R. & Robert , A. Association between ABO blood group and fibrosis severity in chronic hepatitis C infection . Digestive diseases and sciences 51 , 1633 - 1636 , doi:10.1007/s10620-006-9121- 5 ( 2006 ).
28. Engelmann , B. , Schumacher , U. & Haen , E. Epidermal growth factor binding sites on human erythrocytes in donors with different ABO blood groups . American journal of hematology 39 , 239 - 241 ( 1992 ).
29. Melzer , D. et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs) . PLoS genetics 4 , e1000072, doi:10.1371/journal.pgen. 1000072 ( 2008 ).
30. Pare , G. et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women . PLoS genetics 4 , e1000118, doi:10.1371/journal.pgen. 1000118 ( 2008 ).
31. Staunton , D. E. , Marlin , S. D. , Stratowa , C. , Dustin , M. L. & Springer, T. A. Primary structure of ICAM-1 demonstrates interaction between members of the immunoglobulin and integrin supergene families . Cell 52 , 925 - 933 ( 1988 ).
32. Shimizu , Y. et al. Serum concentration of intercellular adhesion molecule-1 in patients with hepatocellular carcinoma is a marker of the disease progression and prognosis . Hepatology (Baltimore , Md.) 22 , 525 - 531 ( 1995 ).
33. Barbalic , M. et al. Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels . Human molecular genetics 19 , 1863 - 1872 , doi:10.1093/hmg/ddq061 ( 2010 ).
34. Witkowska , A. M. & Borawska , M. H. Soluble intercellular adhesion molecule-1 (sICAM-1): an overview . European cytokine network 15 , 91 - 98 ( 2004 ).
35. Kobayashi , H. , Boelte , K. C. & Lin , P. C. Endothelial cell adhesion molecules and cancer progression . Current medicinal chemistry 14 , 377 - 386 ( 2007 ).
36. Balachandran , V. P. , Gonen , M. , Smith , J. J. & DeMatteo , R. P. Nomograms in oncology: more than meets the eye . The Lancet. Oncology 16 , e173 - 180 , doi:10.1016/s1470-2045( 14 ) 71116 - 7 ( 2015 ).