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Blood type, ABO genetic variants, and ovarian cancersurvival.

RESEARCH ARTICLE

Blood type,ABO genetic variants,and ovarian cancer survival

Gabriella D.Cozzi 1,Rebecca T.Levinson 2,Hilary Toole 3,Malcolm-Robert Snyder 1,Angie Deng 1,Marta A.Crispens 4,5,Dineo Khabele 4,5,Alicia Beeghly-Fadiel 1,5*

1Division of Epidemiology,Department of Medicine,Vanderbilt University Medical Center,Nashville TN,United States of America,2Vanderbilt Genetics Institute,Vanderbilt University School of Medicine,Nashville TN,United States of America,3Meharry Medical College,Nashville TN,United States of America,

4Department of Obstetrics and Gynecology,Vanderbilt University Medical Center,Nashville TN,United States of America,5Vanderbilt-Ingram Cancer Center,Nashville TN,United States of America *alicia.beeghly@https://www.sodocs.net/doc/4117590170.html,

Abstract

Objective

Blood type A and the A1allele have been associated with increased ovarian cancer risk.With only two small studies published to date,evidence for an association between ABO blood type and ovarian cancer survival is limited.

Methods

We conducted a retrospective cohort study of Tumor Registry confirmed ovarian cancer cases from the Vanderbilt University Medical Center with blood type from linked laboratory reports and ABO variants from linked Illumina Exome BeadChip data.Associations with overall survival (OS)were quantified by hazard ratios (HR)and confidence intervals (CI)from proportional hazards regression models;covariates included age,race,stage,grade,histologic subtype,and year of diagnosis.

Results

ABO phenotype (N =694)and/or genotype (N =154)data were available for 713predomi-nantly Caucasian (89.3%)cases.In multivariable models,blood type A had significantly bet-ter OS compared to either O (HR:0.75,95%CI:0.60–0.93)or all non-A (HR:0.77,95%CI:0.63–0.94)cases.Similarly,missense rs1053878minor allele carriers (A2)had better OS (HR:0.50,95%CI:0.25–0.99).Among Caucasians,this phenotype association was

strengthened,but the genotype association was attenuated;instead,four variants sharing moderate linkage disequilibrium with the O variant were associated with better OS (HR:0.62,95%CI:0.39–0.99)in unadjusted models.

Conclusions

Blood type A was significantly associated with longer ovarian cancer survival in the largest such study to date.This finding was supported by genetic analysis,which implicated the

A2

Citation:Cozzi GD,Levinson RT,Toole H,Snyder M-R,Deng A,Crispens MA,et al.(2017)Blood type,ABO genetic variants,and ovarian cancer survival.PLoS ONE 12(4):e0175119.https://https://www.sodocs.net/doc/4117590170.html,/10.1371/journal.pone.0175119

Editor:Ludmila Prokunina-Olsson,National Cancer Institute,UNITED STATES Received:November 21,2016Accepted:March 21,2017Published:April 27,2017

Copyright:?2017Cozzi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License ,which permits unrestricted use,distribution,and

reproduction in any medium,provided the original author and source are credited.

Data Availability Statement:Individual level clinical data from VUMC EMR may not be made publicly available;however,tabulated results and summary statistics may be shared via scientific presentations and publications of research

findings.In addition,individual level de-identified datasets may be shared with collaborators after institutional data use agreements have been approved.Requests should be sent to alicia.beeghly@https://www.sodocs.net/doc/4117590170.html, .

Funding:This work was supported by the National Institutes of Health–UL1TR000445(https://www.

allele,although O related variants also had suggestive associations.Further research on ABO and ovarian cancer survival is warranted.

Introduction

Ovarian cancer is the 5th leading cause of cancer deaths among women in the United States (US),with an estimated 22,280new cases and 14,240deaths in 2016[1].Despite improvements in chemotherapy and surgical cytoreduction (debulking)over the last twenty years,overall 5-year survival remains abysmally low at 45%[1].Identifying additional prognostic factors and determining their contribution to disease outcomes could lead to new treatment approaches for women diagnosed with this typically fatal disease.

Landsteiner was awarded the Nobel Prize for his landmark discovery of blood types based on red blood cell (RBC)agglutination.In addition to transfusion medicine,blood type also gained a prominent role in genetics as one of the first traits with a Mendelian mode of inheritance and population-specific phenotypic variation.We now know that blood type is determined by

genetic variation in the ABO gene on chromosome 9q34.The encoded glycosyltransferases cata-lyze the transfer of specific terminal oligosaccharides to the precursor H protein to form ABO https://www.sodocs.net/doc/4117590170.html,mon variants result in different glycosyltransferases,oligosaccharide antigens,and phenotypes:N-acetylgalactosamine for blood type A,D-galactose for blood type B,both for blood type AB,and neither for an unmodified H antigen in blood type O.Blood type A and B differ predominantly by four amino acid substitutions (R176G,G235S,L266M,and G268A)from four common missense variants (rs7853989,rs8176743,r8176746,and rs8176747),while blood type O is predominantly due to a single nucleotide deletion (rs8176719)which shifts the reading frame and results in early protein termination [2–6].In addition,multiple alleles,new mutations,and frequent recombination events add complexity to the genetic diversity of the ABO locus [3,4].

Blood type has been linked to multiple diseases,and genome-wide association studies (GWAS)have found associations between ABO variants and susceptibility to coronary artery disease (CAD),venous thromboembolism (VTE),and pancreatic cancer [7].With regard to ovarian cancer,a meta-analysis conducted by the Ovarian Cancer Association Consortium (OCAC)demonstrated a small but significantly increased risk among women with genotypes conferring blood type A [8].To our knowledge,only two small studies have evaluated ABO blood type and ovarian cancer survival.An early study published in Italian included 92ovarian cancer cases and found 5-year survival rates of 64.5%and 33.3%for type O and A cases,respectively,although no multivariable analyses were conducted [9].A more recent study of 256Chinese women found that blood type A cases had two-fold shorter survival than non-A blood type cases in analyses adjusted for age,stage,and disease grade [10].Multiple mecha-nisms have been postulated to explain the role of blood type in cancer progression,including altered cellular adhesion,immune response,and inflammation [11–13].As current evidence is limited,we undertook this study to evaluate blood type,ABO genetic variation,and overall survival (OS)among women with ovarian cancer.

Materials &methods Study population

After garnering appropriate Institutional Review Board approval (VUMC IRB #121299),Tumor Registry confirmed ovarian (C569)or fallopian tube (C570)cancer cases

were

https://www.sodocs.net/doc/4117590170.html,/);United States Department of Defense–W81XWH-14-1-0104(https://www.sodocs.net/doc/4117590170.html,/)to ABF;National Cancer Institute–T32GM080178(https://https://www.sodocs.net/doc/4117590170.html,/)to RTL;National Center for Research Resources–1S10RR025141-01(https://https://www.sodocs.net/doc/4117590170.html,/research-training/research-resources ).The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the https://www.sodocs.net/doc/4117590170.html,peting interests:All authors attest to having no conflicts of interest.For complete disclosure,Dr.Crispens has participated in clinical trials led by Janssen Pharmaceuticals and Astra-Zeneca,and has served on a medical advisory board for

Helomics.Similarly,Dr.Khabele has participated in clinical trials led by Astra-Zeneca,and has served on medical advisory boards for Vertex

Pharmaceuticals and Genentech.This does not alter our adherence to PLOS ONE policies on sharing data and materials.

identified using International Classification of Disease-Oncology(ICD-O)codes from de-identified electronic medical records(EMR)from the Vanderbilt University Medical Center (VUMC).EMR-linked Tumor Registry data included primary tumor site,histology,date of diagnosis,stage at diagnosis,and grade of disease.VUMC EMR data included date of birth and administratively-assigned race,which was comparable to self-reported race when evalu-ated in relation to genetic ancestry in a VUMC EMR study population[14].Subject vital status was determined from both EMR and linkage to the National Death Index(NDI).Cases were considered to have died if they were listed as deceased in EMR or if there was a date of death from the NDI.Otherwise,OS was censored at the date of last EMR entry.A total of208of

1,328unique subjects identified were excluded,leaving1,120Tumor Registry confirmed cases diagnosed between1980and2013for analysis.Exclusions included codes for a prior cancer diagnoses(N=15),diagnosis before1980(N=12)or after2013(N=6),unknown diagnosis date(N=16),or histology codes that indicated a germ cell tumor(9060,9064,9071,9080, 9082,9084,9085),sex-cord stromal tumor(8620,8634,8640,8670),or other non-epithelial tumor(8240,8243,8800,8802,8890,8910,9500,9680).Cases with unknown histologic sub-type were retained,as most were likely to be epithelial,but we did exclude cases with an age at diagnosis of less than18years(N=3).In addition,cases with diagnosis and death occurring on the same day(N=2),implausible survival times(N=3),or lacking follow-up information (N=58)were excluded.

Blood type and ABO genotype

Blood type was ascertained from EMR-linked laboratory reports from serologic assays con-ducted on whole blood samples by the Vanderbilt Pathology Lab Service.EMR linked genetic data from the Illumina Exome BeadChip were also evaluated.Variants in the ABO gene were selected from post quality control data[15];only common variants with minor allele frequen-cies(MAF)!0.05were included in our analysis.

Statistical analysis

Differences in patient and tumor characteristics across ABO blood types were examined with Student’s t tests and x2tests.Hardy-Weinberg equilibrium(HWE)was evaluated by compar-ing observed and expected genotype frequencies.Associations between traits and genetic vari-ants were assessed using exact tests.Associations with OS were evaluated using Cox proportional hazards regression in both unadjusted and multivariable adjusted models that included adjustment for age,race stage,grade,histologic subtype of disease,and year of diag-nosis.For variants,additive and dominant genetic effect models were employed.Hazard ratios (HRs)and95%confidence intervals(CIs)were used to quantify associations with OS,defined as the interval between the date of diagnosis and either death or last EMR entry.As more than half of women with ovarian cancer die within5years of diagnosis,and confidence intervals generally increase as sample size decreases over time in such analyses,we did not evaluate OS beyond10years.Interactions were evaluated with likelihood ratio tests of nested models.Sur-vival functions were visualized using Kaplan-Meier plots;differences were evaluated with the Log-Rank test.All analyses were performed using SAS version9.4(SAS Institute,Cary,NC) and statistical significance was defined with a two-tailed threshold of0.05.

Results

ABO blood type(N=694)and/or ABO genetic variants(N=154)were available for a total of 713Tumor Registry confirmed ovarian or fallopian tube cancer cases from the VUMC (Table1).Cases were predominantly Caucasian(N=637,89.3%)and had a mean age at

T a b l e 1.C l i n i c a l c h a r a c t e r i s t i c s a n d A B O b l o o d t y p e a m o n g T u m o r R e g i s t r y C o n f i r m e d o v a r i a n c a n c e r c a s e s f r o m V U M C E M R .

a

C o l u m n p e r c e n t a g e s m a y n o t s u m t o 100%d u e t o r o u n d i n g e r r o r b

B o l d v a l u e s d e n o t e s i g n i ?c a n t a s s o c i a t i o n s

h t t p s ://d o i.o r g /10.1371/j o u r n a l.p o n e .0175119.t 00

1

diagnosis of 58.7years.As expected,the majority had advanced stage at diagnosis (Stage III &Stage IV:N =422,59.2%),high grade disease (G3&G4:N =380,53.3%),and serous histology (N =420,58.9%).Blood type from EMR-linked laboratory assays included 312type A (45.0%),85type B (12.2%),39type AB (5.6%),and 258type O (37.2%).Blood type was not associated with any clinical covariate,with the exception of race;Caucasian cases were more likely to be blood type A or O,whereas cases of unknown and other races were more likely to be blood type B or AB (P-value =0.002).When analysis was restricted to Caucasians,blood type was not associated with any patient or tumor characteristic evaluated (data not shown).

Cases with blood type A had significantly better OS in both unadjusted analyses,and after adjustment for clinical covariates and race (Table 2),either compared to blood type O (HR:0.75,95%CI:0.60–0.93)or all non-A blood type cases (HR:0.77,95%CI:0.63–0.94).Results from Kaplan-Meier analyses were in agreement (Fig 1A ),showing significantly better OS for ovarian cancer cases with blood type A as compared to all other blood types by the Log-Rank test (P-value =0.021).When analyses were stratified,results did not vary by histology,stage,or grade (all P-interaction >0.05),although associations among cases with serous histology (HR:0.72,95%CI:0.55–0.94),late stage disease (HR:0.76,95%CI:0.59–0.98),and high grade dis-ease (HR:0.71,95%CI:0.56–0.92)remained statistically significant,while the comparison of blood type A to O did not reach statistical significance among non-serous cases,early-stage cases,and cases with low grade disease (data not shown).The association between blood type and OS differed by race (P-interaction =0.047),such that better survival for type A cases

occurred only among Caucasian cases (HR:0.72,95%CI:0.58–0.89)(Table 2).No

association

Table 2.ABO blood type and overall ovarian cancer survival among Tumor Registry Confirmed cases from VUMC EMR.

a Hazard Ratio (HR)and 95%Con?dence Interval (CI)from proportional hazards regression;bold type denotes signi?cant association b

Adjusted for age,stage,race,histologic subtype,grade,and year of diagnosis

https://https://www.sodocs.net/doc/4117590170.html,/10.1371/journal.pone.0175119.t002

was found among cases of other ethnicities (HR:1.60,95%CI:0.86–3.00),that included 38Black,seven Asian,and two Native women;24cases of unknown race/ethnicity were excluded from race-stratified analyses.

To delve further into the relationship between blood type and ovarian cancer survival,we also examined linked genetic data.Ten common (MAF >0.05)variants in the ABO gene were included on the Illumina Exome BeadChip,passed quality control,and were available for anal-ysis for 154VUMC cases (Table 3).Half of the variants (rs549446,rs8176720,rs8176740,rs8176745,and rs8176746)were found to deviate from HWE.All ten variants were signifi-cantly associated with blood type (all P-values 0.027).No variants were significantly associ-ated with race,and HWE and ABO phenotype associations were unchanged when analyses were restricted to Caucasian cases (data not shown).Based on information compiled from dbSNP [2],OMIM [3],and published literature [4–6],common variants related to

ABO

Fig 1.Kaplan-Meier survival functions for overall ovarian cancer survival.A)Blood type A vs all other types among all cases with blood type from linked EMR;1B)Minor allele carriers of rs1053878(A2)vs non-minor allele carriers among all genotyped cases;1C)Minor allele carriers of rs549446(r 2>0.2with rs505922)vs non-minor allele carriers among genotyped Caucasian cases;X-axis =years of Overall Survival;Y-axis =Percent of Cases Alive.

https://https://www.sodocs.net/doc/4117590170.html,/10.1371/journal.pone.0175119.g001

Table https://www.sodocs.net/doc/4117590170.html,mon ABO variants evaluated and phenotype and related information.

a Major/minor allele on the coding (reverse)strand

b Minor allele Frequency (MAF)

c Hardy-Weinberg equilibrium p-value;bol

d valu

e denotes signi?cant disequilibrium

d p-valu

e from exact test with ABO phenotype or race (dichotomized);bold value denotes signi?cant association

e

O variant rs8176719not included in HapMap or 1000G,but reported to be in perfect linkage disequilibrium with rs505922

https://https://www.sodocs.net/doc/4117590170.html,/10.1371/journal.pone.0175119.t003

phenotype included rs1053878(A2),rs8176746(B),and rs512770(O2),as well as four variants (rs549446,rs8176740,rs8176742,and rs8176745)with moderate (r 2>0.2)

linkage

Table https://www.sodocs.net/doc/4117590170.html,mon ABO variants and overall ovarian cancer survival among Tumor Registry Confirmed cases from VUMC EMR.

a N cases /N deaths for cases with no minor alleles (0),heterozygotes (1),and minor allele homozygotes (2)

b Hazard Ratio (HR)and 95%Con?dence Interval (CI)from proportional hazards regression;bold text denotes signi?cant association c

Adjusted for age,stage,grade,histologic subtype,and year of diagnosis

https://https://www.sodocs.net/doc/4117590170.html,/10.1371/journal.pone.0175119.t004

disequilibrium(LD)with rs505922,which has been reported to be in perfect LD with

rs8176719(O),plus three additional synonymous variants(rs8176720,rs8176741,and

rs8176749)for which no phenotypic relevance was identified.

Associations between ABO variants and OS were first evaluated with additive models,but as the number of cases homozygous for any variant was small(range:0–10,mean=2.6),we also employed dominant models(Table4).The A2variant(rs1053878)was associated with significantly better OS(HR:0.50,95%CI0.25–0.99),but only in multivariable adjusted models among all cases,including139Caucasian,nine unknown,and six Black cases.The four vari-ants in moderate LD with rs505922—and therefore also rs8176719(O)—were associated with better survival,but only in unadjusted analyses among Caucasian cases(HR:0.62,95%CI:

0.39–0.99).Kaplan-Meier analyses were in general agreement,with non-significantly better OS(Log-Rank P-value=0.186)for minor allele carriers of rs1053878(Fig1B),and signifi-cantly better OS(Log-Rank P-value=0.047)for Caucasian minor alleles carriers of rs549446 (Fig1C).Due to limited genetic data,diplotype analysis and analysis among non-Caucasian cases was precluded.

Discussion

In this large single-institution retrospective study of Tumor Registry,EMR,laboratory,and genetic data,we found that ovarian cancer cases with blood type A had approximately20% longer OS than other cases.Our phenotype sample size(N=694)is the largest to date of stud-ies on blood type and ovarian cancer survival,and we found statistically significant associa-tions among all cases and among Caucasian cases.Despite a limited number of genotyped cases(N=154),we also found suggestive associations with ABO variants.First,cases with minor alleles of rs1053878,which distinguishes the A1and A2alleles,had a50%lower risk of death.This agrees with our phenotype results showing better survival for cases with blood type A,and implies that the association may be driven by the A2allele.Second,Caucasian cases with minor alleles of any of four variants in perfect LD(r2=1)had a38%lower risk of death, but significance was attenuated after multivariable adjustment.These four variants(rs549446, rs8176740,rs8176742,and rs8176745)share moderate LD with rs505922,which is in perfect LD with the protein truncating O variant(rs8176719),although the O phenotype was not related to overall ovarian cancer survival in our analysis.

Early studies suggested an association between blood type and ovarian cancer risk,with higher frequencies of type A among women with ovarian cancer than type O[16,17].More recently,a meta-analysis of eight OCAC studies with5,233cases and6,837controls indicated that women with genetic variants corresponding to blood type A had9%greater ovarian can-cer risk than women with variants corresponding to type O[8].Notably,increased risk was only evident for A1and not A2genotype cases[8].Similar to prior studies,we also found a higher prevalence of type A than type O cases among Caucasians our analysis.Further,half of the ABO variants evaluated were found to deviate from HWE.While not definitive,these two findings are generally supportive of a relationship between blood type and ovarian cancer risk. With regards to ovarian cancer survival,prior studies on blood type are limited.One small Ital-ian study reported better5-year survival for type O cases,but included only92ovarian cases and did not conduct regression analysis[9].Among256Chinese women,blood type A was associated with significantly worse overall survival(HR:2.24,95%CI:1.36–3.67)in analyses that included adjustment for age,grade,and stage[10].As these studies contradict our current findings,we sought possible explanations.First,we excluded stage IV cases and amended our adjustment to be comparable to the Chinese study,but still found better survival for type A compared to type O cases(HR:0.69,95%CI:0.54–0.88).Second,we compared the prevalence

of blood types in both study and source populations(S1Table).Our prevalence of type A was higher than Caucasians across the US,while the prevalence of type A among the256Chinese cases was lower than found across China.Thus,selection of ovarian cancer cases might con-tribute to non-representative study populations,and differences in ABO blood type by race/ ethnicity could also add to differences in findings.

Results for ABO blood type and survival from other solid malignancies have also been mixed.For pancreatic cancer,blood type O had longer median survival in one study of316 resected Chinese cases[18],and22%better survival among576resected German cases[19]. On the contrary,blood type was not associated with pancreatic cancer survival among488 Chinese cases[20],and ABO variants were not associated with survival among1,028cases from the PANcreatic Disease ReseArch(PANDoRA)consortium,although analysis was not adjusted for clinical covariates[6].Breast cancer survival results also vary.Some studies have reported significant associations,such as a lower risk of death for blood type O among315 cases[21],longer survival for blood types A and O among335non-metastatic cases[22],and higher rates of recurrence and death for blood types B and AB among1,001invasive cases [23].However,no association between blood type and breast cancer mortality was seen among 426cases[24],468triple-negative cases[25],and2,036cases from the Nurses’Health Study [26].Since the majority of existing studies have evaluated only phenotype,rather than ABO genotype,we speculate that some of the inconsistencies across prior studies may arise from dif-ferences in allelic proportions of A1/A2and O1/O2across diverse populations.

Multiple potential mechanisms to support a role for ABO blood type in cancer development and progression have been proposed.The ABO gene encodes a glycosyltransferase,and ABO antigens are expressed not only on RBCs but also on endothelial and epithelial cells.Dysregu-lation of ABO enzymatic activity could influence cellular adhesion,cell membrane signaling, and host immune response[13].Aberrant ABO antigens have been found on tumor tissues compared to normal cells,such as loss of the A or B epitope and accumulation of the H anti-gen,or incompatible expression of A antigens by tumors in subjects with blood type O[11]. Altered ABO expression may contribute to a malignant phenotype via improved cell motility or enhanced evasion of apoptosis[12].ABO variants have also been linked to several media-tors of inflammation and immune cell recruitment cascades by GWAS,including endothelial leukocyte adhesion molecule,also known as E-selectin,platelet alpha-granule membrane pro-tein,also known as P-selectin[27–30],and soluble intercellular adhesion molecule(ICAM)-1. E-selectin mediates the accumulation of leukocytes during inflammation,and P-selectin enables leukocytes to interact with platelets or activated endothelial cells.ICAM-1is rapidly upregulated by inflammatory cytokines and can block lymphocyte adhesion to endothelial cells[31].Both P-selection and ICAM-1are associated with the A1allele of the ABO blood group[30],which was shown to be associated with increased ovarian cancer risk by OCAC [8].

In addition to antigen and immune dysregulation,ABO blood type may influence ovarian cancer survival by mechanisms related to coagulation.The ABO gene product is responsible for post-translational glycosylation of Von Willebrand factor(vWF),a procoagulant molecule involved in platelet adhesion[32].Venous thromboembolism(VTE)has been associated with poor ovarian cancer survival[33,34],and patients with blood type O have lower rates of VTE, possibly due to lower levels of vWF[35].Recent evidence also suggests that platelets may play a larger role in VTE than previously thought[36].Paraneoplastic thrombocytosis,or elevated platelet levels driven by cancer progression,is a long-recognized phenomenon[37].Pre-diag-nosis thrombocytosis has been associated with reduced ovarian cancer survival[38];postulated mechanisms include paracrine mediators and cytokine communication between platelets, liver,bone marrow,and ovarian cancer cells[39].Thus,thrombocytosis and VTE are

additional ways that blood type may influence ovarian cancer survival.Intriguingly,while GWAS have shown that individuals with blood type O have lower VTE risk and lower vWF levels than non-O blood types,the A2blood type was found to be independently associated with lower VTE risk,and to have the lowest vWF levels of all blood types[40,41].Thus,better survival among ovarian cancer cases with blood type A is biologically plausible,and could be due to the A2allele.

Strengths of this study include a large study population of713Tumor Registry confirmed cancer cases from a single tertiary-care medical center.In contrast,two prior reports of blood type and ovarian cancer survival included only92and256cases[9,10].Additional strengths include evaluation of both blood type and genetic variation in the ABO gene,and employment of appropriate statistical methods,such as multivariable adjustment for known prognostic fac-tors in regression models.Limitations include that our cases were diagnosed over33years, during which time the definitions of optimal debulking[42]and histological classification have changed[43].We did not adjust for surgical debulking,as this information was not read-ily available,but did include adjustment for serous or non-serous histology and calendar year of diagnosis.Our largest limitation is that genotype data was available for only154cases and included only ABO variants that were included on the Exome Beadchip.This platform was designed to capture potentially functional variants within coding regions,rather than provid-ing comprehensive coverage across the genome.We did not have data for the single nucleotide deletion that results in protein truncation and the O phenotype(rs8176719).As this variant is not included in HapMap or1000G,we could not directly assess LD;however,rs505922has been reported to be a perfect proxy for rs8176719(r2=1)[4–6],and in Caucasian populations, this variant has moderate LD(r2=0.218)with four variants that we did evaluate.Given the limited genetic data available,we were also unable to evaluate diplotypes.Thus,further study of ABO genotypes in relation to ovarian cancer outcomes should be undertaken,for example, by OCAC.Finally,race/ethnicity was administratively-assigned in our EMR.This has been shown to be as good as self-report[14],but as our population predominantly included Cauca-sians,generalizability of our results to other racial/ethnic groups may be limited.

In conclusion,ovarian cancer cases with blood type A had more favorable survival.This was evident whether type A was compared to type O or to all other blood types.The associa-tions seemed to be driven by the A2allele,although variants related to the O phenotype also had suggestive associations.Additional research is warranted to either replicate or refute our findings,and ultimately,to determine if ABO variants and blood type are causally related to ovarian cancer development,progression,and survival.

Supporting information

S1Table.ABO blood type and prevalence information.

(DOCX)

Acknowledgments

Dr.Beeghly-Fadiel and this research were supported in part by a Department of Defense Ovar-ian Cancer Research Program Pilot Award(W81XWH-14-1-0104).Rebecca T.Levinson was supported by T32GM080178.Datasets were obtained from the Vanderbilt University Medical Center Synthetic Derivative and BioVU which are supported by institutional funding,the

1S10RR025141-01instrumentation award,and by the CTSA grant UL1TR000445from NCATS/NIH.In addition,the authors gratefully acknowledge the members and supporters of the Vanderbilt Ovarian Cancer Alliance(VOCAL).

Author Contributions

Conceptualization:ABF.

Data curation:RTL MRS GDC ABF.

Formal analysis:RTL ABF.

Investigation:AD MRS.

Methodology:ABF RTL.

Project administration:ABF.

Resources:ABF AD HT MRS.

Supervision:ABF.

Visualization:ABF.

Writing–original draft:HT GDC ABF.

Writing–review&editing:GDC RTL MAC DK ABF.

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