Date Published: April 27, 2017
Publisher: Public Library of Science
Author(s): Gabriella D. Cozzi, Rebecca T. Levinson, Hilary Toole, Malcolm-Robert Snyder, Angie Deng, Marta A. Crispens, Dineo Khabele, Alicia Beeghly-Fadiel, Ludmila Prokunina-Olsson.
Blood type A and the A1 allele 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.
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.
ABO phenotype (N = 694) and/or genotype (N = 154) data were available for 713 predominantly Caucasian (89.3%) cases. In multivariable models, blood type A had significantly better 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 rs1053878 minor 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.
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 allele, although O related variants also had suggestive associations. Further research on ABO and ovarian cancer survival is warranted.
Ovarian cancer is the 5th leading cause of cancer deaths among women in the United States (US), with an estimated 22,280 new cases and 14,240 deaths in 2016 . Despite improvements in chemotherapy and surgical cytoreduction (debulking) over the last twenty years, overall 5-year survival remains abysmally low at 45% . 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.
ABO blood type (N = 694) and/or ABO genetic variants (N = 154) were available for a total of 713 Tumor Registry confirmed ovarian or fallopian tube cancer cases from the VUMC (Table 1). Cases were predominantly Caucasian (N = 637, 89.3%) and had a mean age at diagnosis of 58.7 years. 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 312 type A (45.0%), 85 type B (12.2%), 39 type AB (5.6%), and 258 type 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).
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 approximately 20% longer OS than other cases. Our phenotype sample size (N = 694) is the largest to date of studies on blood type and ovarian cancer survival, and we found statistically significant associations 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 A1 and A2 alleles, had a 50% 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 A2 allele. Second, Caucasian cases with minor alleles of any of four variants in perfect LD (r2 = 1) had a 38% 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.