Significance of Anti-retinal Autoantibodies in Cancer-associated Retinopathy with Gynecological Cancers

Abstract

Background: The presence of autoantibodies (AAbs) is the primary serological indicator of autoimmunity. Cancer-associated retinopathy (CAR) is associated with AAbs and different types of cancer. The goal of the study was to examine the profile of serum autoantibodies in women with gynecological cancers with and without paraneoplastic visual manifestation.

Methods: Retrospective studies of a cohort of 46 women with symptoms of CAR and gynecological tumors, including endometrial, cervical, ovarian, and fallopian tubes, 111 women with similar tumors without symptoms of CAR, and 60 age-matched healthy controls. Presence of serum AAbs and the identity of targeted antigens were performed by western blotting and their significance was evaluated using an Fisher's exact test.

Results: The patients with gynecological CAR had the highest proportion of seropositivity (80%), followed by patients with gynecological cancers without CAR (61%) and healthy controls (58%). Differences in recognition frequencies were found for 17 antigens and 5 retinal antigens were frequently targeted: enolase, aldolase C, carbonic anhydrase II, recoverin and GAPDH. The occurrence of anti-glycolytic enzymes was 2-3 times more frequent in CAR and cancer patients than healthy controls. Anti-recoverin AAbs were prevalent in endometrial CAR. Anti-CAII antibodies were not significantly different between groups of women. In this cohort, cancer was diagnosed before the onset of retinopathy with latency from 2 months to 30 years. The discovery of the ovarian and endometrial cancers and manifestation of visual problems often coincided but Fallopian tube carcinoma was found after visual onset.

Conclusion: New retinal targets were identified for gynecological CAR. Each gynecological-CAR has its own autoantibody profile different from non-CAR profile, implying that a complex autoantibody signature may be more predictable for diagnosis than a singular AAb. Specific anti-retinal AAbs were most prevalent in women with CAR but their profiles were not fully distinguished from cancer controls.

Keywords: Antibody profiling; Autoantibodies; Autoantigen; Autoimmune retinopathy; Cancer; Paraneoplastic; Retina.

Figure 1

Incidence of anti-retinal autoantibodies in 3 groups of patients: CAR group - patients with symptoms of cancer associated retinopathy, Cancer group - patients with gynecological cancers without visual problems, Control group - healthy subjects. The presence of autoantibodies against human retinal proteins was investigated in the following gynecological cancers: endometrial, cervical, ovarian, and fallopian tube. The graph represents percent of seropositive patients within each group compared to controls.

Figure 2

Distribution of specific retinal autoantibodies according to the retinal proteins targeted by autoantibodies within each group of patients. X-axis shows retinal proteins marked by their molecular weight (k=1000). Graph represents the percent of antibodies reacting with each protein within a group.

Figure 3

Trends in autoantibody recognition of five retinal proteins in three groups of patients. (A) Comparison of anti-recoverin antibodies to anti-carbonic anhydrase II protein (CAII) shows an increase in anti-recoverin antibodies in CAR patients compared to controls and no significant change in anti-CAII AAbs between groups. (B) Comparison of autoantibodies against glycolytic proteins, including α-enolase, aldolase C and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in three groups shows a significant increase in those antibodies in CAR patients. P values were calculated by the Fisher’s exact test.

Figure 4

Antibody signatures for five distinct retinal proteins in sera of two groups of patients: (A) CAR group - patients with symptoms of cancer associated retinopathy and (B) Cancer group - patients with gynecological cancers without visual problems divided by the cancer type (endometrial, cervical, and ovarian). Stocked bars show the percent of positive AAbs within each group.

Figure 5

Latency time of finding cancer, onset of visual loss, and detection of anti-retinal autoantibodies in patients with CAR associated with different gynecological cancers. Note that cancer was often diagnosed before diagnosis of retinopathy with latency from 2 months to 30 years with the longest interval in cervical malignancies (on average 21 years). The diagnosis of the ovarian and endometrial cancers and retinopathy often coincided and visual symptoms preceded diagnosis of the fallopian tube cancer.