Evaluation of paraneoplastic antigens reveals TRIM21 autoantibodies as biomarker for early detection of ovarian cancer in combination with autoantibodies to NY-ESO-1 and TP53.

BACKGROUND: The majority of ovarian cancer cases are diagnosed at an advanced stage with poor prognosis. This study evaluates autoantibodies against tumor antigens to identify candidate biomarkers for early detection of ovarian cancer in women at increased risk. OBJECTIVE: To assess the immunoreactivity of paraneoplastic antigens and tumor associated antigens with high-grade serous ovarian cancer (HGSOC) samples. METHODS: Five paraneoplastic antigens along with three tumor-associated antigens were evaluated with HGSOC patient serum samples. Validation screening was performed with n= 164 serum samples consisting of: 50 late stage HGSOC, 14 early stage HGSOC, 50 benign ovarian cyst, and 50 healthy control samples on ELISA and western blot. The four markers TRIM21, NY-ESO-1, TP53, and PAX8 were evaluated on a second validation serum set, n= 150. RESULTS: TRIM21 achieved the highest sensitivity in the first validation screening of 33% with 100% specificity. Combining TRIM21 with NY-ESO-1, TP53, and PAX8 provided 67% sensitivity with 94% specificity, and 56% sensitivity at 98% specificity. These four markers resulted in 46% sensitivity with 98% specificity in the second validation cohort; TRIM21 achieved the highest individual sensitivity of 36%. CONCLUSIONS: Autoantibodies to TRIM21, NY-ESO-1, and TP53 may complement CA125 in screening of women at genetic risk for ovarian cancer.

Utility of paraneoplastic antigens as biomarkers for surveillance and prediction of recurrence in ovarian cancer.

BACKGROUND: Ovarian cancer is frequently diagnosed at an advanced stage and 70% of patients experience recurrence months to years from initial diagnosis. The expression of paraneoplastic antigens can result in the occurrence of onconeural autoantibodies in ovarian cancer that may be associated with neurological disorders that are clinically manifested in patients before diagnosis of ovarian cancer. These paraneoplastic antigens can serve as excellent biomarkers not only for early detection but also for monitoring ovarian cancer recurrence. OBJECTIVE: To assess the immunoreactivity of our previous 3 biomarkers along with 3 paraneoplastic antigens, HARS, Ro52 and CDR2 for the evaluation of their sensitivity in predicting recurrence before the clinical relapse of the ovarian cancer. METHODS: Western blot immunoassays were performed to assess the immunoreactivity of 6 antigens with 21 recurrent ovarian cancer patients. RESULTS: The results indicated that antibodies to HARS, Ro52, CDR2 and 5H6 antigens predicted ovarian cancer recurrence 5.03 months before the clinical or symptomatic relapse in 21 ovarian cancer patients with a sensitivity of 90.5% when CA125 levels were below the standard cutoff (35 U/ml). CONCLUSION: Our study suggests that appearance of onconeural antibodies prior to the rise in CA125 during post treatment surveillance can be a useful diagnostic to predict ovarian cancer recurrence.

Paraneoplastic antigens as biomarkers for early diagnosis of ovarian cancer.

Paraneoplastic syndromes are a group of rare disorders that can be triggered by an abnormal immune response to proteins from tumors of the lung, ovary, lymphatics, or breast. Paraneoplastic clinical syndromes affect < 1% of patients with cancer; however, the frequency of subclinical levels of paraneoplastic autoantibodies in asymptomatic patients with cancer is unknown. Numerous studies have reported that ovarian cancer patients show signs of paraneoplastic neurological syndromes (PNSs) before or after their cancers are diagnosed. PNSs arise from a tumor-elicited immune response against onconeural antigens that are shared by tissues of nervous system, muscle, and tumor cells. Studies on the serum IgGs obtained from ovarian cancer patients have indicated the presence of onconeural antibodies in the absence of any PNS symptoms. The occurrence of PNSs is low in ovarian cancer patients and it can be accompanied by onconeural antibodies. The diagnosis of PNSs is accompanied by a suspicion of a malignant tumor such that neurologists typically refer such patients for a tumor diagnostic workup. There will be tremendous utility if subclinical levels (without paraneoplastic neurological symptoms or myositis) of these autoantibodies to paraneoplastic antigens can be exploited to screen asymptomatic high-risk patients for ovarian cancer, and used as biomarkers in immunoassays for the early detection or recurrence of ovarian cancer. Ovarian cancer overall survival is likely to be improved with early detection. Therefore, a panel of onconeural antigens that can detect paraneoplastic autoantibodies in patient sera should provide diagnostic utility for an earlier therapeutic intervention. Here we review the usefulness of PNS and other paraneoplastic syndromes and their association with paraneoplastic antigens to exploit these autoantibody biomarkers to form diagnostic multi-analyte panels for early detection of ovarian cancer.