Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients- A study of the OVCAD consortium.

OBJECTIVE: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown. METHODS: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi2 or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis. RESULTS: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease. CONCLUSIONS: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation.

Expression profile of COL2A1 and the pseudogene SLC6A10P predicts tumor recurrence in high-grade serous ovarian cancer.

Tumor recurrence, following initial response to adjuvant chemotherapy, is a major problem in women with high-grade serous ovarian cancer (HGSOC). Microarray analysis of primary tumors has identified genes that may be useful in risk stratification/overall survival, but are of limited value in predicting the >70% rate for tumor recurrence. In this study, we performed RNA-Seq analysis of primary and recurrent HGSOC to first identify unique differentially expressed genes. From this dataset, we selected 21 archetypical coding genes and one noncoding RNA, based on statistically significant differences in their expression profile between tumors, for validation by qPCR in a larger cohort of 110 ovarian tumors (71 primary and 39 recurrent) and for testing association of specific genes with time-to-recurrence (TTR). Kaplan-Meier tests revealed that high expression of collagen type II, alpha 1 (COL2A1) was associated with delayed TTR (HR = 0.47, 95% CI: 0.27-0.82, p = 0.008), whereas low expression of the pseudogene, solute carrier family 6 member 10 (SLC6A10P), was associated with longer TTR (HR = 0.53, 95% CI: 0.30-0.93, p = 0.027). Notably, TTR was significantly delayed for tumors that simultaneously highly expressed COL2A1 and lowly expressed SLC6A10P (HR = 0.21, 95% CI: 0.082-0.54, p = 0.0011), an estimated median of 95 months as compared to an estimated median of 16 months for subjects expressing other levels of COL2A1 and SLC6A10P. Thus, evaluating expression levels of COL2A1 and SLC6A10P at primary surgery could be beneficial for clinically managing recurrence of HGSOC.