BRCAness Profile of Sporadic Ovarian Cancer Predicts Disease Recurrence

BACKGROUND:The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. OBJECTIVE:To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. MATERIALS AND METHODS:Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function. RESULTS:High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). CONCLUSIONS:Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance

Transcriptional upregulation of human tissue kallikrein 6 in ovarian cancer: clinical and mechanistic aspects

The human tissue kallikrein family (KLK for protein; KLK for gene) includes 15 members. Twelve kallikreins, including KLK6, are concurrently upregulated in ovarian cancer. However, the mechanism of this phenomenon remains unclear. In this study, we measured KLK6 expression in a large series of ovarian tissue cytosols and examined possible mechanisms of KLK6 up-regulation in ovarian cancer. Using a newly developed enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies, we quantified KLK6 expression in ovarian tissue cytosols, and confirmed the upregulation of KLK6 in ovarian cancer and its unfavourable prognostic value. We then examined KLK6 mRNA expression using reverse transcription–polymerase chain reaction and established its good concordance with KLK6 protein expression. This finding suggested that the KLK6 gene is under transcriptional regulation. We then scrutinised a few mechanisms that could explain KLK6 upregulation. The relative abundance of two KLK6 mRNA transcripts was studied; we found the same differential expression pattern in all samples, regardless of KLK6 levels. Genomic mutation screening of all exons and the 5′-flanking region of the KLK6 gene identified two linked single-nucleotide polymorphisms in the 5′-untranslated region, but neither correlated with KLK6 expression. Ovarian cell lines were separately treated with five steroid hormones. None of the treatments produced significant effects on KLK6 expression. We conclude that KLK6 is transcriptionally upregulated in ovarian cancer, but probably not through alternative mRNA transcript expression, genomic mutation, or steroid hormone induction