Microvesicle proteomics of 187 utero-tubal lavage samples for early diagnosis of HGOC.• Machine learning-based classification of a 9-protein signature with high predictive power.• Signature has 70% sensitivity and 76.2% specificity, predicting stage I lesions.
Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here, we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high grade serous ovarian carcinomas (HGSOCs). We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.
In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.
Background Genetic variants located at 15q25, including those in the cholinergic receptor nicotinic cluster (CHRNA5) have been implicated in both lung cancer risk and nicotine dependence in recent genome-wide association studies. Among these variants, a 22 base pair insertion/deletion, rs3841324 showed the strongest association with CHRNA5 mRNA expression levels. However the influence of rs3841324 on lung cancer risk has not been studied in depth. Methods We have therefore evaluated the association of rs3841324 genotypes with lung cancer risk in a case-control study of 624 Caucasian subjects with lung cancer and 766 age- and sex-matched cancer-free Caucasian controls. We also evaluated the joint effects of rs3841324 with single-nucleotide polymorphisms (SNPs) rs16969968 and rs8034191 in the 15q25 region that have been consistently implicated in lung cancer risk. Results We found that the homozygous genotype with both short alleles (SS) of rs3841324 was associated with a decreased lung cancer risk in female ever smokers relative to the homozygous wild-type (LL) and heterozygous (LS) genotypes combined in a recessive model (OR adjusted = 0.55, 95% CI = 0.31–0.89, P = 0.0168). There was no evidence for a sex difference in the association between this variant and cigarettes smoked per day (CPD). Diplotype analysis of rs3841324 with either rs16969968 or rs8034191 showed that these polymorphisms influenced the lung cancer risk independently. Conclusions and impact This study has shown a sex difference in the association between the 15q25 variant rs3841324 and lung cancers. Further research is warranted to elucidate the mechanisms underlying these observations.
In recent years, the notion that serous ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway that leads to mutagenesis and genomic instability has not been revealed yet. The mutator enzyme activation-induced cytidine deaminase (AID), which is known to be involved in the process of immunoglobulin somatic hypermutations, has also been recently implicated in inflammation-induced epithelial malignancies. In the current study, we propose that AID is a mechanistic link between ovulation-induced inflammation in FTECs and the genotoxic damage that leads to serous carcinogenesis. We tested at the expression of AID in human fallopian tube tissues from patients with various gynecological pathologies, as well as in cultured FTECs in an experimental model mimicking normal ovulation. We also looked at the functional effects of AID up regulation in vitro by analyzing double strand DNA breaks, abasic sites, hypomethylation and chromosomal rearrangements. We also performed a comprehensive bioinformatic analysis of somatic mutations patterns in publically available serous carcinoma sequencing data in search of AID mutational fingerprints. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in human FTECs under physiological conditions, is induced in vitro upon ovulatory-like stimulation and is elevated in vivo under carcinogenesis-associated circumstances. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights on the etiology of serous ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early-detection. Citation Format: Stav Sapoznik, Keren Bahar-Shany, Hadar Brand, Yishay Pinto, Orshay Gabay, Efrat Glick-Saar, Chen Dor, Oranit Zadok, Iris Barshack, Adi Zundelevich, Einav Nili Gal-Yam, Yuval Yung, Ariel Hourvitz, Jacob Korach, Mario Beiner, Jasmine Jacob, Erez Y. Levanon, Michal Barak, Sarit Aviel-Ronen, Keren Levanon. Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A34.
Background: Previous studies in locally advanced esophageal cancer (LAEC) suggested that a change in the tumor's metabolic response, i.e., decrease of its interim 18 F-FDG uptake compared with baseline, may predict histopathological response. We evaluated the possible predictive correlation between various PET-CT and histopathological parameters following a neoadjuvant biological-containing chemoradiotherapy (CRT) regimen.Methods: Patients with resectable LAEC received neoadjuvant cisplatin/5-fluorouracil-based CRT and cetuximab following one cycle of induction chemotherapy and cetuximab. Changes in maximum and mean standardized uptake values (ΔSUV-max and ΔSUV-mean, respectively) and metabolic tumor volume (ΔMTV), measured by PET-CT at baseline and 2 weeks after the onset of treatment, were compared with histopathological findings at surgery. Histopathological response was defined by tumor regression grade (TRG), pathological complete response (pCR) and microscopic or macroscopic residual disease (RD).Results: Of 18 patients, 13 (72%) with adenocarcinoma (AC) and 5 (28%) with squamous cell carcinoma (SCC), were included. None of the changes in the parameters of PET was associated with pCR; only ΔSUVmean was associated with TRG in the AC cohort. In contrast, both ΔSUV-mean% and ΔSUV-max% were significantly associated with RD, both in the whole cohort and in the AC cohort. Changes in FDGuptake predicted RD2 at surgery: only patients with less than 13% decrease in SUV-mean% or less than 29% decrease in SUV-max% had RD2, while all patients with RD0 or RD1 had greater reductions [100% specificity and 100% positive predictive value (PPV)].Conclusions: Changes in ΔSUV-max and ΔSUV-mean after two weeks of onset of cetuximab-based neoadjuvant chemotherapy for LAEC may predict macroscopic RD but not TRG or pCR at surgery.
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