Purpose To elucidate molecular pathways contributing to metastatic cancer progression and poor clinical outcome in serous ovarian cancer. Experimental Design Poor survival signatures from three different serous ovarian cancer datasets were compared and a common set of genes was identified. The predictive value of this gene signature was validated in independent datasets. The expression of the signature genes was evaluated in primary, metastatic, and/or recurrent cancers using qPCR and in situ hybridization. Alterations in gene expression by TGFβ1 and functional consequences of loss of COL11A1 were evaluated using pharmacologic and knockdown approaches, respectively. Results We identified and validated a 10-gene signature (AEBP1, COL11A1, COL5A1, COL6A2, LOX, POSTN, SNAI2, THBS2, TIMP3, VCAN) that is associated with poor overall survival in patients with high-grade serous ovarian cancer. The signature genes encode extracellular matrix proteins involved in collagen remodeling. Expression of the signature genes is regulated by TGFβ1 signaling and is enriched in metastases in comparison to primary ovarian tumors. We demonstrate that levels of COL11A1, one of the signature genes, continuously increase during ovarian cancer disease progression, with the highest expression in recurrent metastases. Knockdown of COL11A1 decreases in vitro cell migration and invasion and tumor progression in mice. Conclusion Our findings suggest that collagen-remodeling genes regulated by TGFβ1 signaling promote metastasis and contribute to poor overall survival in patients with serous ovarian cancer. Our 10-gene signature has both predictive value and biological relevance and thus may be useful as a therapeutic target.

Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

Objective Assess the impact of preoperative serum anti-TNFα drug levels on 30-day postoperative morbidity in inflammatory bowel disease patients. Summary Background Data Studies on the association of anti-TNFα drugs and postoperative outcomes in IBD are conflicting due to variable pharmacokinetics of anti-TNFα drugs.. It remains to be seen whether preoperative serum anti-TNFα drug levels correlate with postoperative morbidity. Methods 30 days postoperative outcomes of consecutive IBD surgical patients with serum drawn within 7 days pre-operatively, were studied. The total serum level of 3 anti-TNF-α drugs (infliximab, adalimumab, certolizumab) was measured, with ≥0.98 µg/ml considered as detected. Data was also reviewed according to a clinical cut off value of 3 µg/ml. Results 217 patients (123 Crohn’s disease (CD) and 94 ulcerative colitis (UC)) were analyzed. 75 of 150 (50%) treated with anti-TNFα therapy did not have detected levels at the time of surgery. In the UC cohort, adverse postoperative outcomes rates between the undetectable and detectable groups were similar when stratified according to type of UC surgery. In the CD cohort, there was a higher but statistically insignificant rate of adverse outcomes in the detectable vs undetectable groups. Using acut-off level of 3 µg/ml, postoperative morbidity (OR=2.5, p=0.03) and infectious complications (OR=3.0, p=0.03) were significantly higher in the ≥ 3 µg/ml group. There were higher rates of postoperative morbidity (p=0.047) and hospital readmissions (p=0.04) in the ≥ 8 µg/ml compared to < 3 µg/ml group. Conclusion Increasing preoperative serum anti-TNFα drug levels are associated with adverse postoperative outcomes in CD but not UC patients.