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2.
Nat Commun ; 11(1): 4755, 2020 09 21.
Article in English | MEDLINE | ID: mdl-32958772

ABSTRACT

We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.


Subject(s)
Homeostasis , Oxygen/metabolism , RNA, Long Noncoding/physiology , Sterols/biosynthesis , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Hypoxia , Cell Line, Tumor , Cell Nucleus/metabolism , Cholesterol/metabolism , Estrogens/metabolism , Gene Expression Regulation , Genome-Wide Association Study , Heterogeneous-Nuclear Ribonucleoprotein Group C/genetics , Heterogeneous-Nuclear Ribonucleoprotein Group C/metabolism , Humans , MCF-7 Cells , Phenotype , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism
3.
Clin Cancer Res ; 24(24): 6204-6211, 2018 12 15.
Article in English | MEDLINE | ID: mdl-30131383

ABSTRACT

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. EXPERIMENTAL DESIGN: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. RESULTS: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), PALB2 (N = 3), MSH2 (N = 1), and FANCF (N = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29-1.14; log-rank P = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04-2.06; P = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15-0.94; P = 0.04) showed presence of DDR gene mutations was associated with improved OS. CONCLUSIONS: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.


Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/mortality , DNA Damage , DNA Repair , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Adenocarcinoma/diagnosis , Adenocarcinoma/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Genes, BRCA1 , Genes, BRCA2 , Germ-Line Mutation , Humans , Irinotecan/administration & dosage , Irinotecan/adverse effects , Irinotecan/therapeutic use , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Middle Aged , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Oxaliplatin/therapeutic use , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/drug therapy , Prognosis , Treatment Outcome
4.
J Am Coll Surg ; 218(4): 608-17, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24491241

ABSTRACT

BACKGROUND: Mucinous pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) have the potential to progress to invasive pancreatic adenocarcinoma, presenting an opportunity for early detection, prevention, and cure. Serous cystic neoplasms (SCN) have no malignant potential, but can mimic mucinous pancreatic cysts on imaging. Therefore, identification of biomarkers that can distinguish between cystic lesions is critically important. We hypothesize that vascular endothelial growth factor (VEGF)-A levels in pancreatic fluid correlate with pathologic diagnosis. STUDY DESIGN: Pancreatic cyst/duct fluid samples were prospectively collected from patients undergoing pancreatic resection and correlated with surgical pathology. VEGF levels were detected by ELISA. VEGF-A and VEGF receptor 2 expression in pancreatic tissue was localized by immunohistochemistry. Genetic alterations of the von Hippel-Lindau gene were determined by targeted next-generation sequencing. RESULTS: Eighty-seven patients met inclusion criteria for enrollment. Final pathologic diagnoses included pseudocyst (n = 9), SCN (n = 17), mucinous cystic neoplasm (n = 24), low/moderate grade intraductal papillary mucinous neoplasm (n = 16), high-grade/invasive intraductal papillary mucinous neoplasm (n = 10), and pancreatic ductal adenocarcinoma (n = 11). VEGF-A was significantly upregulated in SCN cyst fluid compared with all other diagnoses (p < 0.0001). With a cut-off of 8,500 pg/mL, VEGF-A has 100% sensitivity and 97% specificity as an SCN biomarker. VEGF-A and VEGF receptor 2 are overexpressed in SCN cyst tissue. VEGF-C was also significantly elevated in SCN cyst fluid (p < 0.0001). With a cut-off set at 200 pg/mL, VEGF-C identifies SCN with 100% sensitivity and 90% specificity. The presence of a von Hippel-Lindau mutation in SCN cyst tissue correlates with elevated cyst fluid VEGF levels. CONCLUSIONS: This is the first report of a cyst fluid protein biomarker that can positively identify SCN. The ability to distinguish SCN from premalignant/malignant pancreatic cysts can spare the cost and risk of surveillance and surgical intervention in select patients.


Subject(s)
Carcinoma, Pancreatic Ductal/diagnosis , Pancreatic Cyst/diagnosis , Pancreatic Neoplasms/diagnosis , Precancerous Conditions/diagnosis , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Blotting, Western , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/surgery , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Male , Middle Aged , Pancreas/metabolism , Pancreas/surgery , Pancreatectomy , Pancreatic Cyst/metabolism , Pancreatic Cyst/surgery , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/surgery , Pancreatic Pseudocyst/diagnosis , Pancreatic Pseudocyst/metabolism , Pancreatic Pseudocyst/surgery , Precancerous Conditions/metabolism , Precancerous Conditions/surgery , Prospective Studies , Sensitivity and Specificity , Vascular Endothelial Growth Factor Receptor-2/metabolism
5.
Clin Ophthalmol ; 7: 1987-93, 2013.
Article in English | MEDLINE | ID: mdl-24143065

ABSTRACT

PURPOSE: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). METHODS: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. RESULTS: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. CONCLUSION: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy.

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