Susceptibility loci for pancreatic cancer in the Brazilian population

Abstract Background Pancreatic adenocarcinoma (PA) is a very aggressive cancer and has one of the poorest prognoses. Usually, the diagnosis is late and resistant to conventional treatment. Environmental and genetic factors contribute to the etiology, such as tobacco and alcohol consumption, chronic pancreatitis, diabetes and obesity. Somatic mutation in pancreatic cancer cells are known and SNP profile by GWAS could access novel genetic risk factors for this disease in different population context. Here we describe a SNP panel for Brazilian pancreatic cancer, together with clinical and epidemiological data. Methods 78 pancreatic adenocarcinoma and 256 non-pancreatic cancer subjects had 25 SNPs genotyped by real-time PCR. Unconditional logistic regression methods were used to assess the main effects on PA risk, using allelic, co-dominant and dominant inheritance models. Results 9 SNPs were nominally associated with pancreatic adenocarcinoma risk, with 5 of the minor alleles conferring protective effect while 4 related as risk factor. In epidemiological and clinical data, tobacco smoking, diabetes and pancreatitis history were significantly related to pancreatic adenocarcinoma risk. Polygenic risk scores computed using the SNPs in the study showed strong associations with PA risk. Conclusion We could assess for the first time some SNPs related with PA in Brazilian populations, a result that could be used for genetic screening in risk population such as familial pancreatic cancer, smokers, alcohol users and diabetes patients.

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Susceptibility Loci for Pancreatic Cancer in the Brazilian Population

10.21203/rs.3.rs-50762/v1 ◽

2020 ◽

Author(s):

Mateus Aoki ◽

Angelika Stein ◽

Jaqueline Carvalho de Oliveira ◽

Roger Chammas ◽

Miyuki Uno ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Adenocarcinoma ◽

Epidemiological Data ◽

Familial Pancreatic Cancer ◽

Regression Methods ◽

Pancreatic Cancer Cells ◽

Aggressive Cancer ◽

Alcohol Users ◽

Main Effects ◽

First Time

Abstract Background: Pancreatic adenocarcinoma (PA) is a very aggressive cancer and has one of the poorest prognoses. Usually the diagnosis is late and resistant to conventional treatment. Environmental and genetic factors contribute to the etiology, such as tobacco and alcohol consumption, chronic pancreatitis, diabetes and obesity. Somatic mutation in pancreatic cancer cells are known and SNP profile by GWAS could access novel genetic risk factors for this disease in different population context. Here we describe a SNP panel for Brazilian pancreatic cancer, together with clinical and epidemiological data. Methods: 78 pancreatic adenocarcinoma and 256 non-pancreatic cancer subjects had 25 somatic SNP genotyped by real-time PCR. Unconditional logistic regression methods were used to assess the main effects on PA risk, using allelic, co-dominant and dominant inheritance models. Results: 9 SNPs were nominally associated with pancreatic adenocarcinoma risk, with 5 of the minor allele conferring protective effect while 4 related as risk factor. In epidemiological and clinical data, tobacco, diabetes and pancreatitis history were significant related to pancreatic adenocarcinoma risk. Conclusion: We could assess for the first time some SNPs related with PA in Brazilian populations, a result that could be used for genetic screening in risk population such as familial pancreatic cancer, smokers, alcohol users and diabetes patients.

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Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4168 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4168-TPS4168

Author(s):

Laith I. Abushahin ◽

Anne M. Noonan ◽

John L. Hays ◽

Pannaga G. Malalur ◽

Ashish Manne ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Pancreatic Adenocarcinoma ◽

Cell Lines ◽

Dose Intensity ◽

Standard Of Care ◽

Significance Level ◽

Pancreatic Cancer Cells ◽

Metastatic Pancreatic Adenocarcinoma

TPS4168 Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.

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BRCA2 and predisposition to pancreatic and other cancers

Expert Reviews in Molecular Medicine ◽

10.1017/s146239940100309x ◽

2001 ◽

Vol 3 (14) ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Meghan A. Arnold ◽

Michael Goggins

Keyword(s):

Breast Cancer ◽

Pancreatic Cancer ◽

Early Detection ◽

Pancreatic Adenocarcinoma ◽

Germline Mutations ◽

Familial Pancreatic Cancer ◽

Pancreatic Carcinogenesis ◽

Increased Risk ◽

Late Event ◽

Genetic Events

Pancreatic adenocarcinoma is a major cause of cancer deaths in the industrialised world. Recent work has focused on the genetics of pancreatic cancer with a goal of finding an early detection marker that might allow for greater rates of survival than are currently possible. The breast cancer 2 gene (BRCA2) is one of numerous genes implicated in familial pancreatic cancer. Carriers of germline mutations of the BRCA2 gene have an increased risk of several cancers, among them pancreatic adenocarcinoma. During pancreatic carcinogenesis, bi-allelic inactivation of BRCA2 occurs as a late event, suggesting that other genetic events must occur before neoplastic cells can tolerate loss of BRCA2.

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Phase I trial of imexon, Inj. plus gemcitabine in patients with advanced previously untreated pancreatic adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15058 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15058-15058

Author(s):

S. J. Cohen ◽

M. Zalupski ◽

M. Modiano ◽

P. Conkling ◽

D. Mahadevan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase I ◽

Pancreatic Adenocarcinoma ◽

Phase I Study ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Maximum Tolerated Dose ◽

Pancreatic Cancer Cells ◽

Dosing Regimens ◽

Ecog Ps

15058 Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted. No significant financial relationships to disclose.

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Spanish national hereditary pancreatic cancer registry (PanFAM).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e12033 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e12033-e12033

Author(s):

Carmen Guillen-Ponce ◽

Evelina Mocci ◽

Julie Earl ◽

Carmen T Guerrero ◽

Maria Celia Calcedo ◽

...

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Screening Program ◽

Epidemiological Data ◽

Screening Methods ◽

Familial Pancreatic Cancer ◽

Inherited Predisposition ◽

Screening Study ◽

Age Of Diagnosis ◽

Breast And Prostate Cancer

e12033 Background: Inherited predisposition to Pancreatic Cancer (PC) corresponds 10% of all cases and includes members of families affected with hereditary cancer syndromes as Familial Pancreatic Cancer (FPC), Peutz-Jeghers, familial melanoma, hereditary breast and ovarian cancer, hereditary pancreatitis. An inherited predisposition in early onset PC (≤ 50 years) has also been suggested. We report preliminary data on PanFAM patients and screening of high risk individuals. Methods: PamFAM is a part of the European PANGEN PC case/control study of hereditary PC, co-ordinated by the Ramón y Cajal (RC) hospital and the Spanish National Cancer Research Center, with 16 participating hospitals. All families with clinical evidence of an inherited PC syndrome were recruited and multi-generational pedigrees were constructed. Cancer diagnoses were confirmed, when possible, by review of medical records. Blood samples and epidemiological data were collected for all participating family members. A screening program for early detection of PC, based on endoscopic ultrasound (EUS), CT and circulating tumour cells (CTCs) was offered to high risk individuals. Results: Of 505 Spanish PCs collected by PANGEN, 31 (~6%) were FPC cases; 18 (58%) revealed only PC and the remaining showed clustering with other tumor types, gastric cancer was the most common (13%). Among FPC families, 3 had 3 cases of PC and the remaining had 2 cases. The mean age of diagnosis was 67 years (range 47-85), 20 male and 11 female. Four FPCs were previously diagnosed with cancer (Hodgkin lymphoma, breast and prostate cancer) and 3 with acute pancreatitis. 37 PCs with no family history of cancer were diagnosed at the age of 50 years or earlier (mean 45, range 30-50), 18 male and 19 female. Other 27 eligible families were recruited by RyC hospital, 8 (30%) with FPC and 3 (11%) with PC ≤ 50 years. A cohort of 61 high risk individuals participes in the screening study: 3 had abnormal EUS, 1 a benign pancreatic node and 1 a renal angiolipoma; one young man had 2 CTCs. Conclusions: PanFAM is the first registry in Spain collecting hereditary PC cases and it represents an important resource to identify underlying gene defects and to the development of screening methods precursor lesions detection in high risk individuals.

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An RNA aptamer that specifically binds pancreatic adenocarcinoma up-regulated factor inhibits migration and growth of pancreatic cancer cells

Cancer Letters ◽

10.1016/j.canlet.2011.08.027 ◽

2011 ◽

Vol 313 (1) ◽

pp. 76-83 ◽

Cited By ~ 22

Author(s):

Yun-Hee Kim ◽

Ho Jin Sung ◽

Sukyoung Kim ◽

Eun-Ok Kim ◽

Ji Won Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Adenocarcinoma ◽

Rna Aptamer ◽

Pancreatic Cancer Cells

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Alteration of nanomechanical properties of pancreatic cancer cells through anticancer drug treatment revealed by atomic force microscopy

Beilstein Journal of Nanotechnology ◽

10.3762/bjnano.12.101 ◽

2021 ◽

Vol 12 ◽

pp. 1372-1379

Author(s):

Xiaoteng Liang ◽

Shuai Liu ◽

Xiuchao Wang ◽

Dan Xia ◽

Qiang Li

Keyword(s):

Mechanical Properties ◽

Pancreatic Cancer ◽

Atomic Force Microscopy ◽

Cancer Cells ◽

Young’S Modulus ◽

Young's Modulus ◽

Force Microscopy ◽

Pancreatic Cancer Cells ◽

Atomic Force ◽

Aggressive Cancer

The mechanical properties of cells are key to the regulation of cell activity, and hence to the health level of organisms. Here, the morphology and mechanical properties of normal pancreatic cells (HDPE6-C7) and pancreatic cancer cells (AsPC-1, MIA PaCa-2, BxPC-3) were studied by atomic force microscopy. In addition, the mechanical properties of MIA PaCa-2 after treatment with different concentrations of doxorubicin hydrochloride (DOX) were also investigated. The results show the Young's modulus of normal cells is greater than that of three kinds of cancer cells. The Young's modulus of more aggressive cancer cell AsPC-1 is smaller than that of less aggressive cancer cell BxPC-3. In addition, the Young's modulus of MIA PaCa-2 rises with the increasing of DOX concentration. This study may provide a new strategy of detecting cancer, and evaluate the possible interaction of drugs on cells.

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Expression and Activity of Nadph Oxidase 4 (Nox4) is Related to Antiapoptotic Activity of Human Pancreatic Adenocarcinoma Cells

Sveikatos mokslai ◽

10.5200/sm-hs.2015.023 ◽

2015 ◽

Vol 25 (2) ◽

pp. 13-18

Author(s):

Aurelija Maziukienė ◽

Aldona Jakštaitė ◽

Giedrė Šilkūnienė ◽

Kristina Kmieliūtė ◽

Antanas Gulbinas ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nadph Oxidase ◽

Cancer Cells ◽

Pancreatic Adenocarcinoma ◽

Pancreatic Tissue ◽

Mrna Levels ◽

Nadph Oxidase 4 ◽

Pancreatic Cancer Cells ◽

Ros Formation ◽

Antiapoptotic Activity

Pancreatic adenocarcinoma is one of the most aggressive human malignancies with high mortality rates. Low survival rates are due to late diagnosis at advanced stages of the disease. High invasiveness and chemoresistance of pancreatic adenocarcinoma at least partially could be related to the antiapoptotic activity of intracelular ROS generated by Nox4. There are only few studies about Nox4 expression in pancreatic cancer, yet Nox4 is believed to be relevant antiapoptotic factor in pancreatic cancer cells. In this study we have determined the expression of Nox4 in human pancreatic tissue at both protein and mRNA levels. We compared how Nox4 is overexpressed in pancreatic cancer in comparison to human healthy adjacent and healthy donor pancreatic tissue. We have also identified the effect of ROS formation in MiaPaca-2 and Capan-2 cells under treatment with NADPH oxidase inhibitors DPI and apocynin. Our results showed that DPI and apocynin inhibited ROS formation. Moreover, it decreased viability of pancreatic cancer cells and induced apoptosis as well. Result confirms ROS being responsible for antiapoptotic activity of pancreatic cancer cells. These findings point out to NADPH oxidases being a potential terapeutic targets in treatment of cancer.

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Peritumoral Fibroblast SPARC Expression and Patient Outcome With Resectable Pancreatic Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.8824 ◽

2007 ◽

Vol 25 (3) ◽

pp. 319-325 ◽

Cited By ~ 255

Author(s):

Jeffrey R. Infante ◽

Hiroyuki Matsubayashi ◽

Norihiro Sato ◽

James Tonascia ◽

Alison P. Klein ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Adenocarcinoma ◽

Median Survival ◽

Expression Patterns ◽

Relative Hazard ◽

Stromal Fibroblasts ◽

Pancreatic Cancer Cells ◽

Kaplan Meier ◽

Sparc Expression

Purpose SPARC (secreted protein acidic and rich in cysteine) is a protein involved in cell matrix interactions, wound repair, and cell migration, and has been reported to inhibit cancer growth. SPARC undergoes epigenetic silencing in many pancreatic cancers, but stromal fibroblasts adjacent to infiltrating pancreatic adenocarcinomas frequently express SPARC. We evaluated the prognostic significance of tumor and peritumoral SPARC expression in patients with pancreatic adenocarcinoma. Patients and Methods The expression patterns of SPARC were characterized by immunohistochemistry in 299 primary pancreatic ductal adenocarcinoma resection specimens from patients who underwent pancreaticoduodenectomy at Johns Hopkins Hospital (Baltimore, MD) between 1998 and 2003. Kaplan-Meier analysis and Cox proportional hazards regression modeling were used to assess the mortality risk associated with the presence or absence of tumor SPARC and peritumoral SPARC status. Results By Kaplan-Meier analysis, patients whose pancreatic cancer stromal fibroblasts expressed SPARC (median survival, 15 months) had a significantly worse prognosis than patients whose tumor stroma did not express SPARC (median survival, 30 months; log-rank P < .001). In contrast, the expression of SPARC in pancreatic cancer cells was not associated with prognosis (log-rank P = .13). Controlling for other prognostic factors (tumor size, positive lymph nodes, margin status, tumor grade, and age), the relative hazard for patients whose stroma expressed SPARC compared with those whose stroma did not was 1.89 (95% CI, 1.31 to 2.74); the expression of SPARC in pancreatic cancer cells remained unrelated to prognosis (relative hazard, 1.02; 95% CI, 0.73 to 1.42). Conclusion The expression of SPARC by peritumoral fibroblasts portends a poorer prognosis for patients with pancreatic cancer.

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