Bioinformatic analysis reveals pancreatic cancer molecular subtypes specific to the tumor and the microenvironment

<p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a dense desmoplastic reaction surrounding malignant epithelial cells. Interaction between the epithelial and stromal compartments is suggested to enhance its aggressive nature. Indeed, therapies targeting the stroma, as well as the tumor cells, may improve survival outcomes for patients. The evaluated study by Moffitt <i>et al</i>. used bioinformatic techniques to separate gene expression patterns of normal tissues from PDAC and stroma in a large cohort of samples. The researchers identified two different subtypes of PDAC (‘classical’ and ‘basal-like’) and surrounding stroma (‘normal’ and ‘activated’). The basal-like subtype was associated with worse prognosis and a trend towards better response to adjuvant therapy. Hopefully, the molecular stratification of PDAC will potentially allow more personalized treatment strategies and guide clinical decision making.</p

Additional file 2: Supplemental Figure S1. of MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma—a step towards personalized therapy

Immunohistochemical analyses in the cytological sample of the proband’s brother. The stainings for TTF1, CK7, CDX-2, and CK20, summarized in the table, showed patterns of protein expression similar to the expression levels observed in the PEAC component of the proband’s sample. Left column (original magnification ×20); right column (original magnification ×40). (PPTX 32,747 kb

Additional file 1: of MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma—a step towards personalized therapy

Analyses of EGFR, KRAS, ALK and MSI. Detailed methods used for the analyses of EGFR, KRAS mutation, ALK rearrangement, MSI, and miRNA-PCR. (DOC 108 kb

Additional file 3: Supplemental Figure S2. of MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma—a step towards personalized therapy

PCR analysis of miR-31*/-126*/-506/-508-3p/-514. Quantitative “miRNA-targeted” real-time PCR of five miRNA aberrantly expressed in the proband’s PEAC according to the microarray results showed that the microarray data were validated by PCR data as well as that the pattern of modulation of expression of these miRNA was similar in the proband’s brother. Columns and bars, average levels ± SD, compared using the 2-ΔΔCt method to a pool of normal lung tissues, dashed line. (PPTX 158 kb

Correlation between SUV and Patlak at baseline and 4 hours after pemetrexed administration.

<p>Correlation between SUV and Patlak at baseline and 4 hours after pemetrexed administration.</p

<i>AKT1</i> and <i>SELP</i> Polymorphisms Predict the Risk of Developing Cachexia in Pancreatic Cancer Patients

<div><p>Pancreatic ductal adenocarcinoma (PDAC) patients have the highest risk of developing cachexia, which is a direct cause of reduced quality of life and shorter survival. Novel biomarkers to identify patients at risk of cachexia are needed and might have a substantial impact on clinical management. Here we investigated the prognostic value and association of <i>SELP-rs6136</i>, <i>IL6-rs1800796</i> and <i>AKT1-rs1130233</i> polymorphisms with cachexia in PDAC. Genotyping was performed in DNA from blood samples of a test and validation cohorts of 151 and 152 chemo-naive locally-advanced/metastatic PDAC patients, respectively. The association of <i>SELP-rs6136</i>, <i>IL6-rs1800796</i> and <i>AKT1-rs1130233</i> polymorphisms with cachexia as well as the correlation between cachexia and the candidate polymorphisms and overall survival were analyzed. Akt expression and phosphorylation in muscle biopsies were evaluated by specific ELISA assays. <i>SELP-rs6136-AA</i> and <i>AKT1-rs1130233-AA/GA</i> genotypes were associated with increased risk of developing cachexia in both cohorts (<i>SELP: p</i> = 0.011 and <i>p</i> = 0.045; <i>AKT1: p</i> = 0.004 and <i>p</i> = 0.019 for the first and second cohorts, respectively), while patients carrying <i>AKT1-rs1130233-GG</i> survived significantly longer (<i>p</i> = 0.002 and <i>p</i> = 0.004 for the first and second cohorts, respectively). In the multivariate analysis <i>AKT1-rs1130233-AA/GA</i> genotypes were significant predictors for shorter survival, with an increased risk of death of 1.7 (<i>p</i> = 0.002) and 1.6 (<i>p</i> = 0.004), in the first and second cohorts, respectively. This might be explained by the reduced phosphorylation of Akt1 in muscle biopsies from patients harboring <i>AKT1-rs1130233-AA/GA</i> (<i>p</i> = 0.003), favoring apoptosis induction. In conclusion, <i>SELP</i> and <i>AKT1</i> polymorphisms may play a role in the risk of cachexia and death in PDAC patients, and should be further evaluated in larger prospective studies.</p></div

Plasma deoxyuridine over time.

<p>*Significant differences tested with paired t-test, p<0.05, indicated by the accolade.</p

Plasma to blood ratio and parent fraction per scan.

<p>Plasma to blood ratio and parent fraction per scan.</p

Change of ¹⁸F-FLT uptake.

<p>Change of ¹⁸F-FLT uptake in SUV 40–60 min normalised to bodyweight (A) absolute difference, (B) percentage difference.</p

[18F]FLT PET scan.

<p>Example of ¹⁸F-FLT uptake (A) before and (B) 4 hours after pemetrexed administration, showing an increase of ¹⁸F-FLT uptake in the primary tumor (arrow) of 32% after pemetrexed administration.</p