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Table shows the pathway deregulated in OUH and TCGA cohort.

Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092–102. ©2016 AACR.

Summary results for all SNPs at the 4q24 locus associated with breast cancer risk at P

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Table S1: Genes significantly differentially expressed in samples with pathological complete response compared to those without in the Combination arm. Table S2: DAVID analysis of 720 differentially expressed genes in tumors that achieved pathological complete reponse compared to those that did not, in the combination arm. Table S3 : Genes significantly differentially expressed in samples with pathological complete response compared to those without in the Chemotherapy arm. Table S4: DAVID analysis of 1243 differentially expressed genes in tumors that achieved pathological complete reponse compared to those that did not, in the chemotherapy arm. Table S5 : List of genes with significant lower expression in week 12 samples treated with combination therapy compared to those treated with chemotherapy Table S6: DAVID analysis of 42 differentially expressed genes in week-12 tumors in the combination arm compared to chemotherapy arm. Table S7 : Differentially expressed genes between week-0 and week-12 in Basal-like tumors treated with combination therapy Table S8 : Differentially expressed genes between week-0 and week-12 Luminal B tumors treated with combination therapy Table S9 : Differentially expressed genes between week-0 and week-12 Luminal A tumors treated with combination therapy Table S10: Differentially expressed genes between week-0 and week-12 Basal-like tumors treated with chemotherapy Table S11 : Differentially expressed genes between week-0 and week-12 Luminal B tumors treated with chemotherapy Table S12 : Differentially expressed genes between week-0 and week-12 Luminal A tumors treated with chemotherapy Table S13: Pathways significantly altered between Chemotherapy and Combination therapy arms from week-0 to week-12 LuminalB samples Table S14: Pathways significantly altered between anthracycline and taxane treatment in the Luminal A samples in chemotherapy arm

The table shows the genes, chromosomal location and frequency of deletion and amplification of genes in OUH (PAs (n=54), cell lines (n=3) and IPMN (n=3) and TCGA data sets (n=127).

This file contains the legends of supplementary figures and tables.

1a) Amplification and deletion of cytobands in OUH cohort. 1b) Amplification and deletion of cytobands in TCGA cohort. The rows represent the cytobands while the columns represent the samples. The color bars on y-axis represent the chromosomes. The red color in the heatmap represents the amplification, green color represent the deletion while black represent the normal state.

The minor allele frequency is in blue and purple is the total copy number.

Purpose: Chemotherapy-induced alterations to gene expression are due to transcriptional reprogramming of tumor cells or subclonal adaptations to treatment. The effect on whole-transcriptome mRNA expression was investigated in a randomized phase II clinical trial to assess the effect of neoadjuvant chemotherapy with the addition of bevacizumab.Experimental Design: Tumor biopsies and whole-transcriptome mRNA profiles were obtained at three fixed time points with 66 patients in each arm. Altogether, 358 specimens from 132 patients were available, representing the transcriptional state before treatment start, at 12 weeks and after treatment (25 weeks). Pathologic complete response (pCR) in breast and axillary nodes was the primary endpoint.Results: pCR was observed in 15 patients (23%) receiving bevacizumab and chemotherapy and 8 patients (12%) receiving only chemotherapy. In the estrogen receptor–positive patients, 11 of 54 (20%) treated with bevacizumab and chemotherapy achieved pCR, while only 3 of 57 (5%) treated with chemotherapy reached pCR. In patients with estrogen receptor–positive tumors treated with combination therapy, an elevated immune activity was associated with good response. Proliferation was reduced after treatment in both treatment arms and most pronounced in the combination therapy arm, where the reduction in proliferation accelerated during treatment. Transcriptional alterations during therapy were subtype specific, and the effect of adding bevacizumab was most evident for luminal-B tumors.Conclusions: Clinical response and gene expression response differed between patients receiving combination therapy and chemotherapy alone. The results may guide identification of patients likely to benefit from antiangiogenic therapy. Clin Cancer Res; 23(16); 4662–70. ©2017 AACR.

Supplementary figures as referred to in the manuscript

Table shows the correlation score (r) between allele frequency and gene expression in OUH and TCGA cohort

The minor allele frequency is in blue and purple is the total copy number.

The x-axis represents the genomic position and is divided into 22 facets for 22 chromosomes. The y-axis represents the frequency of chromosomal gain and losses for five subtypes based on site of origin. The number of samples in each subtypes are PDAC: 28, bile duct: 4, ampulla P: 6, ampulla I: 7, duodenum: 9.

4A) Scatter plot shows the correlation between GII and ploidy of the tumors in OUH cohort. 4B) Scatter plot shows the correlation between GII and ploidy of the tumors in TCGA cohort. The x-axis represent the genome instability index while the y-axis represent the ploidy of the tumors

Epithelial-to-mesenchymal transition (EMT) contributes to tumor cell survival, immune evasion, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a higher likelihood of metastasis. AXL, a receptor tyrosine kinase, drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer and breast cancer. TANK-binding kinase 1 (TBK1) is central to AXL-driven EMT yet, the mechanism of how TBK1 induces EMT remains unclear. Here, we report that AXL activation stimulates TBK1 binding and phosphorylation of AKT3. TBK1 activation of AKT3 drives binding and phosphorylation of slug/snail resulting in protection from proteasomal degradation and translocation of the complex into the nucleus. We show that nuclear translocation of AKT3 is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast cancer. To advance AKT3 as a therapeutic target, an AKT3-isoform selective allosteric small molecule inhibitor, BGB214, was developed. BGB214 inhibits AKT3 nuclear translocation, EMT-TF stability, AKT3-mediated invasion of breast cancer cells and reduces tumor initiation in vivo. Our results suggest that AKT3 nuclear activity is an important feature of AXL-driven epithelial plasticity and that selective AKT3 inhibition represents a novel therapeutic avenue for treating aggressive cancer.SignificanceNuclear AKT3 activity is an important feature of AXL-TBK1 driven EMT and metastasis, thus selective AKT3 targeting represents a novel approach to treat aggressive cancer.