Landscape of genomic alteration of Pancreatic Neuroendocrine Tumours

Pancreatic Neuroendocrine Tumors (PanNETs) are rare malignancies with a wide range of clinical-pathological characteristics and different prognosis with a challenging clinical management. They typically carry out modifications of tumour suppressor pathways and no oncogenic alterations have been found yet. The recent acquisitions on the biological behavior of these rare tumors, due to the analysis of large cohorts of patients with consistent follow up data, lead to a change in classification of PanNETs in recent years. Our group recently identified novel pathways (mTOR, chromatin-remodeling and DNA repair) involved in PanNETs tumorigenesis, demonstrating that 60% of PanNETs had mutations in one of the genes involved in these pathways. We performed whole genome sequencing of 102 primary G1-G2 PanNETs in order to dissect the genomic events that underpin their pathogenesis. Mutations in DAXX/ATRX, mTOR pathway and alterations in the regulation of telomere length mechanism resulted correlated to worse survival. We describe 5 mutational signatures, including a novel G:C>T:A Base-Excision-Repair-deficiency signature due to MUTYH inactivation. We uncover a larger than expected proportion of germline mutations in clinically sporadic PanNETs. These include previously unreported mutations in DNA repair genes MUTYH, CHEK2, and BRCA2, which together with MEN1 and VHL occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, commonly occurred in genes involved in 4 main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling, (including novel EWSR1 gene fusions), and telomere maintenance. Copy number analysis performed by SNP-array, identified 4 distinct groups characterized by different patterns of chromosomal losses and gains. The group identified by the presence of recurrent chromosomal losses, with recurrent loss of chromosome 11, where resides MEN1 locus, resulted enriched for DAXX/ATRX mutations and altered telomere length. In addition, gene expression analyses identified a subgroup of PanNETs associated with upregulation of hypoxia and HIF signalling. These results open novel scenario on the understanding of PanNETs biology and uncover potential prognostic biomarkers able to better predict and stratify the prognosis of patients and influence their clinical management

Autoimmune biliary diseases: primary biliary cholangitis and primary sclerosing cholangitis

Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. Both may evolve into secondary biliary cirrhosis and its complications. Therapeutic options are limited and liver transplantation remains the only definitive treatment for PBC and PSC. Most PBC and PSC patients have a typical presentation, which does not require liver biopsy. However, in routine clinical practice, important variants or specific subgroups that benefit from liver biopsy for proper management may be observed. Herein, we provide a general overview of clinical and pathological characteristic of PBC and PSC, highlighting the most important features for routine diagnostic practice

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio

The Italian Rare Pancreatic Exocrine Cancer Initiative

INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices

The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type

BACKGROUND: PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. METHODS: We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. RESULTS: The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. CONCLUSIONS: The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise

Transverse sphericity of primary charged particles in minimum bias proton–proton collisions at √s = 0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton–proton collisions at s√=0.9, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is measured in the plane perpendicular to the beam direction using primary charged tracks with p T>0.5 GeV/c in |η|<0.8. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity (N ch) is reported for events with different p T scales (“soft” and “hard”) defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low N ch, whereas the event generators show an opposite tendency. The combined study of the sphericity and the mean p T with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts