Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

Background: A systematic review was undertaken to identify existing quality performance indicators (QPI) for the surgical treatment of gastric adenocarcinoma (GA) with the aim of defining a set of QPIs that can be used to assist in the accreditation of institutions for training, allow cross jurisdiction comparison of treatment and outcomes, as well as provide a basis to develop quality improvement programs. These QPI's capture key components of patient care that are fundamental to overall outcome. Methods: A systematic literature review was conducted searching MEDLINE, PubMed, EMBASE, and SCOPUS with all literature available until the date of 1 August 2021 included. Search terms utilized were 'Quality of health care OR Quality improvement or Quality control OR Quality indicators', AND 'Gastrectomy' OR 'Stomach neoplasm' OR 'Adenocarcinoma' OR 'Gastric resection' OR 'Gastric cancer'. Results: Twelve articles were included in the final analysis. The selected studies included editorials (n = 2), retrospective review of institutional experience (n = 5), cohort studies (n = 2), survey methodology (n = 1), expert guidelines (n = 1) and consensus statement (n = 1). For GC QPIs, process measures included patient discussion at multi-disciplinary meetings, access to perioperative multimodal diagnostic pathways, and specific surgical metrics (margin negative resections and adequate lymphadenectomy). Outcome measures included the RO resection rate, reoperation, readmission rate, and length of hospital stay. Conclusions: There is a relative paucity of internationally agreed QPI for the surgical management of gastric adenocarcinoma. The data from this review will form the basis of a project to develop internationally agreed and feasible QPI for gastric cancer resections.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern -these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of ≥1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudohypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type. IntroductionPancreatic neuroendocrine tumors (pNETs) are clinically heterogeneous tumors derived from neuroendocrine cells of pancreatic islets, which differ from one other by their primary organ of origin and degree of cellular differentiation. Currently, therapeutic decisions must be made with little knowledge of the biological drivers of individual NETs, underlining the importance of improved genomic understanding of these tumors. Although driver mutations in tumor suppressor genes have been found in pNETs (e.g., MEN1, DAXX, ATRX, VHL, YY1, and mechanistic target of rapamycin (mTOR) pathway genes (1-3)) they are infrequent and are not generally able to indicate specific systemic therapies. In addition to these driver mutations, other genomic changes have been observed in pNETs, including: telomeric dysregulation (4, 5), copy number (CN) changes (6), changes in RNA expression that indicate mTOR pathway activation (7), germline MEN1 and MUTYH inactivation (2, 8). Epigenetic changes in methylation (9) and microRNA expression (10) have been described in pNETs, with insulinomas especially enriched for changes to the sequence, methylation and expression of genes encoding epigenetic modifiers (11).

No abstract

No abstract