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.

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).

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.

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Background Small intestinal Neuroendocrine Neoplasms (SI‐NENs) are the most common primary malignancy of the small bowel. The aim of this study is to define the survival of patients with an SI‐NEN in Auckland, Aotearoa New Zealand (AoNZ). Methods A retrospective study of all patients diagnosed with a jejunal or ileal SI‐NEN in the Auckland region between 2000 and 2012 was performed. The New Zealand NETwork! Registry was searched to identify the study cohort. Retrospective data collection was performed to collect stage, survival and follow up data. Results One hundred and seven patients were included in the study. The mean age of patients was 62.8 years (SD 11.9). The 5 and 10‐year disease‐specific survival for all patients was 66.1% (95% CI 56.5–75.7%) and 61.8% (95% CI 51.8–71.8%), respectively. Ten‐year disease‐specific survival was 100% for stage I and II, 74% (95%CI 61.7–84.4%) for stage III and 33.9% (95%CI 16.9–35.6%) for stage IV SI‐NEN. Eleven of 40 (27.5%) patients with stage III disease had recurrence and 3 of 7 (42.8%) patients with stage IV disease had recurrence. In patients with stage IV disease, neither primary resection (HR 2.25, 95% CI 0.92–5.5) nor distant resection (HR 1.72, 95% CI 0.63–4.7) were significantly associated with a disease‐specific or overall survival benefit. Conclusion This study demonstrates that stage at SI‐NEN diagnosis is associated with survival, but resection of the primary or distant metastases in patients with stage IV disease is not. There was no recurrence in patients with stage I or II disease after complete resection.

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Tumor evolution underlies many challenges facing precision oncology, and improving our understanding has the potential to improve clinical care. This study represents a rare opportunity to study tumor heterogeneity and evolution in a patient with an understudied cancer type. A patient with pulmonary atypical carcinoid, a neuroendocrine tumor, metastatic to 90 sites, requested and consented to donate tissues for research. 42 tumor samples collected at rapid autopsy from 14 anatomically distinct sites were analyzed through DNA whole-exome sequencing and RNA-Seq, and five analyzed through linked-read sequencing. Targeted DNA sequencing was completed on two clinical tissue biopsies and one blood plasma sample. Chromosomal alterations and gene variants accumulated over time, and specific chromosomal alterations preceded the single predicted gene driver variant (ARID1A). At the time of autopsy, all sites shared the gain of one copy of Chr 5, loss of one copy of Chr 6 and 21, chromothripsis of one copy of Chr 11, and 39 small variants. Two tumor clones (carrying additional variants) were detected at metastatic sites, and occasionally in different regions of the same organ (e.g., within the pancreas). Circulating tumor DNA (ctDNA) sequencing detected shared tumor variants in the blood plasma and captured marked genomic heterogeneity, including all metastatic clones but few private tumor variants. This study describes genomic tumor evolution and dissemination of a pulmonary atypical carcinoid donated by a single generous patient. It highlights the critical role of chromosomal alterations in tumor initiation and explores the potential of ctDNA analysis to represent genomically heterogeneous disease.