Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

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.fals

Can early aortic root surgery prevent further aortic dissection in Marfan syndrome?

We reviewed 50 patients with Marfan syndrome who underwent surgery for aortic root pathologies comprising a root aneurysm without (n = 25; group A) and with (n = 25; group B) dissection. Aortic root repair included Bentall (n = 37) and valve-sparing (n = 13) procedures. Hospital mortality was 4.0%. Twenty-two patients required 36 repeat surgeries on the distal aorta. The main indication for re-intervention was the dilation of the false lumen. In group A, the distal aorta was stable for up to 7 years, but new dissection developed in 5 (33.3%) of the 15 patients who were followed up for >7 years after the root repair. Actuarial survival including operative mortality was 88.1 and 65.0% at 10 and 20 years, respectively; groups A and B did not significantly differ. Rates of freedom from all-cause death, new dissection or repeated aortic surgery were 60.1, 44.5 and 26.0% at 5, 10 and 15 years, respectively. Group A was significantly better than group B. Prophylactic aortic root repair apparently reduces the likelihood of overall adverse events, but it cannot guarantee the prevention of further aortic dissection. A multidisciplinary approach is needed for patients with Marfan syndrome