The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.
Integrins contribute to lymphopoiesis, whereas Toll-like receptors (TLRs) facilitate the myeloid replenishment during inflammation. The combined role of TLRs and integrin on hematopoiesis remains unclear. gp96 (grp94, HSP90b1) is an endoplasmic reticulum master chaperone for multiple TLRs. We report herein that gp96 is also essential for expression of 14 hematopoietic system-specific integrins. Genetic deletion of gp96 thus enables us to determine the collective roles of gp96, integrins, and TLRs in hematopoiesis. We found that gp96-null hematopoietic stem cells could support long-term myelopoiesis. B-and T-cell development, however, was severely compromised with transitional block from pro-B to pre-B cells and the inability of thymocytes to develop beyond the CD4 ؊ CD8 ؊ stage. These defects were cell-intrinsic and could be recapitulated on bone marrow stromal cell culture. Furthermore, defective lymphopoiesis correlated strongly with failure of hematopoietic progenitors to form close contact with stromal cell niche and was not the result of the defect in the assembly of antigen receptor or interleukin-7 signaling. These findings define gp96 as the only known molecular chaperone to specifically regulate T-and B-cell development. (Blood. 2010;115: 2380-2390) IntroductionIntegrins are a family of 24 ␣ heterodimers in vertebrates formed noncovalently by 18 ␣ and 8  integrins, of which 17 integrins are expressed in the hematopoietic system. 1,2 Known best for their adhesion properties, integrins also orchestrate signals between extracellular matrix and intracellular cytoskeletons in regulating diverse functions of cells, including proliferation and differentiation. However, despite the expression of integrins on hematopoietic stem cells (HSCs) and the role of integrins in HSC homing to the bone marrow (BM) niche, their function in hematopoiesis remains controversial. For example, although ␣4 integrin has been implicated in both T and B lymphopoiesis from fetal HSCs, 3,4 it appears to play a less significant role in adult hematopoiesis. 5,6 Furthermore, combined deletion of both 1 and 7 integrins, which are the only known partners of ␣4 integrin, causes no defect in either lymphopoiesis or myelopoiesis. 7 Genetic 2 integrin deficiency causes myeloid hyperplasia, including profound granulocytosis and splenomegaly, but no significant problems in hematopoiesis. 8 Clearly, both ␣4 and 2 integrins are involved in homing of HSCs in the BM and recruitment of leukocytes to sites of inflammation. 5,9,10 Although pan-integrin deficient system is now available, 11 no resolution of the roles of integrin in hematopoiesis has emerged.Toll-like receptors (TLRs) are pattern recognition receptors that play important roles in sensing pathogen-associated molecular patterns from microbes, which are critical for host immune response. 12 More than 10 TLRs have been described in vertebrates, recognizing a spectrum of microbial moieties, such as endotoxin, flagellin, dsRNA, and DNA. In the steady state, TLRs do not contribute signifi...
Purpose We assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution. Methods Patients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points. Results NGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (50 of 96 samples [52%]), and the presence of loss of heterozygosity resulted in inferior overall survival (P < .01). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes (MEN1, TSC2, and VHL). Conclusion A clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs.
Summary Large cell transformation of mycosis fungoides (MF-LCT) occurs in 20–50% of advanced MF, and is generally associated with poor prognosis, although some patients have indolent disease. We sought to identify clinicopathological prognostic factors in a large number of patients with MF-LCT. We identified patients with MF-LCT treated between 1991 and 2012 at a referral centre for cutaneous lymphoma. Clinical and pathological records, and histopathological slides were reviewed. Associations of clinicopathological variables with disease-specific survival were analysed. In 51 patients with MF-LCT, factors significantly associated with shorter survival were: age >60 years (25 versus 61 months, p = 0.01), stage III/IV (25 versus 44 months, p = 0.049), high serum lactate dehydrogenase (LDH; 24 versus 53 months, p = 0.007), absent papillary dermal involvement (8 versus 30 months, p = 0.008); follicular mucin at transformation (24 versus 42 months, p = 0.007); and the absence of fibrosis at transformation (21 versus 42 months, p = 0.03). Patients presenting with transformation at diagnosis had better survival than those who started with a small cell phenotype (p = 0.02). Age >60 years was independently associated with poorer survival (HR 5.61, 95%CI 1.17–26.8, p = 0.03), and the presence of fibrosis at transformation was independently associated with improved survival (HR 0.30, 95%CI 0.09–0.97, p = 0.045). In patients with MF-LCT, clinical features (age, stage, serum LDH) are important in assessing prognosis. Additional clinical and pathological features identified in this study may also assist in prognostic stratification. Studies of larger cohorts should be performed to validate the prognostic significance of these features.
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