Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for ...beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.
Purpose
While SWI/SNF chromatin remodeling complex alterations occur in approximately 20% of cancer, the frequency and potential impact on clinical outcomes in meningiomas remains to be ...comprehensively elucidated.
Methods
A large series of 255 meningiomas from a single institution that was enriched for high grade and recurrent lesions was identified. We performed next-generation targeted sequencing of known meningioma driver genes, including
NF2
,
AKT1
,
PIK3CA
,
PIK3R1,
and
SMO
and SWI/SNF chromatin remodeling complex genes, including
ARID1A
,
SMARCA4
, and
SMARCB1
in all samples. Clinical correlates focused on clinical presentation and patient outcomes are presented.
Results
The series included 63 grade I meningiomas and 192 high-grade meningiomas, including 173 WHO grade II and 19 WHO grade III. Samples from recurrent surgeries comprised 37.3% of the series. A total of 41.6% meningiomas were from the skull base.
NF2, AKT1, PIK3CA, PIK3R1,
and
SMO
were mutated in 40.8, 7.1, 3.5, 3.9, and 2.4% of samples, respectively.
ARID1A, SMARCA4,
and
SMARCB1
mutations were observed in 17.3, 3.5, and 5.1% of samples, respectively. A total of 68.2% of
ARID1A-
mutant meningiomas harbored a p.Gln1327del in-frame deletion.
ARID1A
mutations were seen in 19.1% of Grade I, 16.8% of Grade II, and 15.8% of Grade III meningiomas (
P
= 0.9, Fisher’s exact). Median overall survival was 16.3 years (95% CI 10.9, 16.8). With multivariable analysis, the presence of an
ARID1A
mutation was significantly associated with a 7.421-fold increased hazard of death (
P
= 0.04).
Conclusion
ARID1A
mutations occur with similar frequency between low and high-grade meningiomas, but
ARID1A
mutations are independently prognostic of worse prognosis beyond clinical and histopathologic features.
Background
The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational ...burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown.
Methods
Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1–25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study.
Results
One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1–25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1–25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1–25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3,
P
= 0.03.
NF2
mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes.
NF2
mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1–25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes,
P
= 0.046.
Conclusions
Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden.
NF2
mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.
Purpose
Meningiomas are the most common primary central nervous system tumor. Emerging data supports that higher mutational burden portends worse clinical outcomes in meningiomas. However, there is a ...lack of imaging biomarkers that are associated with tumor genomics in meningiomas.
Methods
We performed next-generation targeted sequencing in a cohort of 75 primary meningiomas and assessed preoperative imaging for tumor volume and peritumoral brain edema (PTBE). An Edema Index was calculated.
Results
Meningiomas that were high grade (WHO grade II or grade III) had significantly larger tumor volume and were more likely to present with PTBE. Moreover, PTBE was associated with brain invasion on histopathology and reduced overall survival. There was a direct association between Edema Index and mutational burden. For every one increase in Edema Index, the number of single nucleotide variants increased by 1.09-fold (95% CI: 1.02, 1.2) (
P
= 0.01).
Conclusion
These data support that Edema Index may serve as a novel imaging biomarker that can inform underlying mutational burden in patients with meningiomas.
Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular "recipe" or "roadmap" for pathways that control human beta cell regeneration. An ...earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.
Significance Associated with depression and cognitive impairment, chronic stress causes reversible dendritic shrinkage particularly evident in the hippocampal CA3 region in several animal models. In ...further elucidating the molecular events leading to dendritic shrinkage, this study reveals two unexpected mechanisms reduction in translated transcripts of a nuclear pore complex protein, nucleoporin p62 (NUP62), and tyrosine phosphorylation of NUP62, that appear to act cumulatively in chronic stress to reduce NUP62 content in CA3 neurons. Subcellular redistribution of activated proline-rich tyrosine kinase 2 in chronically stressed pyramidal neurons suggests a mechanism for stress-induced tyrosine phosphorylation of NUP62. Furthermore, evidence from cultured hippocampal neurons shows that diminishing the content of NUP62, which functions in nucleocytoplasmic transport and chromatin organization, results in simplification and shortening of dendritic arbors.
Genetic evidence suggests cell-type–specific functions for certain nucleoporins, and gene expression profiling has revealed that nucleoporin p62 (NUP62) transcripts are decreased in the prefrontal cortex of major depressives. Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus. Genetically targeted translating ribosome affinity purification revealed a selective reduction in translated Nup62 transcripts in CA3 of chronically stressed mice, and the Nup62 protein content of nuclei extracted from whole hippocampus was found to be decreased in chronically stressed rats. In cultured cells, phosphorylation of a FAK/proline-rich tyrosine kinase 2 (PYK2) consensus site in the alpha-helical domain of NUP62 (human Y422) is shown to be associated with shedding of NUP62 from the nuclear pore complex (NPC) and/or retention of NUP62 in the cytoplasm. Increased levels of phospho-Y425 Nup62 were observed in cytoplasmic fractions of hippocampi from chronically stressed rats, and immunofluorescence microscopy revealed redistribution of activated Pyk2 to the perinuclear region of stressed pyramidal neurons. Depletion of Nup62 from cultured embryonic day 18 rat hippocampal and cortical neurons resulted in simplification and retraction of dendritic arbors, without disruption of axon initial segment integrity. Thus, at least two types of mechanisms—one affecting expression and the other association with the NPC—could contribute to loss of NUP62 from CA3 pyramidal neurons during chronic stress. Their combined actions may account for the enhanced responsiveness of CA3 apical dendrites to chronic stress and may either be pathogenic or serve to protect CA3 neurons from permanent damage.
PLZF is a transcription repressor, which plays a critical role in development, spermatogenesis and oncogenesis. Down-regulation of PLZF has been found in various tumor cell lines. There has been ...virtually no tissue study on the expression of PLZF in prostate cancer (PCa). PCa is a heterogeneous disease, most of which are indolent and non-lethal. Currently there are no biomarkers that distinguish indolent from aggressive PCa; therefore there is an urgent need for such markers to provide clinical decision support. This study aimed to investigate the expression of PLZF by immunohistochemistry in different grade as well as metastatic PCa and to correlate the alteration of PLZF expression with PCa aggressiveness. We studied a total of 83 primary PCa from biopsies, 43 metastatic PCa and 8 paired primary and metastatic PCa from radical prostatectomies with lymph node dissection. Our results demonstrated that PLZF was strongly expressed in almost all (~100%) benign luminal cells (n=77) and low grade (Gleason pattern 3) PCa (n=70) and weak or absent (100%) in basal cells (n=70). Decreased or lost expression of PLZF was evidenced in 26% of high-grade (Gleason 4 and 5) primary PCa (n=70) and 84% metastatic PCa (n=43). The primary high grade PCa in the prostatectomies shared similar PLZF loss/decrease and histomorphology to that of paired parallel lymph node metastases. These data demonstrated that down-regulation of PLZF is an important molecular process for tumor progression and loss of PLZF expression detected by routine immunohistochemistry is a promising and valuable biomarker for PCa aggressiveness and metastasis in the personalized care of PCa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Emerging evidence suggests that
STK11
mutations may influence clinical outcome and response to immunotherapy in cancer.
Materials and methods
Next-generation targeted sequencing of
STK11
...mutation status in a large cohort of 188 meningiomas.
Results
STK11
loss-of-function mutations were identified in 3.7% of meningiomas.
STK11
mutations were found in both low- and high-grade lesions and samples from primary and recurrent disease. There was a 2.8-fold increased risk of death for patients whose meningioma harbored an
STK11
mutation, after controlling for lesion grade and occurrence status. The median overall survival for patients with
STK11
-mutated meningiomas was 4.4 years compared with 16.8 years.
Conclusion
These data identify recurrent
STK11
mutations in a subset of meningiomas. Genotyping of
STK11
is encouraged for meningioma patients undergoing immunotherapy-based therapy.
PDF
