Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression

Prediction of the evolution of endocrine pancreatic tumors remains difficult based on histological criteria alone. We have previously demonstrated that epigenetic changes are an early event in a mouse model developing insulinomas. Particularly, overexpression of the imprinted IGF2 was caused by the hypermethylation of CpGs in the differentially methylated region 2 (DMR2). Here, we investigated whether IGF2 hypermethylation is also observed in human insulinomas and whether this alteration is common to other human endocrine tumors of the pancreas and the digestive tract. We analyzed the methylation status of 40 CpGs located in the DMR0 and DMR2 of the IGF2 as well as in the H19 DMR by pyrosequencing in a cohort of 62 patients with pancreatic or small intestine endocrine tumors. Altered methylation patterns were observed in all tumor types for the different regions of IGF2, but not for H19. However, hypermethylation of the IGF2 DMR2 was specific for insulinomas and did not occur in any of the other types of tumors which were characterized by a loss of methylation in this region. Gain of methylation in the IGF2 DMR2 in insulinomas correlated with loss-of-imprinting and promoter 4 mediated overexpression of IGF2 at the RNA and protein level. Furthermore, a decreasing degree of methylation in the different regions of IGF2 correlated well with increasing degree of malignancy according to the WHO classification of pancreatic endocrine tumors (PETs), suggesting that methylation of IGF2 might be a useful biomarker for classification and staging of PETs.

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Lateral Laparoscopic Approach to Pancreatic Tail Insulinomas

World Journal of Endocrine Surgery ◽

10.5005/jp-journals-10002-1082 ◽

2012 ◽

Vol 4 (1) ◽

pp. 3-7 ◽

Cited By ~ 1

Author(s):

Deepak Abraham ◽

Jinu Kurian Thomas ◽

Philip Joseph ◽

MJ Paul

Keyword(s):

Laparoscopic Surgery ◽

Traditional Approach ◽

Laparoscopic Approach ◽

Lateral Approach ◽

Pancreatic Tumors ◽

Endocrine Tumors ◽

Pancreatic Tail ◽

First Case ◽

Pancreatic Endocrine Tumors ◽

Splenic Vessels

ABSTRACT Pancreatic endocrine tumors are relatively rare lesions and laparoscopic surgery is being increasingly used, especially for insulinomas because of their relatively small size and low incidence of malignancy. Laparoscopic approach to pancreatic tumors has been described in the supine position, transomentally via the lesser sac with anterior stomach retraction. We propose a simplified lateral laparoscopic approach to insulinomas localized preoperatively to the tail or distal body of pancreas. Four patients with pancreatic tail insulinomas underwent laparoscopic surgery between November 2006 and February 2008. Diagnosis was confirmed by fasting sugar, insulin and proinsulin assays. Lesions were localized by multiphasic CT scan/MRI scan and endoscopic ultrasound. All these cases had definitely identifiable enhancing lesions in the distal body/tail in relation to the splenic hilum that appeared accessible by a lateral approach. Except for the first case which was done through the traditional supine approach, the other cases were done by the lateral approach. The patients were positioned right lateral with a kidney bridge. Four subcostal ports were placed and the left colon and spleen with pancreatic tail were mobilised in the same fashion as for splenectomy or adrenalectomy. Tumors were easily identifiable corresponding to the imaging studies. Laparoscopic enucleation was successfully completed in all four patients with lesions in the tail of pancreas, one by the traditional approach and other three by the proposed lateral approach. One patient had associated splenectomy because of the proximity of the lesion to the splenic vessels. Two patients had minor pancreatic leak managed conservatively. The left lateral transperitoneal laparoscopic approach to insulinomas located in the tail of pancreas is feasible and safe. The procedure can be done with ease by surgeons who are familiar with adrenalectomy and splenectomy. How to cite this article Thomas JK, Abraham D, Joseph P, Paul MJ. Lateral Laparoscopic Approach to Pancreatic Tail Insulinomas. World J Endocr Surg 2012;4(1):3-7.

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64 MACROGLOSSIA IN CLONED PIGLETS IS ASSOCIATED WITH HYPOMETHYLATION AT THE KCNQ-OT1 CpG ISLAND

Reproduction Fertility and Development ◽

10.1071/rdv23n1ab64 ◽

2011 ◽

Vol 23 (1) ◽

pp. 138

Author(s):

C. Li ◽

C. O'Gorman ◽

R. S. Prather ◽

J. A. Green ◽

K. D. Wells

Keyword(s):

Genomic Dna ◽

Cpg Island ◽

Methylation Status ◽

Differentially Methylated Region ◽

Sequencing Data ◽

Chi Square ◽

Cpg Sites ◽

Loss Of Imprinting ◽

Parent Of Origin ◽

Cloned Pig

Beckwith-Wiedeman Syndrome (BWS) is a loss of imprinting (LOI) condition that is associated with macroglossia, midline abdominal defects, and neonatal gigantism among other symptoms. These symptoms have also been seen in animals produced by SCNT. A common feature of BWS is the loss of methylation at the KCNQ-OT1 differentially methylated region. We hypothesised that this locus would show a similar LOI in cloned piglets that display macroglossia. DNA sequence for the porcine KCNQ-OT1 region was assembled in silico from public genome sequencing data. A CpG island was noted as being similarly located in the swine sequence as one which has been described for the human differentially differentiated region. Primers were designed to amplify a portion of this region from bisulfite converted genomic DNA. The amplimer spanned 32 CpG sites. To confirm imprinting status of KCNQ-OT1 in swine, a non-cloned pig was evaluated as to the methylation status across this region using DNA isolated from muscle (M) and the proportion hypermethylated was evaluated by chi-square tests. As seen in humans, this region was hypermethylated in approximately half (12 of 24, P = 1) of the cloned, sequenced amplimers. This observation is consistent with a parent of origin imprint at this locus. Next, 2 cloned piglets that appeared normal were assessed for methylation at KCNQ-OT1. M DNA from each of these animals was consistent with normal methylation at this locus, (7 of 16 and 8 of 18 cloned, sequenced amplimers, P > 0.40). Next, M DNA was isolated from 2 cloned litter mates where 1 piglet presented with macroglossia and the other did not. The non-presenting piglet’s M DNA was methylated in approximately half of the cloned sequenced amplimers (9 of 17, P = 0.67) whereas the macroglossia piglet M DNA was devoid of the methylated allele (0 of 14, P < 0.001). An additional pair of macroglossia presenting and non-presenting cloned littermates was identified. In this pair, the non-presenting piglet showed a normal distribution of methylation at this allele (8 of 19, P = 0.77) and the macroglossia piglet deviated somewhat from normal (6 of 20, P < 0.05). These 2 case studies are consistent with the conclusion that the appearance of macroglossia in cloned pigs may be associated with hypomethylation at KCNQ-OT1 and may model BSW. However, additional abnormal pigs will need to be assessed to completely characterise the LOI in cloned piglets.

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TREATMENT OF PATIENTS WITH PANCREATIC NEUROENDOCRINE TUMOURS DEPENDING ON THE DIFFERENTIATION GRADE

Siberian Journal of Oncology ◽

10.21294/1814-4861-2019-18-5-80-85 ◽

2019 ◽

Vol 18 (5) ◽

pp. 80-85

Author(s):

A. Z. Isyangulova ◽

R. Sh. Khasanov ◽

R. F. Enikeev ◽

M. G. Gordiev

Keyword(s):

Treatment Outcomes ◽

Histological Grade ◽

Survival Rates ◽

Tumor Stage ◽

Pancreatic Tumors ◽

Endocrine Tumors ◽

Pancreatic Endocrine Tumors ◽

Extent Of Surgery ◽

Pancreatic Neuroendocrine Tumours ◽

Clinical Records

The incidence of neuroendocrine tumors has significantly increased over the last years.The purpose of the study was to analyze treatment outcomes in patients with pancreatic endocrine tumors (PETs) with regard to histopathologic diagnosis.Material and Methods. The clinical records of 1077 patients with pancreatic tumors were retrospectively analyzed. Fifty patients were diagnosed with PET. Treatment outcomes were assessed with regard to tumor differentiation grade, tumor stage, extent of surgery and drug therapy.Results. The most common histological grade was G1. Patients with G1 tumors had the best 1-and 3-year survival rates regardless of tumor stage. Factors influencing prognosis in patients with PETs were: radical surgery, Ki67 expression level, histological grade (G1–3), tumor stage at diagnosis.

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