Sex-specific transcriptional differences and loss of gene imprinting in pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) occur more frequently in men and are associated with higher mortality in males; however, the molecular basis for these sexual dimorphisms is unclear. Here, we demonstrate that PNETs are associated with the emergence of unique sex-specific transcriptomic differences that are not observed in non-neoplastic pancreatic islet tissues. We also show that while widespread sex-specific differences are present in the DNA methylation landscapes of control pancreatic islets, they are erased in PNETs. This includes a loss of imprinting with regards to many genes. These results implicate an emergence of sex-associated genetic and epigenetic dysregulations in PNETs.

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Faculty Opinions recommendation of Pancreatic neuroendocrine tumors: targeting the molecular basis of disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725233805.793531213 ◽

2017 ◽

Author(s):

Christos Dervenis ◽

Dionysia Kelgiorgi

Keyword(s):

Neuroendocrine Tumors ◽

Molecular Basis ◽

Pancreatic Neuroendocrine Tumors

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DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Communications Biology ◽

10.1038/s42003-020-01469-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Vanessa Lakis ◽

◽

Rita T. Lawlor ◽

Felicity Newell ◽

Ann-Marie Patch ◽

...

Keyword(s):

Dna Methylation ◽

Neuroendocrine Tumors ◽

Methylation Profile ◽

Pancreatic Neuroendocrine Tumors ◽

Wild Type ◽

Genomic Information ◽

Chromosome 11 ◽

Dna Methylation Profile ◽

Methylation Patterns ◽

Recurrent Patterns

AbstractHere we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

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Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies

Targeted Oncology ◽

10.1007/s11523-012-0229-6 ◽

2012 ◽

Vol 7 (3) ◽

pp. 173-181 ◽

Cited By ~ 16

Author(s):

Annemilaï Tijeras-Raballand ◽

Cindy Neuzillet ◽

Anne Couvelard ◽

Maria Serova ◽

Armand de Gramont ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Targeted Therapies ◽

Molecular Basis ◽

Pancreatic Neuroendocrine Tumors ◽

Preclinical Data

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IGF2 drives formation of ileal neuroendocrine tumors in patients and mice

Endocrine Related Cancer ◽

10.1530/erc-19-0505 ◽

2020 ◽

Vol 27 (3) ◽

pp. 175-186 ◽

Cited By ~ 1

Author(s):

Tanupriya Contractor ◽

Richard Clausen ◽

Grant R Harris ◽

Jeffrey A Rosenfeld ◽

Darren R Carpizo ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Genetic Background ◽

Nuclear Dna ◽

Imprinted Genes ◽

Pancreatic Neuroendocrine Tumors ◽

Classic Model ◽

Loss Of Imprinting

By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.

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