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Benign Tumor Sequences Mined For Pancreatic Beta Cell Clues

NEW YORK (GenomeWeb) – By sequencing the genomes of rare, benign, insulin-producing pancreatic tumors, researchers have started to tease out the genes and pathways that jumpstart insulin-pumping beta cell expansion.

"For the first time, we have a genomic recipe — an actual wiring diagram in molecular terms — that demonstrates how beta cells replicate," senior author Andrew Stewart, director of the Icahn School of Medicine's Diabetes, Obesity, and Metabolism Institute at Mount Sinai, said in a statement.

Stewart led a team from Mount Sinai and other centers in the US and the UK that did exome sequencing and/or RNA sequencing on paired insulinoma and matched normal samples from 38 individuals. Analyses of these data, described online today in Nature Communications, suggest that a range of recurrent mutations, copy number shifts, and epigenetic pathway changes can contribute to insulinoma.

These alterations affected genes from polycomb and trithorax gene families, along with gene expression networks with prior ties to cell proliferation, the authors reported. Their model suggests that "multiple specific 'epigenetic roads' may lead to insulinoma, and conversely, that despite their apparent clinical heterogeneity, insulinomas display marked mutational heterogeneity, which, in retrospect, could only have been observed in a large number of insulinomas."

The importance of beta cells — and the insulin they produce — is underscored by their role in staving off diabetes, the researchers explained. Beta cell destruction by errant immune cells leads to type 1 diabetes, for example, while stifled insulin production by beta cells contributes to type 2 diabetes.

To explore beta cell expansion in a naturally occurring setting, the team began by doing exome sequencing on insulinoma and matched normal samples from 22 individuals, using Illumina HiSeq 2500 instruments to sequence protein-coding sequences captured with Roche NimbleGen SeqCap human exome capture kits.

"[W]e collected benign tumors that don't metastasize and don't cause great harm, and we're trying to use these benign tumors that have beta cell regeneration going on in them, as the only reasonable source of genomic information on how to make beta cells regenerate," Stewart explained. Beta cell replication normally falls off as humans exit childhood.

The researchers analyzed the newly sequenced exomes alongside four previously sequenced insulinoma tumors, focusing on insulinomas missing MEN1 mutations implicated in hereditary pancreatic neuroendocrine tumors. By comparing mutation patterns in the 26 insulinomas with matched normal samples, they uncovered recurrent mutations in seven new and known genes.

Genes with previously reported epigenetic regulatory roles such as ATR, the histone H3 coding gene H3F3A, and YY1 were over-represented in the collection, as were chromatin modification and developmental genes — results supported by the team's copy number analyses of the tumors.

With RNA sequencing on 25 insulinomas, including 13 of the benign tumors assessed by exome sequencing, the researchers narrowed in on more than 2,100 genes with enhanced expression in the tumors relative to the matched normal set and almost 1,600 genes that appeared to be dialed down in the insulinomas. They saw that still other genes had altered splicing in the insulin-pumping growths.

The team considered networks of co-expressed genes in the tumors, including modules containing genes related to cell proliferation, development, epigenetic regulation, and more. It also searched allele-specific expression shifts, and did methylation sequencing on 10 insulinomas to scrutinize epigenetic profiles at a chromosome 11 region suspected of contributing to beta cell proliferation in individuals with other conditions.

"Collectively, this study provides a novel and complex lens through which to view insulinoma and its relationship to normal beta cell function and raises a number of additional questions … that merit further study," the authors wrote.

For the current study, investigators started delving into the function of some genes showing altered expression in insulinoma. They reportedly plan to collaborate with the Mount Sinai spinout Sema4 to assess potential clinical implications of the current findings.