NANETS: Pancreatic Neuroendocrine Tumors Harbor DNA Repair Gene Defects

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pNETs harbor genetic mutations in DNA repair pathways that represent "strong candidates".
pNETs harbor genetic mutations in DNA repair pathways that represent "strong candidates".

Pancreatic neuroendocrine tumors (pNETs) harbor genetic defects in DNA repair pathways that represent “strong candidates” for prospective studies, according to a literature review (NET Abstract #C18) described at the 7th Annual Neuroendocrine Tumors (NET) conference in Nashville, TN. The meeting was organized by the North American Neuroendocrine Tumors Society (NANETS).

The review suggests that PTEN and MEN1 mutations are frequently present in pNETs. 

“Further studies are essential in determining a more thorough repertoire of DNA repair defects in pNETs and the clinical significance of these defects,” said lead study author Iris H. Liu, of Dartmouth College in Hanover, NH, and colleagues. The literature review “synthesizes the existing knowledge of relevant DNA repair pathways and studies of the specific genes that carry out these repair mechanisms in pNETs,” the coauthors reported.

The roles of DNA repair mechanisms in pNET development are poorly understood, but “the existing literature reveals important preliminary trends and targets in the genetic landscape,” the coauthors reported. “Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies.”

Searching PubMed for original studies assessing DNA repair and repair-pathway genes MGMT, MMR, PTEN, and MEN1, the team found 5 published studies each for MGMT and PTEN in pNETs, 3 studies on MEN1, and 4 studies published on MMR.

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“The five studies on MGMT in pNETs found MGMT loss of between 24% and 51% by IHC staining and between 0% and 40% by promoter hypermethylation, revealing discrepancies in methods assessing MGMT expression as well as potential weaknesses in the correlation between MGMT IHC expression and promoter hypermethylation rates,” the coauthors noted. “Four studies on MMR in pNETs indicated similar ambiguities, as promoter hypermethylation of the MLH1 MMR gene ranged from 0% to 31% of pNETs. IHC staining revealed loss of MMR genes in between 0% and 36% of pNETs sampled.”

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