Expression and prognostic value of NSD1 and SETD2 in pancreatic ductal adenocarcinoma and its precursor lesions.

Epigenetic regulation is emerging as a critical mechanism for pancreatic ductal adenocarcinoma (PDA) development. Histone methylation is an important regulatory mechanism, altering chromatin structure and promoter accessibility and causing aberrant gene expression. NSD1 and SETD2 genes encoding two histone H3K36 methyltransferases, are mutated or altered in 8-10% of PDA cases. However, whether there is altered protein expression of NSD1 or SETD2 in PDA and its precursors, and whether they have diagnostic or prognostic utility is unknown. Tissue microarrays composed of a total of 190 and 192 duplicated cases of PDA (n=74 and 75), metastatic PDA (n=17 and 18), pancreatic intraepithelial neoplasia (PanIN; n=19 and 24), intraductal papillary mucinous neoplasm (IPMN; n=36), mucinous cystic neoplasm (MCN; n=12) and benign pancreatic tissues (n=27 and 32) were analysed for expression of NSD1 and SETD2 by immunohistochemistry. We assessed intensity and percentage of positive cells. NSD1 expression was significantly increased in metastatic PDA compared to benign ducts, primary PDA, and all other lesions combined (p=0.03, 0.02, and 0.03 respectively). Additionally, significantly decreased SETD2 protein expression was found in metastatic PDA and PanIN lesions compared to benign ducts (p=0.04 and 0.007, respectively). High NSD1 expression was associated with clinical stage III/IV disease (p=0.026), tumour grade 2 (p=0.022), use of neoadjuvant therapy (p=0.037), and overall higher clinical stage (p=0.022). There is no significant difference in overall and progression-free survival between NSD1/SETD2 high and low PDA. Expression of NSD1 and SETD2 is specifically altered in metastatic PDA and some of the PDA precursor lesions, supporting their important role in PDA development and metastasis. In addition, increased NSD1 expression is significantly associated with higher clinical stage and neoadjuvant therapy, suggesting that NSD1 may be a useful prognostic marker.