PIK3CA Mutations in Mucinous Cystic Neoplasms of the Pancreas

Abstract

Objectives Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110α) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens. Methods Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K(exon 9), and H1047R (exon 20) hot-spotmutations in the PIK3CA gene and the E17K mutation in the AKT1 gene. Results A hot-spotmutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRASG12D mutation. No mutations were identified in the AKT1 gene. Conclusions Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy.

A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas

“…This has enormously added to our knowledge of the whole spectrum of pancreatic neoplasms including PanIN and IPMN 11–19 . In addition, our understanding of the genetics of precursors has greatly expanded with the introduction of routine molecular genetic analyses, including next generation sequencing 20–28 .…”

Insights into the Pathogenesis of Pancreatic Cystic Neoplasms

“…SMAD4 or DPC4 is intact in the non-invasive epithelium of MCN but is lost in the invasive component[24]. Similarly, PIK3CA mutations occur in higher grade lesions in MCNs [25]…”

Mucinous cystic neoplasms of the liver and pancreas: relationship between KRAS driver mutations and disease progression

“…Other studies have indicated that, similarly to what is seen in conventional pancreatic ductal adenocarcinomas, alterations in TP53 , KRAS and SMAD4 are common in invasive carcinomas derived from MCNs‐P . Previous studies have also identified somatic mutations of RNF43 and PIK3CA in MCNs‐P . However, it remains challenging to assess the risk of malignancy before surgery on a case‐by‐case basis.…”

“…However, it remains challenging to assess the risk of malignancy before surgery on a case‐by‐case basis. Large MCNs‐P are not always malignant, whereas invasive cancers sometimes develop in small tumours, suggesting that genetic alterations and the risk of malignancy vary among cases …”