The Sol Goldman Pancreatic Cancer Research Center

Advances and Discoveries Made at Johns Hopkins

Sequencing Pancreatic Cysts
Some lesions in the pancreas produce cysts. Cysts are fluid-filled collections- kind of like a water balloon. Four different types of tumors commonly produce cysts in the pancreas. These include intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), solid-pseudopapillary neoplasms (SPNs) and serous cystadenomas (SCNs). SCNs are virtually always benign, SPNs are malignant (they can spread to other organs), and IPMNs and MCNs are precancerous lesions. Some MCNs and IPMNs, if left untreated, will progress to pancreatic cnacer. Wu et al sequenced all known human genes (the exomes) of a large series of clinically well-characterized cystic tumors of the pancreas and found that each cyst type has a characteristic pattern of genetic changes (mutations). SCNs harbor VHL mutations, SPNs beta-catenin mutations, MCNs harbor KRAS, RNF43, TP53 and p16 mutations, and IPMNs harbor GNAS, KRAS, RNF43, TP53 and p16 mutations. Why is this important? These findings suggest that DNA-based genetic tests can be developed that can help tell the harmful cysts apart from the potentially harmful cysts.

Wu J, Jiao Y, dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Klimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci. 108:21188-93, 2011.

Wu GJ, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman J, Goggins M, Schulick R D, Edil BH, Wolfgang CL, Klein AP, Diaz, Jr. LA, Allen PJ, Schmidt CM, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 3:92ra66, 2011.

Sequencing Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (PanNETs) account for 15% of malignant tumors of the pancreas. PanNETs, although less aggressive than the more common adenocarcinomas of the pancreas, are fully malignant tumors. In order to understand the fundamental genetics driving the development of PanNETs, Jiao and colleagues at Johns Hopkins sequenced the exomes (all of the known coding genes) of a series of clinically well-characterized PanNETs. The results were dramatic. In addition to confirming previous observations that the MEN1 gene is frequently targeted in PanNETs, the investigators discovered a new cancer pathway in which mutations in the genes DAXX or ATRX cause the "alternative lengthening of telomeres" in the tumors. They also found therapeutically potentially targetable mutations in "mTOR pathway" genes in ~15% of PanNETs. This study is important because it opens up this new cancer pathway to study and because it identifies a new approach to "personalized medicine" for patients with a PanNET.

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1 and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 331:1199-203, 2011.

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus JA, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Nagahashi Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 333:425, 2011.

Personalized Therapy
One of the goals of sequencing cancers is to identify patient-specific mutations that could be exploited to develop individualized therapies. Villarroel and colleagues have done just that. They identified a genetic change (PALB2 mutation) in a pancreatic cancer that caused the patients cancer to be exquisitely sensitive to a specific drug (mitomycin C). Although just one case, it does serve as a wonderful example of the potential power of individualized therapy.

Villarroel MC, Rajesh Kumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, Hruban RH, Eshleman JR, Klein AP, Laheru D, Donehower RC, Hidalgo M. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 10:3-8, 2011.

Statement of conflict of interest:
Dr. Hruban and several other authors on this study receive royalty payments from Myriad Genetics for the PALB2 invention.