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Familial and sporadic pancreatic cancer share the same molecular pathogenesis

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.

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Acknowledgments

We acknowledge Drs. Scott Kern, Ming Tseh-Lin, Gloria Petersen, Manuel Hidalgo, Elizabeth Jaffee, Steve Leach, Michael Goggins, Christine Iacobuzio-Donahue, Hiro Kamiyama, Mihoko Kamiyama, and Denise Batista for helpful discussions. We thank Alyza Skaist, Laura Morsberger, Jennifer Meyers, Diane Echavarria, Roxanne Ashworth, and Hong Liang for outstanding technical support. Grants: The Sol Goldman Pancreatic Cancer Research Center (pilot project) (JRE), R21CA164592 (JRE), PanCan/AACR Innovation Award (JRE), SPORE P50-CA62924-13 (Kern) and The Stringer Foundation (JRE).

Ethical standard

This study was performed with approval by the Institutional Review Board at Johns Hopkins Medical Institution. All participants gave informed consent and details that might disclose the identity of the subjects under study have been omitted.

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Author notes

  1. Siân Jones

    Present address: Personal Genome Diagnostics, 2809 Boston St, Suite 503, Baltimore, MD, 21224, USA

Authors and Affiliations

  1. Department of Pathology, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Room 344, Cancer Research Building-II, 1550 Orleans Street, Baltimore, MD, 21231, USA

    Alexis L. Norris, Nicholas J. Roberts, Ralph H. Hruban, Alison P. Klein & James R. Eshleman

  2. Ludwig Center and Howard Hughes Medical Institute, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Nicholas J. Roberts, Siân Jones, Nickolas Papadopoulos, Bert Vogelstein & Kenneth W. Kinzler

  3. Department of Oncology, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Nickolas Papadopoulos, Bert Vogelstein, Kenneth W. Kinzler, Ralph H. Hruban, Alison P. Klein & James R. Eshleman

  4. Department of Oncology Biostatistics, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Sarah J. Wheelan

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  1. Alexis L. Norris
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Correspondence to James R. Eshleman.

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Norris, A.L., Roberts, N.J., Jones, S. et al. Familial and sporadic pancreatic cancer share the same molecular pathogenesis. Familial Cancer 14, 95–103 (2015). https://doi.org/10.1007/s10689-014-9755-y

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