Cancer of the Ampulla of Vater: Analysis of the Whole Genome Sequence Exposes a Potential Therapeutic Vulnerability
Background: Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scalec linical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers.
Methods: We analyzed DNA from a resected cancer of the ampulla of Vater and whole blood DNAfrom a 63 year-old man who underwent a pancreaticoduodenectomy by whole genomesequencing, achieving 37× and 40× coverage, respectively. We determined somatic mutations and structural alterations.
Results: We identified relevant aberrations, including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a distinct oncogenesis from either common bile duct cancer or pancreatic cancer. Furthermore, this combination of genomic aberrations suggests a therapeutic context for dual mTOR/PI3K inhibition.
Conclusions: Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.
- Author (aut): Demeure, Michael J.
- Author (aut): Craig, David W.
- Author (aut): Sinari, Shripad
- Author (aut): Moses, Tracy M.
- Author (aut): Christoforides, Alexis
- Author (aut): Dinh, Jennifer
- Author (aut): Izatt, Tyler
- Author (aut): Aldrich, Jessica
- Author (aut): Decker, Ardis
- Author (aut): Baker, Angela
- Author (aut): Cherni, Irene
- Author (aut): Watanabe, April
- Author (aut): Koep, Lawrence
- Author (aut): Lake, Douglas
- Author (aut): Hostetter, Galen
- Author (aut): Trent, Jeffrey M.
- Author (aut): Von Hoff, Daniel D.
- Author (aut): Carpten, John D.
- Contributor (ctb): College of Liberal Arts and Sciences