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. 2012 Jul 4;4(7):56.
doi: 10.1186/gm357. eCollection 2012.

Cancer of the ampulla of Vater: analysis of the whole genome sequence exposes a potential therapeutic vulnerability

Michael J Demeure  1 , David W Craig  2 , Shripad Sinari  2 , Tracy M Moses  3 , Alexis Christoforides  2 , Jennifer Dinh  3 , Tyler Izatt  2 , Jessica Aldrich  2 , Ardis Decker  4 , Angela Baker  3 , Irene Cherni  3 , April Watanabe  3 , Lawrence Koep  5 , Douglas Lake  6 , Galen Hostetter  3 , Jeffrey M Trent  3 , Daniel D Von Hoff  7 , John D Carpten  3
Affiliations

Cancer of the ampulla of Vater: analysis of the whole genome sequence exposes a potential therapeutic vulnerability

Michael J Demeure et al. Genome Med. .

Abstract

Background: Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scale clinical 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 DNA from a 63 year-old man who underwent a pancreaticoduodenectomy by whole genome sequencing, 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.

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Figures

Figure 1
Figure 1
Circos plot summarizing somatic events contained within pancreatic tumor of the ampulla of Vater. The outer ring shows gene symbols for those genes somatically altered in the tumor relative to their map position against the human genome chromosome karyotype. Blue tick marks denote genes containing nonsynonymous point mutations. Cyan tick marks denote genes containing coding indels. Magenta tick marks represent discordant read pairs supporting putative translocation events and those genes involved in breakpoints. The inner ring represents somatic copy number events with regions of gain shown in red and regions of loss shown in green, with brighter colors denoting higher degrees of gain or loss. Magenta lines in the center represent breakpoint regions for translocation events.
Figure 2
Figure 2
Zoom in of the 10q region containing focal homozygous deletion encompassing the PTEN tumor suppressor gene.
Figure 3
Figure 3
Simplified map and interactions of the phosphoinositide 3-kinase (PI3K) and RAS pathways highlighting the genomic aberrations (-, loss of function mutation, *gain of function mutation) identified in a cancer of the ampulla of Vater and the putative therapeutic site of vulnerability. ERK, extracellular-signal-regulated kinase; grb2, growth factor receptor bound protein 2; mTOR, mammalian target of rapamycin; RTK, receptor tyrosine kinase; SHC, SHC (Src homology 2 domain containing) transforming protein 1; SOS, son of sevenless.
See this image and copyright information in PMC

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