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-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.