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

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.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.Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.Advances in treatments for cancer have generally come incrementally because novel treatments are subjected to large prospective randomized clinical trials. In these studies, several hundred patients are randomized to one treatment arm or another and the treatment associated with the best outcome is advanced. This method has worked well for relatively common cancers, including breast and colon cancers. This approach, however, falls short when one is faced with rare cancers such that prospective trials involving large numbers of patients are difficult or impossible to conduct. In these cases, oncologists may choose chemotherapy regimens because the rare tumor is thought to be similar to a more common cancer for which an accepted standard treatment exists. Such is the case with cancers of the ampulla of Vater. These cancers account for only 0.2% of gastrointestinal cancers and approximately 7% of periampullary tumors. Periampullary tumors arise from either pancreatic ductal epithelium, the distal common bile duct, the duodenal mucosa, or the ampulla of Vater. When resectable, ampullary cancers are treated like pancreatic cancers with a pancreaticoduodenectomy. When they present at