Whole Exome Sequencing of Both Components of a Mixed Adenocarcinoma/Small Cell Carcinoma of the Gallbladder
Laura D Wood, Yuchen Jiao, Anirban Maitra, Pedram Argani, John L Cameron, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban. Johns Hopkins University School of Medicine, Baltimore, MD
Background: Each year 7,200 Americans are diagnosed with cancer of the biliary tract, and each year 3,600 die from their disease. While the majority of carcinomas of the gallbladder are adenocarcinomas, rare mixed adenocarcinoma/small cell carcinomas occur. The molecular genetic alterations underlying the development of these neoplasms are poorly understood.
Design: Each component of a fresh-frozen mixed adenocarcinoma/small cell carcinoma of the gallbladder was macrodissected to achieve a neoplastic cellularity of >70%. Each neoplastic component, as well as normal tissue from the same patient, was analyzed by whole exome sequencing using next-generation sequencing technology. Known SNPs were removed from the analysis, and the alterations in the two components of the neoplasm were compared to the patient's normal sequence to identify somatic (tumor-specific) mutations.
Results: Somatic mutations were identified in a total of 55 genes. Interestingly, the majority of the somatic mutations (35) were shared between both components, including mutations in the tumor suppressor gene TP53 as well as several mutations with predicted functional consequences, such as a nonsense mutation in the ephrin receptor EPHA1 and a frameshift mutation in transmembrane serine protease TMPRSS7. Somatic mutations unique to each morphologic component were also identified. Nine mutations occurred only in the small cell carcinoma, including a nonsense mutation in the GTPase activator ARHGAP28, while the adenocarcinoma possessed 11 unique mutations.
Conclusions: Whole exome sequencing can be used to define the genesis of mixed neoplasms. In this mixed adenocarcinoma/small cell carincoma of the gallbladder, the majority of the somatic mutations were shared between the two components, but unique somatic mutations were also identified in both the adenocaricoma and small cell carcinoma. This suggests a clonal origin followed by divergent genetic changes which subsequently contributed to the distinct morphologies of the two components.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 282, Tuesday Morning