Adenocarcinomas of the gallbladder from United States patients demonstrate less frequent molecular change for several genetic markers than other intra-abdominal cancers

Abstract

Context: The incidence of gallbladder cancer is quite low in the US, with an estimate (2013) for new cases of less than 10,000. The rarity suggests a possible shared molecular pathology that might facilitate a greater understanding of this tumor. Objective: We wished to assess the molecular genetic profile of this tumor, particularly KRAS gene mutations, which are frequent in tumors associated with chronic inflamemation elsewhere within the abdomen. Design: We ascertained 25 cases of gallbladder adenocarcinoma from our pathology department records for 2000-2012. PCR based techniques were used to evaluate the DNA for loss of heterozygosity of the APC and DCC genes; for point mutations in the KRAS gene, codons 12 and 13; for point mutation in the BRAF gene, codon 600; for point mutation in the GNAS gene, codon 201; and for microsatellite instability. Results: Patients included 5 males and 20 females. Approximately three-quarters of cases were associated with gallstones, inflammation and dysplasia. Microsatellite instability and GNAS mutation, both present in just 4% of cases, and BRAF mutation present in no cases, do not appear to be significant parts of carcinogenesis of gallbladder carcinoma. We detected a KRAS gene mutation in only 8% of the cases. Loss of heterozygosity for the APC was detected in 16.7% of informative cases; and for the DCC gene, in 34.8% of informative cases. Conclusions: Many molecular genetic changes frequently seen with tumors arising from other intra-abdominal organs are infrequent in this tumor type. In particular, KRAS mutations were uncommon, in contra-distinction to other malignant tumors developing in the setting of chronic inflammation/infection.