Routine Genotyping of Tubal Gut Adenocarcinomas Yields Novel Molecular Insights
Matthew Stachler, Neal Lindeman, Robert Odze, Amitabh Srivastava. Brigham and Women's Hospital, Boston, MA
Background: Gastrointestinal adenocarcinomas (ACA) develop through the inflammation-dysplasia-carcinoma pathway and depending on location, are believed to carry a predictable underlying mutational phenotype. Routine tumor genotyping has the potential to identify novel mutations, for targeted therapy, that may occur at a low frequency and to identify unique combinations of mutations that may be relevant to clinical trial design. We describe herein our initial observations from routine genotyping of tubal gut adenocarcinomas.
Design: 152 ACAs [12 esophagus, 15 stomach, 3 duodenal, 1 small intestinal unspecified, 118 colorectum (46 right colon, 36 left colon, 32 rectum, 4 unspecified), and 3 appendix] were genotyped on a Sequenom platform for 471 mutations in 41 genes. The genotyping results for each case were analyzed for prevalence of various mutation combinations in the panel of 41 genes. A Fisher's exact test was used to test significance of the observed differences.
Results: At least 1 mutation was present in 100/152 (66%) of all cases tested. Two concurrent mutations were present in 32 (21%), three in 10 (7%) and four in 4 (3%) cases. Five (4%) of the CRC cases had concurrent mutations in APC, TP53, and KRAS and another 22 (19%) had a mutation in 2 out of these 3 genes. Two cases showed concurrent BRAF and TP53 mutation and 1 case was positive for both BRAF and KRAS mutation. Previously reported mutations in PIK3CA, NRAS, and CTNNB1 were found in 12%, 5% and 4% of CRC cases. Rare mutations not typically associated with CRC identified by routine genotyping included AKT, IDH1, KIT, MAP2K1, and GNAS. Interestingly, 4 cases with GNAS mutations were identified and all had mucinous differentiation compared to non-GNAS mutant tumors, where only 15% had mucinous differentiation (p= 0.0007). The 4 GNAS mutated tumors involved the cecum, transverse colon, appendix, and duodenum, and the mean patient age was 55 yrs. A similar genotyping approach in pancreatic cancers (n=26) identified 1 GNAS mutation which was a case of a mucinous ACA arising in an IPMN.
Conclusions: Routine tumor genotyping provides useful information for targeted therapy, and also offers novel insights into the molecular pathogenesis of tubal gut ACAs. The identification of mutations involving multiple genes suggests a more complicated process of carcinoma pathogenesis than previously recognized and this has important implications for clinical trial design. It can also help in identifying unique genotype-phenotype correlations such as the association of GNAS mutations with mucinous ACAs.
Monday, March 4, 2013 1:00 PM
Poster Session II # 134, Monday Afternoon