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Brooke Sylvester
Molecular Genetics of Colorectal Cancer Progression in a Diverse Patient Cohort
Abstract Text:
Background: African American colorectal cancer (CRC) patients have worse outcomes than Caucasian patients. Objective: To determine if differences exist in the molecular pathogenesis of CRC between African Americans and Caucasians, we characterized patient tumors from a single institution by assessing genetic alterations involved in CRC progression and response to treatment. Methods: We retrospectively examined 448 African Americans and Caucasians diagnosed with CRC at The University of Chicago Medical Center between 1992 and 2002. Microsatellite instability (MSI) status was determined by genotyping the BAT25, BAT26, BAT40, D5S346, and BAX loci. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. MSI status and specific mutations were correlated with clinicopathological features. Results: Overall, no difference existed in MSI or BRAF mutation frequencies between African Americans and Caucasians. However, African Americans with microsatellite stable (MSS)/MSI-low (MSI-L) tumors had a higher proportion of KRAS mutations than Caucasians (34% v. 23%, p=0.048) that was isolated to proximal cancers. There was also a difference in the KRAS mutation spectrum between African Americans and Caucasians, especially in codon 13. There was no racial/ethnic difference in receipt of chemotherapy, but African Americans with MSS/MSI-L tumors had a 70% increased mortality risk over Caucasians that could not be explained by known prognostic factors. Conclusions: The observed difference in the KRAS mutation spectrum, if confirmed in additional studies, may impact choice of anti-EGFR therapies in the African American population. Future work will involve characterization of molecular alterations influencing disease progression and response to treatment.
Molecular Genetics of Colorectal Cancer Progression in a Diverse Patient Cohort
Abstract Text:
Background: African American colorectal cancer (CRC) patients have worse outcomes than Caucasian patients. Objective: To determine if differences exist in the molecular pathogenesis of CRC between African Americans and Caucasians, we characterized patient tumors from a single institution by assessing genetic alterations involved in CRC progression and response to treatment. Methods: We retrospectively examined 448 African Americans and Caucasians diagnosed with CRC at The University of Chicago Medical Center between 1992 and 2002. Microsatellite instability (MSI) status was determined by genotyping the BAT25, BAT26, BAT40, D5S346, and BAX loci. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. MSI status and specific mutations were correlated with clinicopathological features. Results: Overall, no difference existed in MSI or BRAF mutation frequencies between African Americans and Caucasians. However, African Americans with microsatellite stable (MSS)/MSI-low (MSI-L) tumors had a higher proportion of KRAS mutations than Caucasians (34% v. 23%, p=0.048) that was isolated to proximal cancers. There was also a difference in the KRAS mutation spectrum between African Americans and Caucasians, especially in codon 13. There was no racial/ethnic difference in receipt of chemotherapy, but African Americans with MSS/MSI-L tumors had a 70% increased mortality risk over Caucasians that could not be explained by known prognostic factors. Conclusions: The observed difference in the KRAS mutation spectrum, if confirmed in additional studies, may impact choice of anti-EGFR therapies in the African American population. Future work will involve characterization of molecular alterations influencing disease progression and response to treatment.
