Genetic variation between East Asians and Caucasians: influence on risk and chemotherapeutic outcome in gastrointestinal cancers

[Truncated abstract] The extent of genetic variability between different ethnic populations has become increasingly well recognized in recent years. Population-based differences have been reported for many diseases, including for the incidence and outcome of disease, effective drug dosage, and response and toxicity to treatment. Examples include the different incidence of stroke between whites and blacks, the higher mortality from breast cancer of African Americans compared to white and Asian Americans, the higher doses of Tacrolimus® required for African-American kidney transplant patients relative to whites, and the higher frequency of toxic epidermal necrolysis in Han Chinese relative to Caucasians. The overall aim of this thesis was to investigate in a systematic fashion whether ethnic differences in the frequency of selected genetic variants could account, at least partially, for population differences in the risk of cancer and in outcomes to chemotherapy. As a proof of principle, East Asians and Caucasians were compared for the risk of gastric cancer (GC) and for outcomes from chemotherapy in colorectal cancer (CRC). Using a meta-analysis approach, 37 single nucleotide polymorphisms (SNPs) within 27 genes were significantly associated with GC in East Asians and 12 SNPs within 11 genes were significantly associated with GC in Caucasians (Chapter 3). Three SNPs (ACE I/D, CCND1 870G>A, IL1B -511C>T) were associated with significantly different odds ratios (ORs) between these two ethnic groups. In a validation cohort comprising 670 GC cases and 437 controls of East Asian origin, 7 SNPs were confirmed as being low risk genetic factors in this population (Chapter 4)...