Racial variations in pharmacogenetics that impact treatment outcomes

PL06-04

Racial Variations in Pharmacogenetics that Impact Treatment Outcomes
 William D. Figg, Molecular Pharmacology Section and Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
 Pharmacogenetics is key to the variability in response to anticancer agents. Difference in elimination and transport of agents is often a result of polymorphisms. In addition, there are also differences in the target response. We are interested in determining genetic markers that are more frequent in African Americans than other races that also influence cancer susceptibility, and clinical outcome. We have conducted some experiments to address this issue that I’ll summarize below:
 1.
 DNA repair enzymes.
 In this study, we evaluated the interethnic differences in genotype frequency between Caucasians (CAUC) and African Americans (AA) by genotyping the following single nucleotide polymorphisms (SNPs): ERCC1 500C>T (N118N), ERCC1 8092C>A, ERCC2 2282A>C (K751Q), XRCC1 1301G>A (R399Q), XRCC1 685 C>T (R194W), PARP1 2446T>C (V762A). We hypothesized that the African American population would carry a higher frequency of DNA repair polymorphisms that have been associated with a poor prognosis following treatment with DNA damaging therapy. We found that African Americans carry a higher frequency of the following alleles: ERCC1 500C (45.8% CAUC vs. 86.2% AA; P < 0.001), ERCC2 2282A (65.3% CAUC vs. 76.0% AA; P = 0.025), XRCC1 1301G (68.4% CAUC vs. 89.4% AA; P < 0.001), and PARP1 2446T (80.7 CAUC vs. 95.4% AA; P < 0.001). As the ERCC1 500C allele has been associated with nearly twice the level of ERCC1 expression as compared to the ERCC1 500T allele, and also resistance to platinum compounds, it is likely that African Americans are more susceptible to a poor prognosis following platinum-based therapy than are Caucasians. The ERCC2 2282A allele has been associated with increased response to oxaloplatin therapy, however, it is also found to be associated with risk in patients with lung cancer, and acute myeloid leukemia. African Americans are much more susceptible to devloping lung cancer than Caucasians, and this polymorphism may be, in part, responsible for this ethnic disparity. Next, The XRCC1 1301G polymorphism has been associated with increased sensitivity to platinum-containing compounds, although this is controversial with other studies finding the opposite relationship. However, this polymorphism is a marker for breast cancer in African Americans, and the high frequency of this SNP may be responsible for the high incidence of breast cancer in African Americans. Finally, genetic variation in PARP1 has been associated with prostate ¼ 
 2.
 OATP1B3
 In this study, we evaluated the frequency of the 334T>G polymorphism within SLCO1B3, the gene encoding OATP1B3. This non-synonymous polymorphism, encoding the S112A amino acid substitution, has been shown by us to be involved in the time taken to develop androgen-independent prostate cancer (AIPC), and also the survival following prostate cancer diagnosis. Those individuals carrying the 112A allele are much less likely to have poor prognosis following diagnosis, and develop androgen-independent disease later than their counterparts that carry the 112S polymorphism. The mechanism for this relationship is still under investigation, but we have shown that OATP1B3 influxes testosterone, and is expressed in prostate cancer but not in normal prostate tissue. Our data suggest that the variant 334T allele is associated with a 2-fold increase in androgen influx, and it is likely that prostate tumors carried by those individuals with the 112S polymorphism have the ability to scavenge low levels of testosterone during treatment with androgen-blockade therapy, resulting in more aggressive disease. The 112S polymorphism is rare in Caucasians (~15%), but is more frequent in African Americans (~65%). Prostate cancer is a major problem in the African American community with many African American males developing prostate cancer, and a poor prognosis following the diagnosis of prostate cancer. We have genotyped African American males for the SLCO1B3 334T>G polymorphism, and have found that the 334T (112S) polymorphism confers a great increase in risk of developing prostate cancer for men with the heterozygous SLCO1B3 334T/G genotype (OR = 2.56, 95% CI = 1.24-5.11; P = 0.0129), and the homozygous SLCO1B3 334TT genotype (OR = 3.19, 95% CI = 1.56-6.54; P = 0.0023). We are continuing to evaluate the contribution of OATP1B3 to androgen influx, and are comparing SLCO1B3 genotypes to survival after prostate cancer diagnosis.
 3.
 CYP1B1
 We have identified a marker for docetaxel resistance in the CYP1B1*3 polymorphism. The CYP1B1*3 allele has also been associated with increased cancer risk and poor prognosis in several cancers including prostate, breast, lung, ovarian, and endometrial cancers. We hypothesize that given the higher frequency of CYP1B1*3 alleles in the African American population, there may be an increased risk of developing cancer, and poor prognosis within the African American community. We are currently genotyping men with prostate cancer and comparing them to normal, race-matched, controls to evaluate whether or not the CYP1B1*3 allele is a risk factor for developing prostate cancer in African Americans.