Saarene Panossian

CYP3A4, CYP3A5, and CYP3A43 Genotypes and Haplotypes in the Etiology and Severity of Prostate Cancer

The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated previously with prostate cancer occurrence and severity. To comprehensively examine the effects of these genes on prostate cancer occurrence and severity, we studied 622 incident prostate cancer cases and 396 controls. Substantial and race-specific linkage disequilibrium was observed between CYP3A4 and CYP3A5 in both races but not between other pairs of loci. We found no association of CYP3A5 genotypes with prostate cancer or disease severity. CYP3A43*3 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10–31.16). CYP3A4*1B was associated inversely with the probability of having prostate cancer in Caucasians (age-adjusted odds ratio = 0.54, 95% confidence interval, 0.32–0.94). We also observed significant interactions among these loci associated with prostate cancer occurrence and severity. There were statistically significant differences in haplotype frequencies involving these three genes in high-stage cases (P < 0.05) compared with controls. The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity.

Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women.

FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

Does MC1R genotype convey information about melanoma risk beyond risk phenotypes

A study was carried out to describe associations of MC1R variants and melanoma in a US population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure measures.

Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (P(corr)) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (P(corr) = 0.007). At NBS1, we observed a P(corr) = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (P(corr) = 0.044) and BARD1 (P(corr) = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (P(corr) = 0.011). At MRE11, we observed a significant haplotype association (P(corr) = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (P(corr) = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations.

Pairwise Combinations of Estrogen Metabolism Genotypes in Postmenopausal Breast Cancer Etiology

Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit–dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (Pinteraction < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (Pinteraction = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (Pinteraction = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation. (Cancer Epidemiol Biomarkers Prev 2007;16(3):444–50)

Joint effects of inflammation and androgen metabolism on prostate cancer severity

Multiple pathways of prostate carcinogenesis have been proposed, including those involving androgen metabolism and inflammation. These pathways are not independent, and may act together in prostate cancer etiology: androgens promote both inflammatory processes and serve as mitogens in prostate tumor growth. To explore the possible joint effects of these pathways in prostate cancer severity, we studied 1,090 Caucasian prostate cancer cases to evaluate whether tumor severity is influenced by a history of benign prostatic hyperplasia (BPH) interacting with genotypes involved in inflammation or androgen metabolism including MSR1, RNASEL, AR, CYP3A4, CYP3A43, CYP3A5 and SRD5A2. We observed a statistically significant interaction between a number of genotypes and BPH. After considering the potential for false positive associations, the only remaining significant associations involved CYP3A43 P340A genotypes and history of BPH on both Gleason grade (interaction p‐value = 0.026) and tumor stage (interaction p‐value = 0.017). These results suggest that androgen metabolism may act in concert with inflammatory phenotypes such as BPH in determining prostate cancer severity.

Relationship of obesity, androgen receptor genotypes and biochemical failure after radical prostatectomy.

Obesity and androgen metabolism have been implicated in the progression of prostate cancer. Obesity has been associated with increased risk for advanced disease and biochemical failure after treatment. This association may be the result of changes in androgen metabolism that occur with obesity and are mediated by the androgen receptor (AR).

Abstract B122: Multi‐SNP analysis of one‐carbon metabolism genes and prostate cancer outcomes

Introduction: There is little known about the epigenetics of prostate severity. One‐carbon metabolism genes in conjunction with folate and B‐vitamins influence DNA repair mechanisms and methylation patterns. Better understanding of the relationship of gene activity that may potentially be altered by nutrient intake can provide new strategies for decreasing the prevalence of advanced prostate cancer. The goal of this project is to determine the association of one‐carbon cycle genes in relation to prostate cancer outcomes. Materials and Methods: We studied prostate cancer patients with one‐carbon genotypes (604 European American, 92 African American.) The genes of interest included CBS, MTHFD1, MTHFR, MTRR, MTR, SHMT1, TYMS, SLC19A1 and TCN2. Data were analyzed with race stratification. Odds ratios (OR) were calculated by logistic regression models adjusted for age and percent African ancestry (African‐Americans only.) These models were used to examine case‐case associations analyzing tumor stage, grade and aggressiveness (high stage and high grade combined) and age at onset. Cox regression models were used to calculate hazard ratios (HR) for the incidence of biochemical failure after treatment. Multi‐SNP associations were conducted in European American cases only using risk scores derived from the per allele ORs from a combination of 6 SNPs (MTHFD1 R653Q, MTHFR A222V, MTRR L333V, MTR D919G, SHMT L474F, TCN R259P) and 9 SNPs (the 6 mentioned previously plus CBS 68bp Ins, SLC19A1 61bpDel and Tyms 3UTRdel6.) Results: Genotypes involved in one‐carbon metabolism differed significantly by race. Among African‐American cases, a significant protective association was found for SLC19A1 61bpDel for aggressive disease (OR=0.1, 95% CI=0.01–0.9, additive model.) Associations with biochemical failure in European Americans were observed for recessive carriage of MTR D919G (HR=2.8, 95% CI=1.1–7.3) and MTRR K350R (HR=4.3, OR=1.1–16.3, additive model.) In the multi‐SNP model, biochemical failure was associated with the risk scores of 9 SNPs (HR=0.77, 95% CI=0.61–0.94.) No additional associations were observed for other clinical characteristics of prostate cancer. Conclusions: These results suggest that one‐carbon metabolism genotypes in combination may be associated with prostate cancer in specific subgroups. Multi‐SNP models may provide more information than single SNP analyses for studying complex genetic pathways. Additional research of gene interactions and effects of nutrient intake may provide clues about prevention and treatment of prostate cancer, especially in groups at high risk for poor outcomes. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B122.