Joel Mefford

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

Purpose: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity. Experimental Design: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. Results: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30–1.91; P = 2.6 × 10−6] and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13–3.28; P = 6.7 × 10−3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. Conclusions: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. Clin Cancer Res; 18(18); 5099–109. ©2012 AACR.

A common 5′-UTR variant in MATE2-K is associated with poor response to metformin

Multidrug and toxin extrusion 2 (MATE2‐K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2‐K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2‐K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants—c.485C>T and c.1177G>A—were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2‐K basal promoter haplotypes containing the most common variant, g.−130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF‐1). Patients with diabetes who were homozygous for g.−130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (−0.027 (−0.076, 0.033)), as compared with carriers of the reference allele, g.−130G (−0.15 (−0.17, −0.13)) (P = 0.002). Our study showed that MATE2‐K plays a role in the antidiabetes response to metformin.

Association of the innate immunity and inflammation pathway with advanced prostate cancer risk.

Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.

The Covariate's Dilemma

An important step in analyzing genetic association study data is deciding whether to adjust for covariates—those variables ancillary to the variants of interest. In particular, when testing for novel associations, should the statistical model also include known genetic or nongenetic covariates that are predictors of the trait (e.g., body mass index when studying type 2 diabetes)? Yes, if the covariates are also correlated with the primary variants but do not mediate their effects, because they may confound the genetic associations. Including them helps control bias and prevent false discoveries (Figure 1a). But the answer is less clear-cut if the covariates are not confounders.

Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.

One‐third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome‐wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor‐α and hepatocyte nuclear factor 4‐α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Association of CYP2C9*2 With Bosentan‐Induced Liver Injury

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug‐induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29−∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan‐induced liver injury and warrants investigation for the optimization of bosentan treatment.

HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease

Background: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans. Methods: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case–control study of more aggressive disease (N = 2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans. Results: In our studies, the mutation was found exclusively among men with prostate cancer (carrier frequency = 1.48%) or unaffected brothers of cases carrying the mutation (frequency = 0.34%), and carrying the mutation gave an OR for disease = 4.79 (P = 0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P = 3.5 × 10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P < 1 × 10−5. Conclusions: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 675–80. ©2013 AACR.

Mutational Landscape of Aggressive Prostate Tumors in African American Men.

Prostate cancer is the most frequently diagnosed and second most fatal nonskin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor-sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biologic significant role in the incidence and clinical outcomes of prostate cancer in African Americans. Cancer Res; 76(7); 1860-8. ©2016 AACR.

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10−6) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.