Mapping genes that predict treatment outcome in admixed populations

Baye, Tesfaye M.; Wilke, Russell A.

doi:10.1038/tpj.2010.71

Cited by 30 publications

(29 citation statements)

References 122 publications

(134 reference statements)

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“…The distributions of sex, age, and race/ethnicity were similar between cases and controls. Since Hispanics are a recently admixed group (36), a proportion (34-37%) of our Hispanic population reported “Mixed or Other” race and 49-51% of them reported “White and Caucasian” race. The frequency of hyperdiploid ALL (>50 chromosomes) was 30%, and the frequency of TEL-AML1 ALL was 8%.…”

Section: Resultsmentioning

confidence: 98%

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics

Hsu

Briggs

Shao

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The incidence of acute lymphoblastic leukemia (ALL) is nearly 20% higher among Hispanics than non-Hispanic Whites. Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes. However, variants identified only account for <10% of the genetic risk of ALL. Methods We applied pathway-based analyses to GWAS data from the California Childhood Leukemia Study to determine whether different biological pathways were overrepresented in childhood ALL and major ALL subtypes. Furthermore, we applied causal inference and data reduction methods to prioritize candidate genes within each identified overrepresented pathway, while accounting for correlation among SNPs. Results Pathway analysis results indicate that different ALL subtypes may involve distinct biological mechanisms. Focal adhesion is a shared mechanism across the different disease subtypes. For ALL, the top five overrepresented Kyoto Encyclopedia of Genes and Genomes pathways include axon guidance, protein digestion and absorption, melanogenesis, leukocyte transendothelial migration, and focal adhesion (PFDR < 0.05). Notably, these pathways are connected to downstream MAPK or Wnt signaling pathways which have been linked to B-cell malignancies. Several candidate genes for ALL, such as COL6A6 and COL5A1 were identified through targeted maximum likelihood estimation. Conclusions This is the first study to show distinct biological pathways are overrepresented in different ALL subtypes using pathway-based approaches, and identified potential gene candidates using causal inference methods. Impact The findings demonstrate that newly developed bioinformatics tools and causal inference methods can provide insights to furthering our understanding of the pathogenesis of leukemia.

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Section: Resultsmentioning

confidence: 98%

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics

Hsu

Briggs

Shao

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Cases generally had lower annual household income compared to controls. Since Hispanics are a recently admixed group (32), a proportion (34%-37%) of our Hispanic population reported “ Mixed or Other” race and 49% -51% of them reported “White and Caucasian” race. In our data, the frequency of B-cell precursor (BCP) ALL is 91.9% among Hispanics (N=297) and the frequency of BCP high-hyperdiploid ALL (>50 chromosomes) for Hispanics is 30% (N=97).…”

Section: Resultsmentioning

confidence: 97%

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

Hsu

Chokkalingam

Briggs

et al. 2015

Cancer Causes Control

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Background Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on: IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early life infections (presence of older siblings, daycare attendance, and ear infections). Methods Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study (CCLS) were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated for each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early life infections using logistic regression models that included an interaction term. Results Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified; rs7780012, OR=0.50, 95% confidence interval (CI): 0.35-0.71 (p=0.004); rs7089424, OR=2.12, 95% CI: 1.70-2.65 (p=1.16 x 10-9); rs4982731, OR=1.69, 95% CI: 1.37-2.08 (p=2.35 x 10-6), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early life infections with ALL risk was not observed. Conclusions Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Impact Results implicate the ARID5B, CEBPE and IKZF1 genes in the pathogenesis of childhood ALL.

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“…SNPs occur every 100-300 bases along the human genome and several studies suggest that the risk to many complex diseases, like cancer, can be extensively affected by the individual's SNP profile. Presumably, it will be the combination between the SNP profile and environmental factors that contribute to sporadic cancer development [30][31][32] . Genetic polymorphisms in DNA repair genes seem to determine the overall DNA repair capacity, which in turn may affect the risk of OC [15] .…”

Section: Oc and Dna Repairmentioning

confidence: 99%

“…Hyper-gonadotropic conditions are common in infertile, in polycystic ovarian syndrome and in post-menopausal women The formation of a protective progestagenic hormonal milieu can stimulate apoptosis in genetically damaged ovarian epithelial cells, preventing tumor development Hormonal stimulation [92] High androgen levels are harmful while an increase in progesterone levels is benefic Protective effect due to multiparity and oral contraceptive use. Harmful effect is associated with higher androgen levels as in polycystic ovarian syndrome women Inflammation [25] Ovulation is accomplished by an inflammatory response: redox potential alteration, cellular infiltration, cytokine release that can introduce DNA damage in epithelial cells involved in ovary rupture/repair file [30][31][32]35] . The aim of these areas is to establish a relationship between the genotype (i.e., polymorphisms or mutations), gene expression profile and phenotype (both in drugs' pharmacokinetic and pharmacodynamics), interpreted as the variability between individuals concerning the toxicity, effectiveness and therapy outcome [35][36][37][38][39] .…”

Section: Oc and Dna Repairmentioning

confidence: 99%

Ovarian cancer and DNA repair: DNA ligase IV as a potential key

Assis

Pereira²,

Medeiros³

2013

WJCO

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Ovarian cancer (OC) is the sixth most common cancer and the seventh cause of death from cancer in women. The etiology and the ovarian carcinogenesis still need clarification although ovulation may be determinant due to its carcinogenic role in ovarian surface epithelium. The link between ovarian carcinogenesis and DNA repair is well established and it became clear that alterations in DNA damage response may affect the risk to develop OC. Polymorphisms are variations in the DNA sequence that exist in normal individuals of a population and are capable to change, among other mechanisms, the balance between DNA damage and cellular response. Consequently, genetic variability of the host has a great role in the development, progression and consequent prognosis of the oncologic patient as well as in treatment response. Standard treatment for OC patients is based on cytoreductive surgery, followed by chemotherapy with a platinum agent and a taxane. Although 80% of the patients respond to the first-line therapy, the development of resistance is common although the mechanisms underlying therapy failure remain mostly unknown. Because of their role in oncology, enzymes involved in the DNA repair pathways, like DNA Ligase IV (LIG4), became attractive study targets. It has been reported that variations in LIG4 activity can lead to a hyper-sensitivity to DNA damage, deregulation of repair and apoptosis mechanisms, affecting the susceptibility to cancer development and therapy response. To overcome resistance mechanisms, several investigations have been made and the strategy to target crucial molecular pathways, such as DNA repair, became one of the important areas in clinical oncology. This review aims to elucidate the link between DNA repair and OC, namely which concerns the role of LIG4 enzyme, and how genetic polymorphisms in LIG4 gene can modulate the activity of the enzyme and affect the ovarian carcinogenesis and treatment response. Moreover, we try to understand how LIG4 inhibition can be a potential contributor for the development of new cancer treatment strategies.

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Mapping genes that predict treatment outcome in admixed populations

Cited by 30 publications

References 122 publications

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

Ovarian cancer and DNA repair: DNA ligase IV as a potential key

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