Abstract:Objective: Third-generation aromatase inhibitors (AI) are potent suppressors of aromatase activity. The aim of this study was to measure the incidence of adverse effects in breast cancer patients treated with AI-based adjuvant therapy and the relationship with the CYP19A1 genotypes.
Materials and Methods:Forty-five postmenopausal breast cancer patients (46-85 yrs) in AI adjuvant treatment were genotyped for the rs4646 polymorphisms of CYP19A1 gene and three variations were identified. Toxicities were registere… Show more
“…1 ) [ 12 , 13 ]. Further, we and others have previously found polymorphisms in CYP19A1 , a gene regulating aromatase synthesis, to be associated with patient-reported AIAA symptoms [ [14] , [15] , [16] , [17] ]. Fig.…”
Background
Arthralgia is a common and debilitating toxicity of aromatase inhibitors (AI) that leads to premature drug discontinuation. We sought to evaluate the clinical and genetic risk factors associated with AI-associated arthralgia (AIAA).
Methods
We performed a cross-sectional study among postmenopausal women with stage 0-III breast cancer who were prescribed a third-generation AI for adjuvant therapy. The primary outcome was patient-reported AIAA occurrence. We extracted and assayed germline DNA for single nucleotide polymorphisms (SNPs) of genes implicated in estrogen and inflammation pathways. Multivariable logistic regression models examined the association between demographic, clinical, and genetic factors and AIAA. Analyses were restricted to White participants.
Results
Among 1049 White participants, 543 (52%) reported AIAA. In multivariable analyses, women who had a college education [Adjusted Odds Ratio (AOR) 1.49, 95% Confidence Interval (CI) 1.00–2.20], had a more recent transition into menopause (<10 years) (5–10 years AOR 1.55, 95% CI 1.09–2.22; <5 years AOR 1.78, 95% CI 1.18–2.67), were within one year of starting AIs (AOR 1.61, 95% CI 1.08–2.40), and those who received chemotherapy (AOR 1.38, 95% CI 1.02–1.88) were significantly more likely to report AIAA. Additionally, SNP rs11648233 (
HSD17B2
) was significantly associated with higher odds of AIAA (AOR 2.21, 95% CI 1.55–3.16).
Conclusions
Time since menopause and start of AIs, prior chemotherapy, and SNP rs11648233 within the
HSD17B2
gene in the estrogen pathway were significantly associated with patient-reported AIAA. These findings suggest that clinical and genetic factors involved in estrogen withdrawal increase the risk of AIAA in postmenopausal breast cancer survivors.
“…1 ) [ 12 , 13 ]. Further, we and others have previously found polymorphisms in CYP19A1 , a gene regulating aromatase synthesis, to be associated with patient-reported AIAA symptoms [ [14] , [15] , [16] , [17] ]. Fig.…”
Background
Arthralgia is a common and debilitating toxicity of aromatase inhibitors (AI) that leads to premature drug discontinuation. We sought to evaluate the clinical and genetic risk factors associated with AI-associated arthralgia (AIAA).
Methods
We performed a cross-sectional study among postmenopausal women with stage 0-III breast cancer who were prescribed a third-generation AI for adjuvant therapy. The primary outcome was patient-reported AIAA occurrence. We extracted and assayed germline DNA for single nucleotide polymorphisms (SNPs) of genes implicated in estrogen and inflammation pathways. Multivariable logistic regression models examined the association between demographic, clinical, and genetic factors and AIAA. Analyses were restricted to White participants.
Results
Among 1049 White participants, 543 (52%) reported AIAA. In multivariable analyses, women who had a college education [Adjusted Odds Ratio (AOR) 1.49, 95% Confidence Interval (CI) 1.00–2.20], had a more recent transition into menopause (<10 years) (5–10 years AOR 1.55, 95% CI 1.09–2.22; <5 years AOR 1.78, 95% CI 1.18–2.67), were within one year of starting AIs (AOR 1.61, 95% CI 1.08–2.40), and those who received chemotherapy (AOR 1.38, 95% CI 1.02–1.88) were significantly more likely to report AIAA. Additionally, SNP rs11648233 (
HSD17B2
) was significantly associated with higher odds of AIAA (AOR 2.21, 95% CI 1.55–3.16).
Conclusions
Time since menopause and start of AIs, prior chemotherapy, and SNP rs11648233 within the
HSD17B2
gene in the estrogen pathway were significantly associated with patient-reported AIAA. These findings suggest that clinical and genetic factors involved in estrogen withdrawal increase the risk of AIAA in postmenopausal breast cancer survivors.
“…SNPs are often used as genetic markers for the prediction of patient response to therapy and to predict susceptibility to the development or diagnosis of a particular disease [1,2].…”
Objective: The objectives of this study were to evaluate the impact of two X-ray repair cross complementing 1 (XRCC1) gene polymorphisms (Arg194Trp and Arg399Gln) on the risk of development of colorectal cancer (CRC) and to assess the expression levels of microRNA-21 (miR-21) in CRC patients.
Materials and Methods:A case-control cross sectional study was conducted on 50 CRC patients and 50 cancer-free subjects. DNA and miR-21 were extracted from whole blood samples. The expression levels of the XRCC1 polymorphisms and miR-21 were assessed by real-time PCR in all subjects of the study.Results: Genotype analysis revealed a significant association between CRC risk and both the Arg194Trp genotype (OR=11.407, 95% CI=4.039-32.221, p<0.001) and the Arg399Gln genotype (OR=3.778, 95% CI= 1.6-8.919, p=0.002). The expression levels of circulating miR-21 were able to detect CRC cases significantly (p=0.022) with a sensitivity of 82% and a specificity of 56% (Area under the curve (AUC)=0.633) but were unable to distinguish between early and late cases (AJCC classification) (p=0.194).
Conclusion:The XRCC1 Arg194Trp and Arg399Gln polymorphisms both confer high susceptibility for the development of CRC. Circulating miR-21 expression levels are a potentially diagnostic non-invasive genetic marker of CRC.Keywords: Colorectal cancer, miRNA-21, XRCC1, DNA repair, single nucleotide polymorphisms ÖZ Amaç: Bu çalışmanın amacı iki XRCC1 gen polimorfizminin (Arg194Trp ve Arg399Gln) kolorektal kanser (KRK) gelişimi riski üzerindeki etkisini değerlendirmek ve KRK hastalarında microRNA-21 (miR-21) ekspresyonu düzeylerini incelemektir.Gereç ve Yöntemler: 50 KRK hastası ve 50 kansersiz denekle vaka-kontrollü bir kesitsel çalışma gerçekleşti-rildi. Tüm kan numunelerinden DNA ve miR-21 alındı. XRCC1 polimorfizmlerinin ve miR-21'in ekspresyon seviyeleri, çalışmadaki tüm deneklerde gerçek zamanlı PCR ile değerlendirildi. Bulgular: Genotip analizinde KRK riski ile Arg194Trp (OR=11.407, 95% CI=4.039-32.221, p<0,001) ve Arg399Gln (OR=3.778, 95% CI=1, p=0,002) genotipleri arasında önemli bir ilişki ortaya konuldu. Dolaşımdaki miR-21 ekspresyon düzeyleriyle KRK olguları %82 duyarlılık ve %56 özgüllük (AUC=0,633) ile anlamlı bir şekilde (p=0,022) saptanabildi, ancak erken ve geç vakalar ayırt edilemedi (AJCC sınıflandırması) (p=0,194).Sonuç: XRCC1 Arg194Trp ve Arg399Gln polimorfizmlerinin her ikisi de KRK gelişimine yüksek düzeyde yatkınlık göstermektedir. Dolaşımdaki miR-21 ekspresyon seviyeleri potansiyel olarak KRK'nın tanısal noninvasiv genetik belirtecidir.Anahtar Kelimeler: Kolorektal kanser, miRNA-21, XRCC1, DNA onarımı, SNPs Eurasian J Med 2017; 49: 132-6 Original Article
“…Therefore, it is meaningful to study the relationship between rs4646 polymorphism and the specific disease in the population of Chinese Han. CYP19A1 rs4646 was wildly discussed in estrogen-related diseases, and the rs4646 polymorphism was believed to affect the aromatase activity and the effect of estrogen [ 30 ]. Meanwhile, De et al highlighted the protective role of estrogen in diabetes and illustrated gender differences in the performance and outcome of diabetes based on clinical and preclinical data [ 31 ].…”
Background: Type 2 diabetes mellitus (T2DM), one of the global health issues, is a group of metabolic diseases and is affected by several genetic loci in the clinical phenotype. This study intended to ascertain associations between CYP19A1 and CYP1A2 gene polymorphisms with the T2DM risk in Chinese Han. Methods: Seven single nucleotide polymorphisms (SNPs) in total including five of CYP19A1 (rs4646, rs6493487, rs1062033, rs17601876 and rs3751599) and two of CYP1A2 (rs762551 and rs2470890) from 512 T2DM patients and 515 non-diabetic controls were genotyped in the platform of Agena MassARRAY. SPSS 18.0 was utilized for analyzing genotyping results. Logistic regression models were conducted for the risk assessment by the odds ratios (ORs) and 95% confidence intervals (CIs). Results: The results suggested a significant association between genotype GC of rs1062033 with a decreased T2DM risk (OR = 0.73, 95% CI = 0.55-0.96, P = 0.025) under the co-dominant (heterozygous) model. The results of stratification analysis with age and gender adjustment revealed that the effects of all selected SNPs in CYP19A1 and CYP1A2 on the T2DM susceptibility were dependent on age, body mass index (BMI) and disease progression (P < 0.05). The haplotype analysis was further conducted and the results indicated that C rs1062033 G rs17601876 A rs3751599 in CYP19A1 played a protective role (OR = 0.48, 95% CI = 0.25-0.91, P = 0.026) in T2DM patients with diabetic retinopathy. Conclusion: This population-based case-control study suggested that CYP19A1 and CYP1A2 variations might affect the susceptibility of T2DM. The findings provide a theoretical basis for searching the clinical therapeutic markers and attractive drug targets of T2DM.
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