Evaluation of the C3435T polymorphism in the MDR1 gene in patients with hepatocellular carcinoma

Baldissera, Vanessa Dido; Mattos, Ângelo Alves de; Coral, Gabriela Perdomo; Araujo, Fernanda Branco de; Marroni, Cláudio Augusto; Brandão, Ajácio Bandeira de Mello; Fontes, Paulo Roberto Ott; Cerski, Carlos Thadeu Schmidt; Hartmann, A; Filho, Nélson Alexandre Kretzmann

doi:10.1016/s1665-2681(19)31416-4

Cited by 20 publications

(10 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, Baldissera et al . describe higher ABCB1 expression for 3435T allele carriers in hepatocellular carcinoma samples. Furthermore, cell populations in peripheral blood and bone marrow express ABCB1 .…”

Section: Discussionmentioning

confidence: 82%

ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

Björn

Falk

Vergote

et al. 2018

Basic Clin Pharma Tox

View full text Add to dashboard Cite

The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB1, and 1196A>G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n = 260) or Taxol (Arm B, n = 265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR = 0.590) and in Arm B (HR = 0.627), as well as increased OS in All (HR = 0.443) and in Arm A (HR = 0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p = 0.039) and less neutrophil decrease in All (p = 0.048) and in Arm B (p = 0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

show abstract

Section: Discussionmentioning

confidence: 82%

ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

Björn

Falk

Vergote

et al. 2018

Basic Clin Pharma Tox

View full text Add to dashboard Cite

show abstract

“…No difference in P-gp messenger (m)RNA and protein levels was observed in non-tumor cells with either 3435 CT or TT polymorphism 15. However, a previous study in humans found that liver tumors with 3435 CT genotype expressed higher levels of P-gp protein compared to CC and TT genotype 39. The increased P-gp protein expression limits drug penetration into intratumor cells.…”

Section: Discussionmentioning

confidence: 92%

Association of CYP3A4/5, ABCB1 and ABCC2 polymorphisms and clinical outcomes of Thai breast cancer patients treated with tamoxifen

Sensorn

Sirachainan²,

Chamnanphon³

et al. 2013

PGPM

View full text Add to dashboard Cite

BackgroundPharmacogenetic study of cytochrome P450 (CYP) gene CYP2D6 and tamoxifen outcomes remain controversial. Apart from CYP2D6, other drug-metabolizing enzymes and transporters also play a role in tamoxifen metabolic pathways. The aim of this study is to investigate the impact of CYP3A4/5, ABCB1, and ABCC2 polymorphisms on the risk of recurrence in Thai patients who received tamoxifen adjuvant therapy.MethodsPatients with early-stage breast cancer who received tamoxifen adjuvant therapy were recruited in this study. All six single-nucleotide polymorphisms (SNPs), including CYP3A4*1B (−392 A>G)/*18(878 T>C), CYP3A5*3(6986 G>A), ABCB1 3435 C>T, ABCC2*1C(−24 C>T), and ABCC2 68231 A>G, were genotyped using real-time polymerase chain reaction assays. The impacts of genetic variants on disease-free survival (DFS) were analyzed using the Kaplan–Meier method and Cox regression analysis.ResultsThe ABCB1 3435 C>T was found to have the highest allele frequency among other variants; however, CYP3A4*1B/*18 could not be found in this study. Patients with heterozygous ABCB1 3435 CT genotype showed significantly shorter DFS than those with homozygous 3435 CC genotype (P = 0.041). In contrast, patients who carried homozygous 3435 TT genotype showed no difference in DFS from wild-type 3435 CC patients. Cox regression analysis showed that the relative risk of recurrence was increased by five times (P = 0.043; hazard ratio = 5.11; 95% confidence interval: 1.05–24.74) in those patients carrying ABCB1 3435 CT genotype compared to those with ABCB1 3435 CC.ConclusionABCB1 3435 C>T is likely to have a clinically significant impact on recurrence risk in Thai patients with breast cancer who receive tamoxifen adjuvant therapy.

show abstract

“…Thus, it contributes to preventing the initiation of hepatocarcinogenesis[ 49 , 50 ]. Many studies have described MDR1 over-expression in various tumor tissues, including liver cancer[ 51 ]; thus, this membrane carrier and its functional genetic variants are good candidates for influencing liver susceptibility to HCC. ABCB1 rs1128503 is a synonymous variant (Gly412Gly) of a residue located in the cytoplasmic domain of the transporter.…”

Section: Discussionmentioning

confidence: 99%

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

Mattia

Cecchin

Polesel

et al. 2017

WJG

View full text Add to dashboard Cite

AIMTo uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.METHODSThe present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.RESULTSFive genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95%CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95%CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95%CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95%CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95%CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV- or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95%CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95%CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility.CONCLUSIONWe identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.

show abstract

Evaluation of the C3435T polymorphism in the MDR1 gene in patients with hepatocellular carcinoma

Cited by 20 publications

References 27 publications

ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

Association of CYP3A4/5, ABCB1 and ABCC2 polymorphisms and clinical outcomes of Thai breast cancer patients treated with tamoxifen

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

Contact Info

Product

Resources

About