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BACKGROUND: Breast cancer recurrence and metastasis are associated with alterations in the cellular stress responses that influence tumour signalling. Sirtuin3 (SIRT3), a mitochondrial deacetylase is the regulator of mitochondrial metabolism and oxidative stress affecting tumour cell responses. Genetic variants or dysregulation of SIRT3 was known to associate with poor prognosis of recurrence and relapse in few cancers. METHODS: The current case-control study was conducted in Hyderabad, India. A total of 200 primary female breast cancer cases were recruited, irrespective of age and clinical subtype. However, secondary or recurrent breast cancer cases were excluded from the study. A total of 202 age and gender-matched healthy controls without any familial inheritance of either breast or other cancer and having similar ethnicity as cases were recruited. The blood samples of both cases and controls were collected from Nizam's Institute of Medical Sciences (NIMS), Hyderabad. Our study is an attempt to evaluate the association of SIRT3 VNTR polymorphism in intron 5 with the development and progression of breast cancer by PCR-based genotyping.  Result: The statistical analysis of the results with respect to epidemiological and clinical phenotypes revealed significant association of 0R allele and 0R/0R genotype with breast cancer risk (p<0.01). The odds ratios also were found to be significant i.e., 0R/0R [OR(CI): 2.67(1.54-4.65); p=0.000005] genotype. Also, the epidemiological and clinical variables have shown significant association with the risk of onset of the disease. Therefore, the influence of lack of repeats at intron 5 harbouring enhancer site on altered expression of SIRT3 might confer increased susceptibility to breast cancer. CONCLUSION: The VNTR polymorphism in the intron 5 region of SIRT3 gene could serve as a molecular marker for detection of breast cancer onset. Further studies are warranted to study the prognostic and therapeutic significance of this SIRT3 polymorphism.

Asunto(s)

Neoplasias de la Mama , Sirtuina 3 , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Intrones , Repeticiones de Minisatélite , Recurrencia Local de Neoplasia/genética , Polimorfismo Genético , Sirtuina 3/genética

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INTRODUCTION: Desisting from disease directed treatment in the past weeks of life is a quality criterion in oncology service. Patients with advanced cancer have unrealistic expectations from chemotherapy and hold on to it as a great source of hope. Many oncologists continue futile and unnecessary treatments, instead of conveying to the patients the lack of benefit, resulting in delayed referral for palliative care (PC). MATERIALS AND METHODS: This is a retrospective analysis of case records from June 2014 to December 2015. The primary objective was to study, how far back in time terminally ill cancer patients received definitive cancer directed therapy (DCDT). Apart from patient demographics, the diagnosis, stage, and details of DCDT, and death were captured. PC referral data were recorded. DCDT to death was taken as treatment-free interval (TFI). Analysis was performed using IBM SPSS Statistics for Windows, Version 20. RESULTS: A total of 292 case records were evaluated. Seventy-three had inadequate treatment details. Hence, 219 records were analyzed. PC referral was done in 78.5% of patients. Only best supportive care (BSC) without any DCDT was given in 27 patients. The most common reason for BSC was a poor performance status in 92.5%. The median time from PC referral till death was 43.5 days (range: 1-518 days). Chemotherapy was the most common DCDT in 52.9% of patients. The median time from DCDT and death was 49 days (range: 0-359 days). Cervical and ovarian cancers patients had the longest TFI; shortest in unknown primary. Most patients died at home (70.4%). Patients receiving PC preferred home or hospice as place of death. Of the 80 patients given hospice care, 39 (36.5%) died in the hospice. CONCLUSION: While DCDT needs to be started at the right time, it should also be discontinued when futile. Early involvement of the PC team, even while patients are on DCDT makes the transition smoother and more meaningful.

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INTRODUCTION: The Sokal and Hasford (Euro) scores were developed in the chemotherapy and interferon eras and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, European Treatment and Outcome Study (EUTOS) scoring system was introduced. Data on risk stratification in pediatric CML population was lacking due to its rarity (<3%). OBJECTIVE: To study the effectiveness in predicting the response and outcome with three prognostic scores in pediatric CML-chronic phase patients on front line Imatinib. Materials and Methods: We retrospectively analyzed the hospital records of newly diagnosed CML CP patients (aged ≤18 years) from 2006 to 2010 for their risk score, cytogenetic response at 18 months and event free survival (EFS) at the end of 4 years. Events include loss of hematological response, loss of cytological response, progression to accelerated/blast phase (AP/BC). All received free Imatinib under Gleevac international patient assistance program. RESULTS: Data of 106 children was analyzed with median age of 13.5 (ranged 5-18 years) and male preponderance (M:F = 1.14:1). The distribution of children was 63%, 32% and 5% in Sokal low, intermediate and high risk respectively, 50%, 43% and 5% in Hasford/Euro low, intermediate and high risk respectively, 71% and 29% in EUTOS low and high risk respectively. The overall cumulative complete hematological response at the end of 3 month was 94%, and complete cytogenetic response at 12 months was 75%. The CCyR at 18 month was seen in 90%,74% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 84% and 86% EUTOS low and high risk groups respectively. The EFS at the end of 48 months was seen in 87%,79% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 86% and 80% EUTOS low and high risk groups respectively. CONCLUSION: None of the scoring systems predicted the response and outcome effectively in children with CML CP on front line Imatinib.

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INTRODUCTION: The patent expiration of imatinib mesylate (Gleevec; Novartis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost-effective alternative. The objective of our study was to determine the molecular and cytogenetic responses, survival endpoints (event-free survival, failure-free survival, transformation-free survival, overall survival), and safety of innovator and generic brands of imatinib. MATERIALS AND METHODS: In this retrospective analysis, data from 1812 patients with chronic myeloid leukemia treated with frontline imatinib mesylate (innovator/generic) at a single institution between 2008 and 2014 is included. Of these, 445 were excluded owing to inadequate data and follow-up, and a further 156 were excluded as they were in either the accelerated phase or blast crisis at diagnosis. Thus, data from 1067 patients who were treated with Gleevec (Novartis), and 144 patients with Veenat (NATCO) were available for analysis, and included in the study. RESULTS: There was no significant difference in event-free survival (P = .05), failure-free survival (P = .07), transformation-free survival (P = .12), or overall survival (P = .24) between the 2 groups. The frequency of reported nonhematologic adverse events and hematologic adverse events was comparable between the study groups. CONCLUSION: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia.

Asunto(s)

Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven

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INTRODUCTION: Vascular endothelial growth factor A (VEGFA) and its kinase insert domain receptor (VEGFR2/KDR) were reported to be upregulated in chronic myeloid leukemia (CML); however, the influence of polymorphisms in VEGFA and VEGFR2 in CML pathogenesis and therapeutic response, have not yet been elucidated. METHODS: We aimed to analyze these polymorphisms in 212 CML patients and 212 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. RESULTS: The VEGFA+936C>T polymorphism did not differ significantly between the CML patients and controls. The frequency of CT genotype was higher in CML patients than in controls (25 vs. 18%), higher in males than in females (29 vs. 18%), was more prevalent in the patients with splenomegaly (p = 0.03), and was negatively associated with lactate dehydrogenase (LDH) levels (p = 0.01). The frequency of VEGFR2 mutant T-allele was higher in CML patients than controls (p < 0.0001). In the dominant model, patients having the combined AT and TT genotypes were associated with 2.6-fold higher risk of CML [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.71­3.97, p < 0.0001]. VEGFR2 AT genotype was significantly associated with high blast count (p = 0.006), minor hematological response (p = 0.03) and poor cytogenetic response (p = 0.003), indicating its role in therapeutic resistance. In contrast, poor molecular response was observed in patients with TT genotype (p = 0.02). VEGFA+936C>T polymorphism was found to have synergistic interaction with VEGFR2+1416A>T in inflating the risk for CML further (P(interaction) = 0.0002). CONCLUSION: Our results indicate that VEGFR2+1416A>T polymorphism may be a useful marker in assessing the disease progression in CML patients. In addition, VEGFA+936C>T was observed to have additive effect in inflating the risk further.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Adulto , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Humanos , India , L-Lactato Deshidrogenasa/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factores de Riesgo , Análisis de Secuencia de ADN , Regulación hacia Arriba

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CONTEXT: Lung cancer is an important cause of cancer-related deaths worldwide. There is an increasing incidence of lung cancer in never smokers and a shift of histology from squamous cell to adenocarcinoma globally in the recent past. Data on treatment outcomes with newer platinum doublets is scant from India. AIMS: To study the clinicopathological features, response rates (RRs), progression-free survival (PFS), overall survival (OS), and the 1, 2, and 3 years survival, in patients with advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Data of all patients who received chemotherapy for Stage IIIB and IV NSCLC between January 2010 and June 2014 were retrospectively analyzed. STATISTICAL ANALYSIS USED: Univariate analysis for OS was done by plotting Kaplan-Meier curves and the log-rank test was used to calculate P values. Logistic regression analysis for OS was carried out using MedCalc statistical software. RESULTS: A total of 353 patients received chemotherapy. Of these, 256 were evaluable for outcome parameters. The median age at presentation was 58 years with a male:female ratio of 2.53:1. The smoker:nonsmoker ratio was 1:1. Adenocarcinomatous histology was the most common both in smokers and nonsmokers reported in 70.8% patients. Epidermal growth factor receptor (EGFR) mutation and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocation were seen in 35% and 3% of patients, respectively. The RR, median PFS, OS, 1, 2, and 3 years survival were 80%, 8 months, 12.1 months, 51.5%, 12.7%, and 4.2%, respectively. There was no significant survival difference among the treatment regimen used but the response to I line chemotherapy impacted survival. Female gender, performance status, and nonsquamous histology were significant predictors of OS (P = 0.0443, P = 0.0003, P = 0.048, respectively). CONCLUSIONS: There was an increase in the incidence of nonsmokers. Adenocarcinoma was the most common histology in both smokers and nonsmokers. Treatment outcomes in advanced lung cancer were better compared to the past with the advent of newer platinum doublets and EGFR tyrosine kinase inhibitors. The response to first-line chemotherapy significantly impacts outcomes in advanced NSCLC.

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INTRODUCTION: Renal cell carcinoma (RCC) is the most common cancer of the kidney accounting for 85% of renal tumors. Metastatic RCC (mRCC) had a poor prognosis and with the introduction of tyrosine-kinase inhibitors, such as sunitinib, pazopanib the outcomes improved. There is only one study reported from India on the use of sunitinib in mRCC. We present our analysis of mRCC and use of sunitinib at our institute over 5 years. MATERIALS AND METHODS: All patients with mRCC receiving sunitinib were analyzed with respect to patient characteristics, response, toxicity, and outcomes. RESULTS: A total of 108 patients were seen during the study period. The male to female ratio was 9.8:1. The median age of patients at presentation was 58 years (range: 15-80 years). Of the 108 patients, 68.51% had metastatic disease at initial presentation. The most common sites of metastases were lung followed by bone. Of the 97 patients eligible for sunitinib, only 76 received at least one cycle of sunitinib, out of which only 48 received further cycles (range: 2-36). The median progression-free survival (PFS) and overall survival (OS) in our patients were 10.2 and 28.2 months, respectively. The most common adverse effect noticed in our population was mucositis followed by hand-foot syndrome. CONCLUSION: Sunitinib is an option for the treatment of mRCC and shows a good PFS in Indian patients. Median OS and PFS in this study are similar to other reported studies despite the presence of poor risk factors in the patient population. The pitfall in this study is significant attrition due to poor compliance to treatment and follow-up, which is a major factor in the clinic thereby compromising outcomes.

RESUMEN

The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in NRAS gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, NRAS mutations were detected using bidirectional sequencing in 264 acute leukemia cases--129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls. Missense mutation was observed only in the 12th codon of NRAS gene in 4.7% of AML and 3.16% of ALL cases. The presence of NRAS mutation did not significantly influence blast % and lactate dehydrogenase (LDH) levels in AML patients. When the data were analyzed with respect to clinical variables, the total leukocyte count was elevated for mutation positive group, compared to negative group. In AML patients with NRAS mutations, 60% failed to achieve complete remission (CR), as compared to 34.8% in mutation negative group. These results indicated that NRAS mutations might confer poor drug response. In AML, disease free survival (DFS) in NRAS mutation positive group was lesser, compared to mutation negative group (9.5 months vs. 11.68 months). In ALL patients, DFS of NRAS mutation positive group was lesser than mutation negative group (9.2 months vs. 27.5 months). The CR rate was also lower for mutation-positive patients group, compared to mutation-negative group. In conclusion, these results suggested that presence of NRAS mutation at 12th codon was associated with poor response and poorer DFS in both ALL and AML.

Asunto(s)

GTP Fosfohidrolasas/genética , Leucemia Mieloide Aguda/genética , Proteínas de la Membrana/genética , Mutación/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prevalencia , Pronóstico , Tasa de Supervivencia

RESUMEN

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = -0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.

Asunto(s)

Neoplasias de la Mama/genética , Islas de CpG , Metilación de ADN , Genes Supresores de Tumor , Obesidad/genética , Xenobióticos/metabolismo , Adulto , Secuencia de Bases , Neoplasias de la Mama/complicaciones , Cartilla de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Obesidad/complicaciones , Reacción en Cadena de la Polimerasa

RESUMEN

BACKGROUND: Mitochondrial displacement loop (D-loop) is the hot spot for mitochondrial DNA (mtDNA) alterations which influence the generation of cellular reactive oxygen species (ROS). Association of D-loop alterations with breast cancer has been reported in few ethnic groups; however none of the reports were documented from Indian subcontinent. METHODOLOGY: We screened the entire mitochondrial D-loop region (1124 bp) of breast cancer patients (n = 213) and controls (n = 207) of south Indian origin by PCR-sequencing analysis. Haplotype frequencies for significant loci, the standardized disequilibrium coefficient (D') for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software. PRINCIPAL FINDINGS: We identified 7 novel mutations and 170 reported polymorphisms in the D-loop region of patients and/or controls. Polymorphisms were predominantly located in hypervariable region I (60%) than in II (30%) of D-loop region. The frequencies of 310'C' insertion (P = 0.018), T16189C (P = 0.0019) variants and 310'C'ins/16189C (P = 0.00019) haplotype were significantly higher in cases than in controls. Furthermore, strong LD was observed between nucleotide position 310 and 16189 in controls (D' = 0.49) as compared to patients (D' = 0.14). CONCLUSIONS: Mitochondrial D-loop alterations may constitute inherent risk factors for breast cancer development. The analysis of genetic alterations in the D-loop region might help to identify patients at high risk for bad progression, thereby helping to refine therapeutic decisions in breast cancer.

Asunto(s)

Neoplasias de la Mama/genética , ADN Mitocondrial/genética , Secuencias Reguladoras de Ácidos Nucleicos , Secuencia de Bases , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Haplotipos , Humanos , India , Desequilibrio de Ligamiento , Mutagénesis Insercional , Mutación Puntual , Polimorfismo de Nucleótido Simple , Factores de Riesgo

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OBJECTIVE: To screen two important FLT3 mutations (internal tandem duplication (ITD) and D835 point mutations) in chronic myeloid leukemia (CML) patients from Southern India and report their incidence. METHODS: Screened 350 CML patients and 350 controls for the two FLT3/mutations through polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: ITDs were detected in 12 of the 350 CML patients (3.4%) and D835 mutations in only four cases (1.14%), relatively low in frequency as compared to those reported earlier from non-Indian populations. None of the cases showed simultaneous occurence of both ITD and D835 mutations. DISCUSSION: These FLT3 mutations seem to be very rare in CML, and it is possible that these could be found only in a subset of patients who are in the progressive stage and/or with varied drug response. Prospective studies are needed to confirm the role of FLT3 mutations in CML pathogenesis, which may help devising therapeutic interventions.

Asunto(s)

Duplicación de Gen , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación Missense , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Ácido Aspártico/genética , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Humanos , India , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Tirosina/genética , Adulto Joven

RESUMEN

CCAAT/enhancer binding protein alpha is one of the crucial transcription factors for myeloid cell development that has been found to be involved in hematopoietic differentiation and leukemiogenesis. Recently, epigenetic regulation of CEBPA expression through DNA methylation has been demonstrated in leukemia. The aim of this study was to investigate the methylation status of CEBPA gene in chronic myeloid leukemia (CML) patients. The methylation status of CEBPA promoter was studied in 100 patients with CML and 98 normal healthy individuals from Hyderabad, India, using methylation-specific polymerase chain reaction. The aberrant methylation of CEBPA gene promoter was found in 32 of the 100 CML cases. A highly significant association was found between the frequency of CEBPA gene promoter hypermethylation and the CML stages (P = 0.017), but association with respect to age and gender of the patient was not found. The results suggest that aberrant methylation in the CpG island of the promoter region of this gene might be a common event in CML, and systemic expression studies will be needed to unfold the role of CEBPA promoter methylation in the development, progression, and prognosis of CML.

Asunto(s)

Proteínas Potenciadoras de Unión a CCAAT/genética , Metilación de ADN , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adulto , Anciano , Islas de CpG , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas

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Our recent study showing association of hyperhomocysteinemia and hypomethioninemia in breast cancer and other studies indicating association of hyperhomocysteinemia with metastasis and development of drug resistance in breast cancer cells treated with homocysteine lead us to hypothesize that homocysteine might modulate the expression of certain tumor suppressors, i.e., RASSF1, RARß1, CNND1, BRCA1, and p21, and might influence prognostic markers such as BNIP3 by inducing epigenetic alteration. To demonstrate this hypothesis, we have treated MCF-7 and MDA-MB-231 cells with different doses of homocysteine and observed dose-dependent inhibition of BRCA1 and RASSF1, respectively. In breast cancer tissues, we observed the following expression pattern: BNIP3 > BRCA1 > RARß1 > CCND1 > p21 > RASSF1. Hyperhomocysteinemia was positively associated with BRAC1 hypermethylation both in breast cancer tissue and corresponding peripheral blood. Peripheral blood CpG island methylation of BRCA1 in all types of breast cancer and methylation of RASSF1 in ER/PR-negative breast cancers showed positive correlation with total plasma homocysteine. The methylation of RASSF1 and BRCA1 was associated with breast cancer initiation as well as progression, while BRCA1 methylation was associated with DNA damage. Vitamin B12 showed inverse association with the methylation at both the loci. RFC1 G80A and cSHMT C1420T variants showed positive association with methylation at both the loci. Genetic variants influencing remethylation step were associated positively with BRCA1 methylation and inversely with RASSF1 methylation. GCPII C1561T variant showed inverse association with BRCA1 methylation. We found good correlation of BRAC1 (r = 0.90) and RASSF1 (0.92) methylation pattern between the breast cancer tissue and the corresponding peripheral blood. To conclude, elevated homocysteine influences methionine dependency phenotype of breast cancer cells and is associated with breast cancer progression by epigenetic modulation of RASSF1 and BRCA1.

Asunto(s)

Epigénesis Genética , Homocisteína/farmacología , Hiperhomocisteinemia/metabolismo , Proteína BRCA1/antagonistas & inhibidores , Proteína BRCA1/metabolismo , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/genética , Células MCF-7 , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transcriptoma/efectos de los fármacos , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/metabolismo , Vitamina B 12/farmacología

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BACKGROUND: E-cadherin (CDH1) plays an important role in intercellular adhesion, cell signaling, and cellular differentiation. Association of single-nucleotide polymorphisms (SNPs) of CDH1 has been identified in a number of epithelial malignancies; however, studies related to breast cancer are very few. AIM: To investigate the association between CDH1 SNPs and breast cancer risk in south Indian women. METHODS: Genotyping of CDH1 functional SNPs (-347G/GA, -160C/A, and +54C/T) was carried out on genomic DNA of blood from breast cancer patients (n=202) and controls (n=250) of south Indian origin by PCR-sequencing and PCR-restriction fragment length polymorphism techniques. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview Software. RESULTS: The frequencies of -160A/A genotypes (p=0.038) and -160A alleles (p=0.046) were significantly higher in patients compared to controls. In addition, the frequency of the -347GA/-160A/+54C haplotype was also significantly elevated in patients (p=0.0238). Strong LD was observed between -347G/GA and +54C/T loci (D'=0.44) in patients compared to controls. CONCLUSION: The CDH1 -160C/A polymorphism may constitute an inheritable risk factor for breast cancer in south Indian women.

Asunto(s)

Neoplasias de la Mama/genética , Cadherinas/genética , Polimorfismo de Nucleótido Simple , Antígenos CD , Pueblo Asiatico , Neoplasias de la Mama/etnología , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , India , Desequilibrio de Ligamiento , Reacción en Cadena de la Polimerasa , Factores de Riesgo

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Chronic myeloid leukemia (CML), a clonal myeloproliferative disorder, is characterized primarily by the presence of chimeric BCR-ABL oncogene, and its progression from chronic to blast phase is associated with the accumulation of additional molecular and chromosomal abnormalities. The molecular mechanisms underlying this genetic instability are poorly understood. The activity of BCR-ABL is known to be associated with the increased production of intracellular reactive oxygen species and spontaneous DNA damage, which when effected by impaired/inaccurate DNA repair systems result in increased susceptibility to CML progression. Using case-control study design, we explored possible association of the repair gene, XRCC1, particularly the codons 399, 280, and 194 polymorphisms screened through PCR-RFLP, with the CML in the sample of 350 cases (206 male and 144 female) and 350 controls from Hyderabad, the capital city of state of the Andhra Pradesh, India. The patient group constituted 301 early chronic phase cases followed by 28 accelerated and 21 blast phase cases. The median age of the patients was 42 years (range, 9-70 years). The genotype distribution revealed significant association of codons 399 (χ(2) = 11.904, degree of freedom (d.f.) = 2; P = 0.002) and 194 (χ(2) = 8.091, d.f. = 2, P = 0.017) with CML, not 280 (P = 0.29). Although these polymorphisms are known to affect the function of XRCC1, the nature and extent of their genetic association with CML does not indicate their direct role in its development. The results seem to suggest that XRCC1 gene might have an important role in CML progression but not in its causation.

Asunto(s)

Codón , Proteínas de Unión al ADN/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Progresión de la Enfermedad , Femenino , Proteínas de Fusión bcr-abl/genética , Inestabilidad Genómica , Humanos , India , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X

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In view of the pivotal role of glutamate carboxypeptidase II (GCPII) in carcinogenesis, its expression as prostate specific membrane antigen (PSMA) and folate hydrolase (FOLH1) may be influenced by its haplotypes, contributing to the etiology of prostate and breast cancer. To test this hypothesis, breast and prostate cancer cases and controls were subjected to whole gene screening of GCPII and correlated with plasma folate levels and PSMA expression. The impact of variants on a 3-dimensional structure of GCPII was explored by in silico studies. Six novel variations i.e. V108A, P160S, Y176H, D191V, G206R and G245S; and two known variations i.e. R190W and H475Y were identified in GCPII. All-wild haplotype and a haplotype harbouring D191V showed association with breast cancer risk while haplotypes harbouring V108A and P160S reduced the risk. Haplotypes with V108A and G245S variants showed increased risk for prostate cancer due to high PSMA expression while P160S conferred protection against prostate cancer. In silico studies suggests that P160S and R190W variants result in relaxed substrate binding facilitating either rapid catalysis or exchange of substrates and products in the active site which was substantiated by high plasma folate levels associated with these variants. On the contrary, D191V was associated with very low plasma folate levels despite having a high PSMA expression. This is the first comprehensive study examining variations in GCPII in relation to breast and prostate cancer risk. Changes in the plasma folate levels and changes in PSMA expression are associated with breast and prostate cancer risk respectively.

Asunto(s)

Antígenos de Superficie/genética , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Glutamato Carboxipeptidasa II/genética , Neoplasias de la Próstata/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/sangre , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Conformación Proteica , Factores de Riesgo , Adulto Joven

RESUMEN

OBJECTIVES: Conjunctival xerosis is a marker for vitamin A deficiency. Conjunctival impression cytology (CIC) is a widely used technique to detect xerosis in field studies. Inadequate and acellular samples are generally considered technical failures and are treated as uninterpretable. The purpose of this study is to determine the significance of acellular smears in the detection of vitamin A deficiency. STUDY DESIGN: CIC with transfer (CICT) and blood samples were collected from freshly diagnosed cancer patients and healthy controls. CICT smears were classified as cellular or acellular. Serum vitamin A levels were tested by high-performance liquid chromatography. CICT results were compared with vitamin A levels. RESULTS: CICT was collected from 1,694 subjects. There were 118 (7%) acellular smears, i.e. 99 in patients and 19 in controls. Serum vitamin A levels were available in 112 of these subjects. Levels <20 µg/dl were seen in 82.1% of the subjects with acellular smears and in 18.9% of the subjects with cellular smears (p < 0.001). Of the gastrointestinal and hepatobiliary and hematologic cancers, 15.6% and 10.5% showed acellular smears, respectively. CONCLUSIONS: Acellular smears in conjunctival imprint cytology may indicate hypovitaminosis A, provided technical failure to obtain cellularity is ruled out.

Asunto(s)

Conjuntiva/patología , Enfermedades de la Conjuntiva/diagnóstico , Deficiencia de Vitamina A/diagnóstico , Neoplasias del Sistema Biliar/complicaciones , Cromatografía Líquida de Alta Presión , Enfermedades de la Conjuntiva/sangre , Enfermedades de la Conjuntiva/complicaciones , Citodiagnóstico/métodos , Femenino , Neoplasias Gastrointestinales/complicaciones , Neoplasias Hematológicas/complicaciones , Humanos , Neoplasias Hepáticas/complicaciones , Sensibilidad y Especificidad , Vitamina A/sangre , Deficiencia de Vitamina A/sangre , Deficiencia de Vitamina A/complicaciones

RESUMEN

Glutamate carboxypeptidase II (GCPII) is predominantly expressed in brain, intestinal mucosa and prostate cancer in the form of three splice variants i.e. N-acetylated-α-linked acidic dipeptidase (NAALADase), folyl poly-γ-glutamate carboxypeptidase (FGCP) and prostate specific membrane antigen (PSMA) respectively. Its inhibition was found to confer protection against certain neurological disorders and cancer. Despite the pivotal role of this enzyme, the most common polymorphism i.e. H475Y has not been explored comprehensively in all its splice variants. In this study, we have determined the role of this variant in different disease conditions such as breast and prostate cancers, autism, coronary artery disease (CAD) and miscarriages (N=1561). Genotyping was done by PCR-RFLP and dideoxy sequencing. Plasma folate levels were estimated by Axysm folate kit. GCPII expression was studied by semi-quantitative RT-PCR. In silico model was developed using PYMOL. We observed the protective role of H475Y variant in cancers [breast cancer; OR (95% CI): 0.81 (0.55-1.19), prostate cancer: OR (95% CI): 0.00 (0.00-0.66)], and in autism (OR (95% CI): 0.47 (0.21-1.03), whereas inflated risk was observed in CAD (OR (95% CI): 1.69 (1.20-2.37) and miscarriages [Maternal OR (95% CI): 3.26 (2.11-5.04); Paternal OR(95% CI): 1.99 (1.23-3.21)]. Further, this variant was found to impair the intestinal folate absorption in subjects with dietary folate intake in the lowest tertile (CC vs. CT in lowest tertile; 7.56±0.85ng/ml vs. 2.73±045ng/ml, p=0.005). In silico model of GCPII showed steric hindrance with H475Y resulting in stereochemical alteration of catalytic site, thus interfering with ligand binding. Statistically significant association was not observed between dietary folate levels and GCPII expression. However, a positive correlation was seen between plasma folate levels and GCPII expression (r=0.70, p<0.05). To conclude, our data suggests that GCPII H475Y variant shows inverse association with autism and cancer while showing positive association with CAD and miscarriages.

Asunto(s)

Antígenos de Superficie/genética , Predisposición Genética a la Enfermedad , Glutamato Carboxipeptidasa II/genética , Aborto Espontáneo/enzimología , Aborto Espontáneo/genética , Trastorno Autístico/enzimología , Trastorno Autístico/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/enzimología , Enfermedad de la Arteria Coronaria/genética , Femenino , Ácido Fólico/sangre , Genotipo , Humanos , Masculino , Polimorfismo Genético , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética

RESUMEN

In view of recent studies highlighting the prognostic relevance of expression and CpG island methylator phenotype (CIMP) of Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) in invasive duct cell carcinoma (IDC), we hypothesized in this article that impaired one-carbon metabolism might influence CIMP phenotype of BNIP3. In order to substantiate the prognostic relevance of BNIP3, we explored its association with 8-oxo-2'deoxyguanosine (8-oxodG), a marker of oxidative stress with prognostic relevance. BNIP3 expression and CIMP phenotype were studied using semi-quantitative RT-PCR and combined bisulfite restriction analysis (COBRA), respectively, in 56 IDC tumors. Eight polymorphisms in one-carbon metabolism were studied using PCR-RFLP and PCR-AFLP approaches. 8-oxodG was measured using competitive ELISA kit. BNIP3 was found to be upregulated in IDC (cases vs. controls: 0.94 ± 0.05 vs. 0.18 ± 0.08, P < 0.0001). COBRA analysis confirmed hypomethylation of BNIP3 promoter CpG island in these cases. CIMP phenotype of BNIP3 showed positive association with tubule formation (P = 0.034) and methionine synthase reductase (MTRR) A66G (P = 0.002); inverse association with cytosolic serine hydroxyl methyltransferase (cSHMT) C1420T (P < 0.005) and 8-oxodG (<10% vs. >10% methylation: 7.24 ± 2.77 ng/ml vs. 4.42 ± 2.93 ng/ml, P < 0.0005); and no association with nuclear pleomorphism or mitotic index or ER, PR, and HER statuses. Synergistic effect of MTR A2756G and MTRR A66G variants on BNIP3 hypermethylator phenotype was clearly evident (P < 0.0007). MTRR A66G and cSHMT C1420T polymorphisms influence CIMP phenotype of BNIP3, thus epigenetically regulating BNIP3 in breast cancer. The linear association between BNIP3 and 8-oxodG substantiates the role of BNIP3 as redox sensor as well as prognostic marker in breast cancer.

Asunto(s)

Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Epigénesis Genética , Ferredoxina-NADP Reductasa/genética , Glicina Hidroximetiltransferasa/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , 8-Hidroxi-2'-Desoxicoguanosina , Análisis del Polimorfismo de Longitud de Fragmentos Amplificados , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Metilación de ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Femenino , Ferredoxina-NADP Reductasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Glicina Hidroximetiltransferasa/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Estrés Oxidativo , Fenotipo , Polimorfismo Genético , Pronóstico , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , Análisis de Secuencia de ADN

RESUMEN

We have earlier demonstrated the role of aberrant one-carbon metabolism in the etiology of breast cancer. In the current study, we examine the clinical utility of these factors in predicting the subtype of breast cancer and as indicators of disease progression. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) approaches were used for genetic analysis. Plasma folate and homocysteine were measured using Axsym folate kit and reverse phase HPLC, respectively. Multiple linear regression models were used to test the predictability of disease progression. Luminal A subtype was associated with late age of onset, higher body mass index and lack of family history of breast cancer. Thymidylate synthase (TYMS) 5'-UTR 28 bp tandem repeat (OR: 2.09, 95% CI: 1.05-4.16) and methylene tetrahydrofolate reductase (MTHFR) C677T (OR: 4.10, 95% CI: 1.40-11.95) were strongly associated with Luminal B. Reduced folate carrier (RFC1) G80A (OR: 2.92, 95% CI: 1.22-6.97) and methionine synthase (MTR) A2756G (OR: 4.71, 95% CI: 1.66-13.31) polymorphisms were associated with LuminA-HH subtype while MTHFR C677T showed association with HER-enriched (OR: 30.41, 95% CI: 6.47-142.91). Cytosolic serine hydroxymethyltransferase (cSHMT) conferred protection against basal-like breast cancer (OR: 0.47, 95% CI: 0.22-0.98). HER-enriched and basal-like subtypes showed positive association with familial breast cancer and inverse association with plasma folate. Hyperhomocysteinemia was observed in Luminal B and basal-like subtypes. Multiple linear regression models of aberrant one-carbon metabolism were found to be moderate predictors of breast cancer grade (area under the receiver operating characteristic curve, C = 0.72, 95% CI: 0.58-0.87, P = 0.008). To conclude, aberrations in one-carbon metabolism predict the subtype of breast cancer and disease progression.

Asunto(s)

Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carbono/metabolismo , Enzimas/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Índice de Masa Corporal , Estudios de Casos y Controles , Enzimas/metabolismo , Femenino , Ácido Fólico/metabolismo , Glicina Hidroximetiltransferasa/genética , Humanos , Menopausia , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Longitud del Fragmento de Restricción , Timidilato Sintasa/genética