RESUMO
The enzymes encoded by glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism of wide range of carcinogens that are ubiquitous in the environment. Homozygous deletions of the GSTM1 and GSTT1 genes are commonly found and result in lack of enzyme activity. This study was undertaken to evaluate the association between GSTM1, GSTT1 and GSTP1 gene polymorphism and breast cancer risk in Mizoram population. Odd ratio (OR) and 95% confidence interval (CI) from conditional logistic regression model were used to estimate the association between genetic polymorphism and breast cancer risk. The GSTM1 and GSTT1 null genotypes were associated with an increased risk of breast cancer [OR = 10.80 (95% CI 1.16-100.43)]. The risk of breast cancer associated with the GSTT1 null genotype was observed to be low among postmenopausal women. When considered together, GSTM1 and GSTT1 genotypes were found to be associated with an increased risk of breast cancer. The relationship between GSTM1 and GSTT1 gene deletions and breast cancer risk was substantially altered by consumption of Smoked Meat/Vegetable. In the present study, GSTP1Ile105Val (rs1695) polymorphism was related to breast cancer susceptibility or phenotype. Our data provides evidence for substantially increased risk of breast cancer associated with GSTM1 and/or GSTT1 homozygous gene deletions in Mizoram population.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Polimorfismo Genético , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Feminino , Genótipo , Humanos , Índia/epidemiologia , Pessoa de Meia-IdadeRESUMO
Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations as it is prone to oxidative stress. The aim of the present study is to assess the novel mutations in mitochondrial genes from blood samples among the breast cancer patients from a less studied Northeast Indian population. D, B, L haplogroups were observed in the cancer samples and a total of 44 mtDNA D-loop sequence variations at 42 distinct nucleotide positions were found. All the sequence variations were transitional substitutions and 6 were heteroplasmic states, except for a cytosine copy number change (9C/8C) at np 303e309 in three samples examined. A total of 88 Cytochrome Oxidase C subunit I (COXI) sequence differences with respect to the Revised Cambridge Reference Sequence (rCRS) were identified including 20 missense variants with 100 % sample mutation frequency. All 20 missense mutations are highly conserved with a Cumulate Index of 100 %. Among 88 COXI mutations, 24 (13 were Non-Synonymous and 11 were Synonymous) were not previously reported (novel mutation) in the literature or the public mtDNA mutation databases. Analysis of three-dimensional structure of COXI open reading frame (ORF) predicted the effect of one single codon (96R > C, 217T > I, 224-225GG > EE and 227D > T) mutations located in the signal peptide binding position. Analysis of mitochondrial DNA mutations, as a viable alternative, has the advantage of being capable of detecting inherent risk factors for breast cancer development.
Assuntos
Neoplasias da Mama/genética , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Polimorfismo Genético , Adulto , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Análise por Conglomerados , Complexo IV da Cadeia de Transporte de Elétrons/química , Feminino , Frequência do Gene , Haplótipos , Humanos , Índia , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Filogenia , Estrutura Secundária de Proteína , Fatores de RiscoRESUMO
BACKGROUND: Leukemia is the most common type of cancer in pediatrics. Genomic mutations contribute towards the molecular mechanism of disease progression and also helps in diagnosis and prognosis. This is the first scientific mutational exploration in whole exome of pediatric leukemia patients from a cancer prone endogamous Mizo tribal population, Northeast India. RESULT: Three non-synonymous exonic variants in NOTCH1 (p.V1699E), MUTYH (p.G143E) and PTPN11 (p.S502P) were found to be pathogenic. A novel in-frame insertion-deletion within the juxtamembrane domain of FLT3 (p.Tyr589_Tyr591delinsTrpAlaGlyAsp) was also observed. CONCLUSION: These unique variants could have a potential mutational significance and these could be candidate genes in elucidating the possibility of predisposition to cancers within the population. This study merits further investigation for its role in diagnosis and prognosis and also suggests the need for population wide screening to identify unique mutations that might play a key role towards precision medicine.
Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Criança , Humanos , Mutação INDEL , Índia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etnologia , Mutação , Sequenciamento do Exoma , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Leukemia is the most common childhood malignancy and studies had been carried out with promising revelations in its diagnosis and prognosis. However, majority of the studies are focused on nuclear alterations, while mitochondrial mutations are not well studied. Although there are studies of mitochondrial mutations in the adult leukemias, it does not represent the same for childhood malignancy. This is the first scientific report on the mtDNA mutational pattern of pediatric leukemic cases from a endogamous tribal population in Northeast India. ATP6 involved in the Complex V was found to be more altered with respect to the Non-synonymous variants. mtDNA variations in the non-coding region (D-Loop - g.152 T>C) and in the coding region (MT-ND2, g.4824 A>G, p.T119A) showed a maternal inheritance which could reveal a genetic predisposition with lower penetrance. D-Loop variant (g.152 T>C) could be a diagnostic marker in accordance with previous report but is in contrast to pertaining only in AML - M3 subtype rather was found across in myeloid malignancies.
Assuntos
Leucemia/genética , Mitocôndrias/genética , ATPases Mitocondriais Próton-Translocadoras/genética , NADH Desidrogenase/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genes Mitocondriais , Predisposição Genética para Doença , Humanos , Índia/etnologia , Leucemia/etnologia , Masculino , Herança Materna , ATPases Mitocondriais Próton-Translocadoras/química , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Seleção Genética , Sequenciamento Completo do GenomaRESUMO
Mutations in mitochondrial D-loop region of DNA (mtDNA) may serve as a potential sensor for cellular DNA damage and marker for cancer development. We investigated the restriction fragment length polymorphism (RFLP) pattern of the D-loop region in the blood samples of breast cancer patients among Mizoram population. Significant differences were observed among breast cancer and healthy blood samples in the RFLP pattern using AluI, HaeIII and RsaI enzymes. Polymorphic information content (PIC - 0.258), band informativeness (∑Ib - 3.283) and marker index (MI - 0.006) were highest in the case of RsaI enzyme. Our data suggest that the RsaI polymorphic site in the mitochondrial control region is an informative marker for breast cancer development in Mizo population.
Assuntos
Neoplasias da Mama/genética , Genoma Mitocondrial/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , DNA Mitocondrial/genética , Feminino , Genes Mitocondriais , Genoma/genética , Humanos , Mitocôndrias/genética , Mongólia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição/genética , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
BACKGROUND: Mizoram has the highest incidence of cancer in India. Among women, breast cancer is most prevalent and the state occupies fifth position globally. The reason for high rate of cancer in this region is still not known but it may be related to ethnic/racial variations or lifestyle factors. METHODS: The present study aims to identify the candidate mitochondrial DNA (mtDNA) biomarkers-ND1and ATPase for early breast cancer diagnosis in Mizo population. Genomic DNA was extracted from blood samples of 30 unrelated breast cancer and ten healthy women. The mtNDI and mtATP coding regions were amplified by step-down PCR and were subjected to restriction enzyme digestion and direct sequencing by Sanger method. Subsequently, the results of the DNA sequence analysis were compared with that of the revised Cambridge Reference Sequence (rCRS) using Mutation Surveyor and MITOMAP. RESULTS: Most of the mutations were reported and new mutations that are not reported in relationship with breast cancer were also found. The mutations are mostly base substitutions. The effect of non-synonymous substitutions on the amino acid sequence was determined using the PolyPhen-2 software. Statistical analysis was performed for both cases and controls. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated from logistic regression. High intake of animal fat and age at menarche was found to be associated with a higher risk of breast cancer in Mizo population. CONCLUSION: Our results also showed that ATPase6 as compared to ATPase8 gene is far more predisposed to variations in Mizo population with breast cancer and this finding may play an important role in breast cancer prognosis.