High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14–3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31–0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40–26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45–12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two‐way interactions were mostly synergistic. These results suggest that high order gene–gene interactions play an important role in AL risk. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.     

Coronavirus disease (COVID‐19): An updated review based on current knowledge and existing literature for dermatologists

The world entered the year 2020 with reports of the emergence of a new viral illness in Wuhan city, Hubei province, China. In January 2020, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was identified to be the causative novel coronavirus for the cluster of patients suffering from pneumonia in China. The disease was later named as coronavirus disease (COVID‐19) and was declared a pandemic by the World Health Organization on March 11, 2020. Several studies, since then, have tried to study and explain the origin of SARS‐CoV‐2, its structure and pathogenicity, epidemiology, modes of transmission, spectrum of illness and causes of mortality and morbidity. The current management strategies focus on supportive care and prevention of complications. With no definite treatment, as of now, encouraging reports of some anti‐viral and anti‐malarial drugs in the management of COVID‐19 generate some hope. This review intends to cover the current known aspects of COVID‐19 and SARS‐CoV‐19, based on the available literature.     

Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis

AIM: To identify alterations in genes and molecular functional pathways in esophageal cancer in a high incidence region of India where there is a widespread use of tobacco and betel quid with fermented areca nuts. METHODS: Total RNA was isolated from tumor and matched normal tissue of 16 patients with esophageal squamous cell carcinoma. Pooled tumor tissue RNA was labeled with Cy3-dUTP and pooled normal tissue RNA was labeled with Cy5-dUTP by direct labeling method. The labeled probes were hybridized with human 10K cDNA chip and expression profiles were analyzed by Genespring GX V 7.3 (Silicon Genetics). RESULTS: Nine hundred twenty three genes were differentially expressed. Of these, 611 genes were upregulated and 312 genes were downregulated. Using stringent criteria (P ≤ 0.05 and ≥ 1.5 fold change), 127 differentially expressed genes (87 upregulated and 40 downregulated) were identified in tumor tissue. On the basis of Gene Ontology, four different molecular functional pathways (MAPK pathway, G-protein coupled receptor family, ion transport activity, and serine or threonine kinase activity) were most significantly upregulated and six different molecular functional pathways (structural constituent of ribosome, endopeptidase inhibitor activity, structural constituent of cytoskeleton, antioxidant activity, acyl group transferase activity, eukaryotic translation elongation factor activity) were most significantly downregulated. CONCLUSION: Several genes that showed alterations in our study have also been reported from a high incidence area of esophageal cancer in China. This indicates that molecular profiles of esophageal cancer in these two different geographic locations are highly consistent.     

Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis

Polymorphisms in DNA repair and cell cycle genes contribute to increased breast cancer (BC) risk. Their association and interaction in relation to betel quid and tobacco chewing habits need exhaustive multi-analytical investigation to explain BC predisposition due to DNA damage. Polymorphism in TP53-72Arg>Pro, RAD51-135G>C, BRCA2, and CCND1-G870A were examined in 204 BC cases and 217 controls from Northeast Indian population. Multifaceted analytic approaches were used to explore relationships between polymorphisms, tobacco history, and BC susceptibility. Betel quid chewing was identified as the predominant risk factor. CCND-AA and dominant model showed protection towards BC in betel quid chewer (BQC) [(0.28 (0.10–0.77), 0.01 and 0.32 (0.12–0.81), 0.01)] and non-betel quid chewers (NBQC) [(0.26 (0.09–0.78), 0.01 and 0.37 (0.16–0.87), 0.02)]. TP53-Pro/Pro genotype showed protection towards BC in NBQC (0.29 (0.10–0.81), p?=?0.01) and (0.51 (0.32–0.80), p?=?0.003, respectively). RAD51-C allele was associated with BC risk (2.03 (1.26–3.30) 0.002) in BQC. Two BQC cases had BRCA2 8415G>T:K2729N mutation in Exon18. MDR analysis showed best four locus model with TBA 0.6765 (0.005) and CVC of 10/10 in NBQC. Interaction diagram concurred the interactions between TP53 and RAD51 (1.32 %) with independent effect (1.89 %) of CCND1in NBQC. In CART analysis, BQC with CCND1 GG genotype were at risk (OR?=?33.0; 95 % CI?=?6.08–179.07), p?<?0.001) followed by combination of BQC, CCND1, No-Smk, and Alc (OR?=?42.00; 95 % CI?=?5.11–345.11, p?<?0.001). Risk was also observed in BQC, CCND1, No-Smk, Non-Alc, and TP53 combination (OR?=?14.84; 95 % CI?=?3.13–70.34, p?<?0.001) and BQC, CCND1, No-Smk, Non-Alc, TP53 (OR?=?9.40; 95 % CI?=?1.99–44.34, p?<?0.001). NBQC group showed risk with combination of NBQC and TP53 (OR?=?5.54; 95 % CI?=?1.11–27.42, p?=?0.03). Genetic variants in DNA repair and cell cycle genes contribute to BC risk through gene–gene and gene–environmental interactions.     

Aberrant phenotypes in childhood and adult acute leukemia and its association with adverse prognostic factors and clinical outcome

Occurrence of aberrant phenotypes in childhood and adult acute leukemia (AL) differs considerably in independent studies and their association with prognostic factors is still controversial. In the present study, 214 patients with AL (106 children and 108 adults) were evaluated for the aberrant expression of CD33 in ALL (B cell and T cell) and CD3, CD5, CD7, and CD19 in AML. In B-ALL, aberrant expression of CD33 was found in 39 and 23% cases of adult and children, respectively. In T-ALL, CD33 was seen in 33% cases of adults while in children CD33 was not observed. In AML, aberrant expression of CD19 was expressed in 52 and 32% while CD7 was expressed in 14 and 15% cases of childhood and adult AML, respectively. Among FAB subtypes, aberrant expression of CD19 and CD7 was more commonly seen in M5 subtype. One adult patient (AML-M5) showed expression of CD3, CD5, and CD19. In summary, aberrant phenotype was commonly seen in adults than childhood B-ALL while in AML, aberrant phenotype was more common in children than adults. CD19 was most commonly expressed antigen followed by CD7 in both childhood and adult AML. Interestingly, aberrant phenotype was not found in childhood T-ALL; however, it was seen in 33% cases of adults. We did not find any association of aberrant phenotype with adverse prognosis factors, CD34 marker, and clinical outcome except the absence of auer rod which was found to be significantly associated with aberrant phenotype of childhood AML (P = 0.01).     

Mutation of NPM1 and FLT3 Genes in Acute Myeloid Leukemia and Their Association with Clinical and Immunophenotypic Features

Background. Mutations in NPM1 and FLT3 genes represent the most frequent genetic alterations and important diagnostic and prognostic indicators in patients with acute myeloid leukemia (AML). Objective. We investigated the prevalence and clinical characteristics of NPM1 and FLT3 mutations in 161 patients of de novo AML including adults and children. Results. NPM1 mutation was found in 21% and FLT3 mutation in 25% of the AML patients. Thirteen (8%) samples were positive for both NPM1 and FLT3/ITD mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (25.8% versus 8.8%; P = 0.02). Further, NPM1 mutation was found to be more frequent in patients above 45 years of age (P = 0.02). NPM1 mutation was significantly associated with higher platelet count (P = 0.05) and absence of hepatosplenomegaly (P = 0.01), while FLT3/ITD mutation was associated with higher white blood count (P = 0.01). Immunophenotypically, NPM1 mutation was associated with the lack of CD34 (P < 0.001) and HLD-DR expression (P < 0.001), while FLT3/ITD mutation was positively associated with the expression of CD7 (P = 0.04). No correlation was found between NPM1 mutation and fusion gene. Interestingly, FLT3/ITD mutation was found to be inversely associated with AML/ETO fusion gene (P = 0.04). Conclusions. The results suggest that distinct clinical and immunophenotypic characteristics of NPM1 and FLT3/ITD mutations present further insight into the molecular mechanism of leukemogenesis.     

Subcutaneous panniculitis-like T-cell cutaneous lymphoma

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma classified in the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification as a unique extranodal lymphoma with characteristic by T cell receptor (TCR) gene rearrangement. We report here a case of SPTCL in a 22 year-old woman who had presented with variably sized multiple nodules on both her legs. Initial differential diagnoses considered were panniculitis and lupus panniculitis. The histopathology showed a predominantly subcutaneous lobular infiltrate with atypical lymphocytes, karyorrhexis and rimming of adipocytes by lymphoid cells. Immunohistochemistry showed CD4-, CD8+, CD56- T-cell phenotype. Although TCR rearrangement studies were not done, the above T-cell phenotype and sparing of epidermis and dermis suggested the possibility of an SPTCL alpha/beta type. The patient received five cycles of a cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen which resulted in the regression in her skin lesions and constitutional symptoms.     

Role of epoxide hydrolase 1 gene polymorphisms in esophageal cancer in a high‐risk area in India

Background and Aim: Microsomal epoxide hydrolase 1 (EPHX1) is involved in the metabolism of environmental and tobacco carcinogens. Tobacco smoking, betel quid chewing, and alcohol consumption are the major known risk factors for esophageal cancer. The present case‐control study evaluated the influence of EPHX1 genetic variations on esophageal cancer susceptibility in 142 patients and 185 healthy controls from a high‐incidence region of India where tobacco use and alcohol consumption are widespread and the users of these two substances are also betel quid chewers. Methods: EPHX1 polymorphic alleles (exon 3, Tyr113His and exon 4, His139Arg) were genotyped by polymerase chain reaction–restriction fragment length polymorphism method and direct sequencing. The results were analyzed using logistic regression to calculate odds ratios (OR) and confidence intervals (CI). Results: Patients with exon 4 genotypes (139His/Arg, 139Arg/Arg) and the 139Arg allele were significantly associated with a risk of esophageal cancer (OR_His139Arg 1.887, 95% CI = 1.112–3.201, P = 0.019; OR_Arg139Arg 7.140, 95% CI = 1.276–393.953, P = 0.025 and OR_Arg 1.83, 95% CI = 1.19–2.82, P = 0.003). The 139His/Arg genotype was a significant risk factor for esophageal cancer in tobacco chewers and betel quid chewers. Patients with the 139Arg/Arg genotype were at significantly higher risk for developing a well‐differentiated and moderately‐differentiated grade of tumor. In contrast, the 113His/His genotype of exon 3 was a significant protective factor for esophageal cancer in tobacco smokers (OR 0.291, 95% CI = 0.138–0.616, P = 0.001), betel quid chewers (OR 0.434, 95% CI = 0.236–0.797, P = 0.007), and alcohol users. Conclusion: EPHX1 exon 4 139His/Arg, and 139Arg/Arg genotypes were associated with a higher risk of esophageal cancer in a high‐risk area of India.     

Expression of genes related to multiple drug resistance and apoptosis in acute leukemia: response to induction chemotherapy

Resistance to chemotherapy is a major impediment to the successful treatment of acute leukemia (AL). Expression of genes involved in drug resistance and apoptosis may be responsible for this. This study aimed to investigate the expression of drug resistance (MDR1, MRP1, LRP, BCRP, GSTP1, DHFR) and apoptotic genes (p53, BCL-2, Survivin) in adult acute leukemias and compare them with clinical and hematological findings and response to induction chemotherapy. Eighty-five patients with AL [45 with acute myeloid leukemia (AML) and 40 with acute lymphoblastic leukemia (ALL)] were used as a study group. Real-time PCR results showed that expression level of MDR1 was significantly higher in AML whereas expression of DHFR, BCRP and Survivin was significantly higher in ALL patients. In AML, significant correlation was observed between LRP and MRP1 (r(s)=0.44, p=0.016), LRP and DHFR (r(s)=0.41, p=0.02), MDR1 and BCL-2 (r(s)=0.38, p=0.03). Expression of GSTP1 and LRP correlated with high white blood count (p=0.03 and p=0.03) and BCL-2 with high peripheral blast count (p=0.009). MDR1 expression was significantly associated with the expression of immature stem cell marker CD34 (p=0.002). In ALL, significant association was found between LRP gene and female sex (p<0.0001), LRP and B-ALL patients (p=0.04) and LRP and BCR/ABL positive patients (p=0.004). High expression of MDR1 and BCL-2 in AML and MRP1 gene in ALL was associated with response to induction chemotherapy (p=0.001, p=0.02 and p=0.007 respectively). These results showed the potential clinical relevance of MDR1, MRP1 and BCL-2 in adult patients with acute leukemia in the context of induction chemotherapy.