Publications by authors named "Arindam Maitra"

42 Publications

Spontaneous preterm birth: the underpinnings in the maternal and fetal genomes.

NPJ Genom Med 2021 Jun 8;6(1):43. Epub 2021 Jun 8.

National Institute of Biomedical Genomics, Kalyani, India.

Preterm birth (PTB) is a major cause of neonatal mortality and health complications in infants. Elucidation of its genetic underpinnings can lead to improved understanding of the biological mechanisms and boost the development of methods to predict PTB. Although recent genome-based studies of both mother and fetus have identified several genetic loci which might be implicated in PTB, these results suffer from a lack of consistency across multiple studies and populations. Moreover, results of functional validation of most of these findings are unavailable. Since medically indicated preterm deliveries have well-known heterogeneous causes, we have reviewed only those studies which investigated spontaneous preterm birth (sPTB) and have attempted to suggest probable biological mechanisms by which the implicated genetic factors might result in sPTB. We expect our review to provide a panoramic view of the genetics of sPTB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00209-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187433PMC
June 2021

Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer.

NPJ Genom Med 2021 May 12;6(1):32. Epub 2021 May 12.

National Institute of Biomedical Genomics, Kalyani, India.

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM-receptor interaction, PI3K-Akt signaling, cytokine-cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes-CD274, CD80, and IDO1-were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00195-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115176PMC
May 2021

Panel of significant risk factors predicts early stage gastric cancer and indication of poor prognostic association with pathogens and microsatellite stability.

Genes Environ 2021 Feb 10;43(1). Epub 2021 Feb 10.

Department of Biotechnology, Mizoram University, Aizawl, Mizoram, 796004, India.

Background: There are very few studies covering the epidemiological risk factors associated with Epstein Barr Virus (EBV) and Microsatellite stability for Gastric Cancer (GC) cases. Early diagnosis of GC through epidemiological risk factors is very necessary for the clinical assessment of GC. The aim of this study was to find out the major risk factors to predict GC in early stage and the impact of pathogen infection and MSI on survival rate of patients. GC samples were screened for Helicobacter pylori, Epstein Barr Virus, and Mismatch repair (MMR) gene status (microsatellite stable or instable). Chi-square and logistic regression analysis of Odd ratio and 95% confidence interval (OR, 95% CI) were performed to find out the association between epidemiological factors and the risk of gastric cancer. The pathogen and MMR gene status were analysed to predict their effect on overall survival and the risk score and hazard ratio was calculated for prognostic assessment.

Results: Excess body weight, consumption of extra salt, smoked food, alcohol, and smoking were the major risk factors for GC development. This study achieved a high area under the curve (AUC 0.94) for the probable GC patients in early-stage using the five-panel epidemiological risk factors. H. pylori infected cases were significant with smoked food, while EBV was found to be associated with tuibur intake and smoked food. In overall survival analysis EBV infected and microsatellite stable (HR: 1.32 and 1.34 respectively) GC cases were showing poor prognosis.

Conclusion: This study might provide new opportunities for personalized treatment options using this epidemiological factor risk score and clinicopathological factors assessment for early detection and prognosis in high-risk GC populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s41021-021-00174-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877109PMC
February 2021

Maternal DNA Methylation During Pregnancy: a Review.

Reprod Sci 2021 Jan 19. Epub 2021 Jan 19.

National Institute of Biomedical Genomics, Kalyani, West Bengal, 741251, India.

Multiple environmental, behavioral, and hereditary factors affect pregnancy. Recent studies suggest that epigenetic modifications, such as DNA methylation (DNAm), affect both maternal and fetal health during the period of gestation. Some of the pregnancy-related risk factors can influence maternal DNAm, thus predisposing both the mother and the neonate to clinical adversities with long-lasting consequences. DNAm alterations in the promoter and enhancer regions modulate gene expression changes which play vital physiological role. In this review, we have discussed the recent advances in our understanding of maternal DNA methylation changes during pregnancy and its associated complications such as gestational diabetes and anemia, adverse pregnancy outcomes like preterm birth, and preeclampsia. We have also highlighted some major gaps and limitations in the area which if addressed might improve our understanding of pregnancy and its associated adverse clinical conditions, ultimately leading to healthy pregnancies and reduction of public health burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43032-020-00456-4DOI Listing
January 2021

Application of Random Forest and data integration identifies three dysregulated genes and enrichment of Central Carbon Metabolism pathway in Oral Cancer.

BMC Cancer 2020 Dec 14;20(1):1219. Epub 2020 Dec 14.

National Institute of Biomedical Genomics, Kalyani, 741251, India.

Background: Studies of epigenomic alterations associated with diseases primarily focus on methylation profiles of promoter regions of genes, but not of other genomic regions. In our past work (Das et al. 2019) on patients suffering from gingivo-buccal oral cancer - the most prevalent form of cancer among males in India - we have also focused on promoter methylation changes and resultant impact on transcription profiles. Here, we have investigated alterations in non-promoter (gene-body) methylation profiles and have carried out an integrative analysis of gene-body methylation and transcriptomic data of oral cancer patients.

Methods: Tumor and adjacent normal tissue samples were collected from 40 patients. Data on methylation in the non-promoter (gene-body) regions of genes and transcriptome profiles were generated and analyzed. Because of high dimensionality and highly correlated nature of these data, we have used Random Forest (RF) and other data-analytical methods.

Results: Integrative analysis of non-promoter methylation and transcriptome data revealed significant methylation-driven alterations in some genes that also significantly impact on their transcription levels. These changes result in enrichment of the Central Carbon Metabolism (CCM) pathway, primarily by dysregulation of (a) NTRK3, which plays a dual role as an oncogene and a tumor suppressor; (b) SLC7A5 (LAT1) which is a transporter dedicated to essential amino acids, and is overexpressed in cancer cells to meet the increased demand for nutrients that include glucose and essential amino acids; and, (c) EGFR which has been earlier implicated in progression, recurrence, and stemness of oral cancer, but we provide evidence of epigenetic impact on overexpression of this gene for the first time.

Conclusions: In rapidly dividing cancer cells, metabolic reprogramming from normal cells takes place to enable enhanced proliferation. Here, we have identified that among oral cancer patients, genes in the CCM pathway - that plays a fundamental role in metabolic reprogramming - are significantly dysregulated because of perturbation of methylation in non-promoter regions of the genome. This result compliments our previous result that perturbation of promoter methylation results in significant changes in key genes that regulate the feedback process of DNA methylation for the maintenance of normal cell division.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07709-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737291PMC
December 2020

Whole Genome DNA Methylation and Gene Expression Profiling of Oropharyngeal Cancer Patients in North-Eastern India: Identification of Epigenetically Altered Gene Expression Reveals Potential Biomarkers.

Front Genet 2020 8;11:986. Epub 2020 Oct 8.

Department of Zoology, North Eastern Hill University (NEHU), Shillong, India.

Oropharyngeal cancer is a subtype of head and neck squamous cell carcinoma that is associated with unique risk exposures like consumption of smokeless tobacco and areca nut and is highly prevalent in the northeastern region of India, especially Meghalaya. However, the underlying epigenetic and transcriptomic changes in this cancer type is yet to be delineated. We have undertaken a study on genome wide somatic alterations in the DNA methylation and transcriptome in oropharyngeal cancer patients from this region using genome wide techniques in paired tumors and adjacent normal tissues. By using integrative approaches, we have identified 194 epigenetically silenced and 241 epigenetically overexpressed genes in the tumor tissue of these patients. Pathways that are significantly enriched by these genes include the pathways of immune systems, such as the interleukin signaling pathways and Toll-like receptor signaling pathway. Also, osteoclast differentiation pathway was found to be epigenetically upregulated. The pathways enriched by the epigenetically downregulated genes were found to be predominantly those involved in xenobiotic metabolism and keratinization. Two major transcription factors - and were identified as epigenetically dysregulated, which further modulates 129 downstream genes. Comparison of our observations with the head and neck cancer data from TCGA revealed distinct DNA methylation and gene expression landscapes which might be specific for oropharyngeal cancer. HPV DNA sequences were not detected in any of the tumor samples in RNA-Seq data. The results obtained in this study might provide improved understanding of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578381PMC
October 2020

Mutations in SARS-CoV-2 viral RNA identified in Eastern India: Possible implications for the ongoing outbreak in India and impact on viral structure and host susceptibility.

J Biosci 2020 ;45

National Institute of Biomedical Genomics, PO: NSS, Kalyani 741 251, India.

Direct massively parallel sequencing of SARS-CoV-2 genome was undertaken from nasopharyngeal and oropharyngeal swab samples of infected individuals in Eastern India. Seven of the isolates belonged to the A2a clade, while one belonged to the B4 clade. Specific mutations, characteristic of the A2a clade, were also detected, which included the P323L in RNA-dependent RNA polymerase and D614G in the Spike glycoprotein. Further, our data revealed emergence of novel subclones harbouring nonsynonymous mutations, viz. G1124V in Spike (S) protein, R203K, and G204R in the nucleocapsid (N) protein. The N protein mutations reside in the SR-rich region involved in viral capsid formation and the S protein mutation is in the S domain, which is involved in triggering viral fusion with the host cell membrane. Interesting correlation was observed between these mutations and travel or contact history of COVID-19 positive cases. Consequent alterations of miRNA binding and structure were also predicted for these mutations. More importantly, the possible implications of mutation D614G (in S domain) and G1124V (in S subunit) on the structural stability of S protein have also been discussed. Results report for the first time a bird's eye view on the accumulation of mutations in SARS-CoV-2 genome in Eastern India.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269891PMC
June 2020

Study of Caspase 8 mutation in oral cancer and adjacent precancer tissues and implication in progression.

PLoS One 2020 3;15(6):e0233058. Epub 2020 Jun 3.

Human Genetics Unit, Indian Statistical Institute, Kolkata, India.

It is hypothesized that same driver gene mutations should be present in both oral leukoplakia and cancer tissues. So, we attempted to find out mutations at one of the driver genes, CASP8, in cancer and adjacent leukoplakia tissues. Patients (n = 27), affected by both of cancer and adjacent leukoplakia, were recruited for the study. Blood and tissue DNA samples were used to identify somatic mutations at CASP8 by next generation sequencing method. In total, 56% (15 out of 27) cancer and 30% (8 out of 27) leukoplakia tissues had CASP8 somatic mutations. In 8 patients, both cancer and adjacent leukoplakia tissues, located within 2-5 cm of tumor sites, had identical somatic mutations. But, in 7 patients, cancer samples had somatic mutations but none of the leukoplakia tissues, located beyond 5cm of tumor sites, had somatic mutations. Mutated allele frequencies at CASP8 were found to be more in cancer compared to adjacent leukoplakia tissues. This study provides mutational evidence that oral cancer might have progressed from previously grown leukoplakia lesion. Leukoplakia tissues, located beyond 5cm of cancer sites, were free from mutation. The study implies that CASP8 mutation could be one of the signatures for some of the leukoplakia to progress to oral cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233058PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269231PMC
August 2020

Next-Generation Sequencing-Based Diagnosis of Unexplained Inherited Hemolytic Anemias Reveals Wide Genetic and Phenotypic Heterogeneity.

J Mol Diagn 2020 04 6;22(4):579-590. Epub 2020 Feb 6.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

Determination of the cause of inherited hemolysis is based on clinical and stepwise conventional laboratory tests. Patients with obscure etiology require genetic diagnosis, which is time-consuming, expensive, and laborious, mainly because of numerous causal genes. This study enrolled 43 patients with clinical and laboratory evidence of unexplained hemolytic anemia. Initially, 13 patients were tested using a commercial (TruSight One) panel, and remaining cases underwent targeted sequencing using a customized 55-gene panel. Pyruvate kinase deficiency was found in eight, glucose-6-phosphate dehydrogenase (G6PD) deficiency in three (G6PD Guadalajara in two and p.Tyr227Ser: novel, named as G6PD Chandigarh), and glucose-6-phosphate isomerase (GPI) deficiency in two (GPI:p.Arg347His and p.Phe304Leu: novel, named as GPI Chandigarh). Three patients had Mediterranean stomatocytosis/macrothrombocytopenia, and two had overhydrated stomatocytosis. Xerocytosis was found in three patients, whereas six had potentially pathogenic variants in membrane protein-coding genes. Overall, 63% cases received a definite diagnosis. Timely determination of etiology was helpful in diagnosis, genetic counseling, and offering a prenatal diagnosis. Therapeutic implications include performing or avoiding splenectomy that may ameliorate the anemia in many but also predispose to thrombosis in other groups of patients. This first study on the genetic spectrum of unexplained hemolytic anemia from the Indian subcontinent also represents, currently, one of the largest cohort worldwide of such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2020.01.007DOI Listing
April 2020

Phenotypic and genetic heterogeneity arising from a novel substitution at amino acid position Val205 in GATA1 related X-linked thrombocytopenia with dyserythropoietic anemia.

Blood Cells Mol Dis 2020 03 30;81:102391. Epub 2019 Nov 30.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2019.102391DOI Listing
March 2020

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer.

Clin Epigenetics 2019 12 3;11(1):178. Epub 2019 Dec 3.

National Institute of Biomedical Genomics, P.O.: N.S.S, Kalyani, 741251, India.

Background: Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. Although genomic drivers of OSCC-GB have been identified by whole exome and whole genome sequencing, no epigenome-wide study has been conducted in OSCC-GB; our study has filled this gap, and has discovered and validated epigenomic hallmarks of gingivobuccal oral cancer.

Methods: We have carried out integrative analysis of epigenomic (n = 87) and transcriptomic (n = 72) profiles of paired tumor-normal tissues collected from OSCC-GB patients from India. Genome-wide DNA methylation assays and RNA-sequencing were performed on high-throughput platforms (Illumina) using a half-sample of randomly selected patients to discover significantly differentially methylated probes (DMPs), which were validated on the remaining half-sample of patients.

Results: About 200 genes showed significant inverse correlation between promoter methylation and expression, of which the most significant genes included genes that act as transcription factors and genes associated with other cancer types. Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation.

Conclusions: In OSCC-GB patients, there are significant alterations in expression of key genes that (a) regulate normal cell division by maintenance of balanced DNA methylation and transcription process, (b) maintain normal physiological signaling (PPAR, B cell receptor) and metabolism (arachidonic acid) pathways, and (c) provide immune protection against antigens, including tumor cells. These findings indicate novel therapeutic targets, including immunotherapeutic, for treatment of OSCC-GB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0782-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889354PMC
December 2019

A nonsense variant in the Hexokinase 1 gene (HK1) causing severe non-spherocytic haemolytic anaemia: genetic analysis exemplifies ambiguity due to multiple Isoforms.

Br J Haematol 2019 09 23;186(5):e142-e145. Epub 2019 May 23.

Department of Haematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15981DOI Listing
September 2019

Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects.

Int J Cancer 2019 11 16;145(9):2568-2579. Epub 2019 Apr 16.

National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, Kalyani, West Bengal, India.

Oral squamous cell carcinoma (OSCC) is highly prevalent in south and southeast Asia. Many (30-50%) OSCC patients develop lymph node metastasis (LNM), which is the most important prognostic factor in OSCC. To identify genomic correlates of LNM, we compared exome sequences and copy number variation data of blood and tumor DNA from highly contrasting subgroups of patients to reduce false inferences-(i) patients with LNM and (ii) patients with late stage disease but without LNM. We found that LNM is associated with (i) specific hotspot somatic mutations in TP53 and CASP8; (ii) rare nonsilent germline mutations in BRCA2 and FAT1; (iii) mutations in mito-G2/M and nonhomologous end joining (NHEJ) pathways; (iv) recurrent deletion of genes for DNA repair by homologous recombination; and (v) chromosomal instability. LN+ patients with NHEJ pathway mutations have longer disease-free survival. Five genomic features have a high predictive value of LNM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32305DOI Listing
November 2019

Genome-wide miRNA methylome analysis in oral cancer: possible biomarkers associated with patient survival.

Epigenomics 2019 04 15;11(5):473-487. Epub 2019 Mar 15.

Department of Pathology, Division of Health Science, University of Otago, Dunedin, Otago, MD 20892, New Zealand.

Aim: The methylome associated with miRNA loci was investigated in oral cancer to explore tobacco specific methylation and potential biomarkers for patient survival.

Methods: Methylome data was generated from 16 pairs of cancer-normal tissues by reduced representation bisulfite sequencing method. Differentially methylated regions were identified using the DMAP pipeline. In silico validation and Kaplan-Meier survival analyses were performed on The Cancer Genome Atlas data based on our miRNA methylome data.

Results: A total of 4310 unique differentially methylated regions, mapping to 144 miRNA loci, were identified. Three distinct groups of miRNAs were differentially methylated in cancer tissues from smokers, chewers and mixed habitués. Hypermethylation of miR-503, miR-200a/b, miR-320b and miR-489 was associated with worse 5-year survival.

Conclusion: Differential methylation patterns in miRNA loci are associated with poor survival underscoring their potential as predictive and prognostic biomarkers in oral cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2018-0078DOI Listing
April 2019

First report of homocystinuria-megaloblastic anaemia, cobalamin E complementation type, in an Indian child.

Pathology 2019 Jan 19;51(1):95-98. Epub 2018 Nov 19.

Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pathol.2018.07.008DOI Listing
January 2019

Altered Levels of Long NcRNAs Meg3 and Neat1 in Cell And Animal Models Of Huntington's Disease.

RNA Biol 2018 26;15(10):1348-1363. Epub 2018 Oct 26.

b Crystallography and Molecular Biology Division , Saha Institute of Nuclear Physics, HBNI , Kolkata , India.

Altered expression levels of protein-coding genes and microRNAs have been implicated in the pathogenesis of Huntington's disease (HD). The involvement of other ncRNAs, especially long ncRNAs (lncRNA), is being realized recently and the related knowledge is still rudimentary. Using small RNA sequencing and PCR arrays we observed perturbations in the levels of 12 ncRNAs in HD mouse brain, eight of which had human homologs. Of these, Meg3, Neat1, and Xist showed a consistent and significant increase in HD cell and animal models. Transient knock-down of Meg3 and Neat1 in cell models of HD led to a significant decrease of aggregates formed by mutant huntingtin and downregulation of the endogenous Tp53 expression. Understanding Meg3 and Neat1 functions in the context of HD pathogenesis is likely to open up new strategies to control the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15476286.2018.1534524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284602PMC
January 2019

Profiling of genomic alterations of mitochondrial DNA in gingivobuccal oral squamous cell carcinoma: Implications for disease progress.

Mitochondrion 2019 05 24;46:361-369. Epub 2018 Sep 24.

National Institute of Biomedical Genomics, Kalyani, West Bengal 741251, India. Electronic address:

We have identified 164 somatic mutations in mitochondrial DNA in gingivobuccal oral cancer by deep sequencing the mitochondrial genome from paired tumor and blood DNA samples from 89 patients. We have found evidence of positive selection of somatic nonsynonymous mutations. Non-synonymous mutations in mitochondrial respiratory genes were found to increase the risk of lymph node metastasis (P = 0.0028). We have observed a significant reduction in mitochondrial DNA copy number in tumor DNA of these patients compared to the DNA from adjacent normal tissue samples (P < 1 × 10). Analysis of transcriptome data of tumor and adjacent normal tissue revealed patients harboring mutations in mitochondrial protein-coding genes exhibited reduced expression of mitochondrial transcripts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mito.2018.09.006DOI Listing
May 2019

Homozygous KLF1 mutation c.901C>T (p.Arg301Cys) resulting in mild thalassemia intermedia in an Indian: A next-generation sequencing diagnosis.

Blood Cells Mol Dis 2018 09 28;72:19-21. Epub 2018 Jun 28.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2018.06.003DOI Listing
September 2018

Pre-operative progesterone benefits operable breast cancer patients by modulating surgical stress.

Breast Cancer Res Treat 2018 Jul 21;170(2):431-438. Epub 2018 Mar 21.

National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani, 741251, West Bengal, India.

Purpose: We have reported a survival benefit of single injection of hydroxyprogesterone prior to surgery for primary tumour in patients with node-positive operable breast cancer. Hydroxyprogesterone was meant to recapitulate the luteal phase of menstrual cycle in these women. We wanted to understand the molecular basis of action of hydroxyprogesterone on primary breast tumours in a peri-operative setting.

Methods: We performed whole transcriptome sequencing (RNA-Seq) of primary breast tumour samples collected from patients before and after hydroxyprogesterone exposure and controls. Paired breast cancer samples were obtained from patients who were given hydroxyprogesterone before surgery and a group of patients who were subjected to only surgery.

Results: A test of significance between the two groups revealed 207 significantly altered genes, after correction for multiple hypothesis testing. We found significantly contrasting gene expression patterns in exposed versus unexposed groups; 142 genes were up-regulated post-surgery among exposed patients, and down-regulated post-surgery among unexposed patients. Significantly enriched pathways included genes that respond to progesterone, cellular stress, nonsense-mediated decay of proteins and negative regulation of inflammatory response. These results suggest that cellular stress is modulated by hydroxyprogesterone. Network analysis revealed that UBC, a mediator of stress response, to be a major node to which many of the significantly altered genes connect.

Conclusions: Our study suggests that pre-operative exposure to progesterone favourably modulates the effect of surgical stress, and this might underlie its beneficial effect when administered prior to surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-018-4749-3DOI Listing
July 2018

Overhydrated stomatocytosis associated with a complex genotype including a novel mutation.

J Clin Pathol 2018 Jul 20;71(7):648-652. Epub 2018 Mar 20.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the gene. We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis. Extensive haemolytic work-up including flow cytometry for eosin-5'-maleimide and CD47 expression levels was carried out. Targeted resequencing revealed two probably causative heterozygous mutations in (Leu336Ser and Ile149Met) and one heterozygous mutation in (Glu1046Lys) involvement was confirmed by decreased RhAG macrocomplex component indicated by the reduced CD47 expression on erythrocytes. analysis concordantly flagged :Leu336Ser and :Glu1046Lys as likely deleterious mutation, whereas :Ile149Met was reported as likely neutral by PROVEAN. Family screening by Sanger sequencing revealed :Leu336Ser in a mother and :Glu1046Lys in a father who were both asymptomatic, excluding them as causative dominant events, thus establishing :Ile149Met, novel mutation as probably causative. This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data, as in silico analysis alone can be misleading. Erudite generation of diagnostic possibilities based on a thorough baseline clinical and laboratory work-up remains as important as ever, even as NGS brings about a paradigm shift in the diagnostic work-up of rare haemolytic anaemias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2018-205018DOI Listing
July 2018

Harnessing genomics to improve outcomes for women with cancer in India: key priorities for research.

Lancet Oncol 2018 02;19(2):e102-e112

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; Centre for Computational Biology, University of Birmingham, Birmingham, UK.

Cumulatively, breast, cervical, ovarian, and uterine cancer account for more than 70% of cancers in women in India. Distinct differences in the clinical presentation of women with cancer suggest underlying differences in cancer biology and genetics. The peak age of onset of breast and ovarian cancer appears to be a decade earlier in India (age 45-50 years) than in high-income countries (age >60 years). Understanding these differences through research to develop diagnosis, screening, prevention, and treatment frameworks that ar e specific to the Indian population are critical and essential to improving women's health in India. Since the sequencing of the human genome in 2001, applications of advanced technologies, such as massively parallel sequencing, have transformed the understanding of the genetic and environmental drivers of cancer. How can advanced technologies be harnessed to provide health-care solutions at a scale and to a budget suitable for a country of 1·2 billion people? What research programmes are necessary to answer questions specific to India, and to build capacity for innovative solutions using these technologies? In order to answer these questions, we convened a workshop with key stakeholders to address these issues. In this Series paper, we highlight challenges in tackling the growing cancer burden in India, discuss ongoing genomics research and developments in infrastructure, and suggest key priorities for future research in cancer in India.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(17)30726-XDOI Listing
February 2018

First report of Mediterranean stomatocytosis/macrothrombocytopenia in an Indian family: a diagnostic dilemma.

Pathology 2017 Dec 26;49(7):811-815. Epub 2017 Oct 26.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pathol.2017.06.010DOI Listing
December 2017

Whole genome DNA methylation profiling of oral cancer in ethnic population of Meghalaya, North East India reveals novel genes.

Genomics 2018 03 7;110(2):112-123. Epub 2017 Sep 7.

Department of Zoology, North Eastern Hill University (NEHU), Shillong, India. Electronic address:

Oral Squamous Cell Carcinoma (OSCC) is a serious and one of the most common and highly aggressive malignancies. Epigenetic factors such as DNA methylation have been known to be implicated in a number of cancer etiologies. The main objective of this study was to investigate physiognomies of Promoter DNA methylation patterns associated with oral cancer epigenome with special reference to the ethnic population of Meghalaya, North East India. The present study identifies 27,205 CpG sites and 3811 regions that are differentially methylated in oral cancer when compared to matched normal. 45 genes were found to be differentially methylated within the promoter region, of which 38 were hypermethylated and 7 hypomethylated. 14 of the hypermethylated genes were found to be similar to that of the TCGA-HNSCC study some of which are TSGs and few novel genes which may serve as candidate methylation biomarkers for OSCC in this poorly characterized ethnic group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygeno.2017.09.002DOI Listing
March 2018

Analysis of the whole transcriptome from gingivo-buccal squamous cell carcinoma reveals deregulated immune landscape and suggests targets for immunotherapy.

PLoS One 2017 8;12(9):e0183606. Epub 2017 Sep 8.

Human Genetics Unit, Indian Statistical Institute, Kolkata, India.

Background: Gingivo-buccal squamous cell carcinoma (GBSCC) is one of the most common oral cavity cancers in India with less than 50% patients surviving past 5 years. Here, we report a whole transcriptome profile on a batch of GBSCC tumours with diverse tobacco usage habits. The study provides an entire landscape of altered expression with an emphasis on searching for targets with therapeutic potential.

Methods: Whole transcriptomes of 12 GBSCC tumours and adjacent normal tissues were sequenced and analysed to explore differential expression of genes. Expression changes were further compared with those in TCGA head and neck cohort (n = 263) data base and validated in an independent set of 10GBSCC samples.

Results: Differentially expressed genes (n = 2176) were used to cluster the patients based on their tobacco habits, resulting in 3 subgroups. Immune response was observed to be significantly aberrant, along with cell adhesion and lipid metabolism processes. Different modes of immune evasion were seen across 12 tumours with up-regulation or consistent expression of CD47, unlike other immune evasion genes such as PDL1, FUT4, CTLA4 and BTLA which were downregulated in a few samples. Variation in infiltrating immune cell signatures across tumours also indicates heterogeneity in immune evasion strategies. A few actionable genes such as ITGA4, TGFB1 and PTGS1/COX1 were over expressed in most samples.

Conclusion: This study found expression deregulation of key immune evasion genes, such as CD47 and PDL1, and reasserts their potential as effective immunotherapeutic targets for GBSCC, which requires further clinical studies. Present findings reiterate the idea of using transcriptome profiling to guide precision therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590820PMC
October 2017

Next-generation sequencing unravels homozygous mutation in glucose-6-phosphate isomerase, GPIc.1040G>A (p.Arg347His) causing hemolysis in an Indian infant.

Clin Chim Acta 2017 May 20;468:81-84. Epub 2017 Feb 20.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address:

Introduction: Inherited anemias diagnostic workup requires a step-wise algorithm. Causal genes implicated in congenital hemolytic anemia are numerous, making a gene-by-gene approach by Sanger sequencing time consuming, expensive and labour intensive. Targeted resequencing can be of great use in explaining these cases.

Methodology: Six months female presented with neonatal jaundice and negative family history. Clinical and laboratory evidences were suggestive of hemolytic anemia. G6PD deficiency, thalassemias, hemoglobinopathies, autoimmune hemolytic anemia, hereditary spherocytosis and pyruvate kinase deficiency were excluded. Targeted resequencing on Illumina MiSeq using TruSight One sequencing panel was performed to identify the causative mutations.

Results: 35-40% of RBCs were acanthocytes and echinocytes. A missense homozygous mutation was found inglucose-6-phosphate isomerase, GPI [c.1040G>A (p.Arg347His), rs137853583] which results in nonspherocytic hemolytic anemia.

Conclusion: This study describes GPI p.Arg347His mutation for the first time from India and is the first report of red cell GPI deficiency diagnosed using NGS-based resequencing and highlights the potential of this technique in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cca.2017.02.012DOI Listing
May 2017

Sebum and Hydration Levels in Specific Regions of Human Face Significantly Predict the Nature and Diversity of Facial Skin Microbiome.

Sci Rep 2016 10 27;6:36062. Epub 2016 Oct 27.

National Institute of Biomedical Genomics, Kalyani, West Bengal, India.

The skin microbiome varies across individuals. The causes of these variations are inadequately understood. We tested the hypothesis that inter-individual variation in facial skin microbiome can be significantly explained by variation in sebum and hydration levels in specific facial regions of humans. We measured sebum and hydration from forehead and cheek regions of healthy female volunteers (n = 30). Metagenomic DNA from skin swabs were sequenced for V3-V5 regions of 16S rRNA gene. Altogether, 34 phyla were identified; predominantly Actinobacteria (66.3%), Firmicutes (17.7%), Proteobacteria (13.1%) and Bacteroidetes (1.4%). About 1000 genera were identified; predominantly Propionibacterium (58.6%), Staphylococcus (8.6%), Streptococcus (4.0%), Corynebacterium (3.6%) and Paracoccus (3.3%). A subset (n = 24) of individuals were sampled two months later. Stepwise multiple regression analysis showed that cheek sebum level was the most significant predictor of microbiome composition and diversity followed by forehead hydration level; forehead sebum and cheek hydration levels were not. With increase in cheek sebum, the prevalence of Actinobacteria (p = 0.001)/Propionibacterium (p = 0.002) increased, whereas microbiome diversity decreased (Shannon Index, p = 0.032); this was opposite for other phyla/genera. These trends were reversed for forehead hydration levels. Therefore, the nature and diversity of facial skin microbiome is jointly determined by site-specific lipid and water levels in the stratum corneum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep36062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081537PMC
October 2016

Genetic epidemiology of coronary artery disease: an Asian Indian perspective.

J Genet 2015 Sep;94(3):539-49

Functional Genomics Thrombosis Research Institute, Bengaluru 560 099,

Coronary artery disease (CAD) has emerged as a major cause of morbidity and mortality worldwide. Recent findings on the role of genetic factors in the aetiopathology of CAD have implicated novel genes and variants in addition to those involved in lipid and lipoprotein metabolism. However, our present knowledge is limited due to lack of clarity on their exact identity and the quantum of impact on disease susceptibility, and incident risk. It is a matter of great interest to understand the role of genetic factors in ethnic populations that have a strong underlying predisposition to CAD such as the South Asian populations, particularly among Asian Indians living in India and abroad. Although, a number of isolated studies do implicate certain gene polymorphisms towards enhanced disease susceptibility, the available data remains scanty and inconclusive as they have not been validated in large, prospective cohorts. The present review aims to consolidate the available literature on the genetics of CAD in Asian Indians and seeks to provide insights on the concerns that need to be addressed in future studies to generate information having clinical value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12041-015-0547-4DOI Listing
September 2015

Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM.

Sci Rep 2015 Jan 21;5:7915. Epub 2015 Jan 21.

National Institute of Biomedical Genomics, Kalyani, West Bengal 741251, India.

Neoplastic cells of Glioblastoma multiforme (GBM) may or may not show sustained response to temozolomide (TMZ) chemotherapy. We hypothesize that TMZ chemotherapy response in GBM is predetermined in its neoplastic clones via a specific set of mutations that alter relevant pathways. We describe exome-wide enrichment of variant allele frequencies (VAFs) in neurospheres displaying contrasting phenotypes of sustained versus reversible TMZ-responses in vitro. Enrichment of VAFs was found on genes ST5, RP6KA1 and PRKDC in cells showing sustained TMZ-effect whereas on genes FREM2, AASDH and STK36, in cells showing reversible TMZ-effect. Ingenuity pathway analysis (IPA) revealed that these genes alter cell-cycle, G2/M-checkpoint-regulation and NHEJ pathways in sustained TMZ-effect cells whereas the lysine-II&V/phenylalanine degradation and sonic hedgehog (Hh) pathways in reversible TMZ-effect cells. Next, we validated the likely involvement of the Hh-pathway in TMZ-response on additional GBM neurospheres as well as on GBM patients, by extracting RNA-sequencing-based gene expression data from the TCGA-GBM database. Finally, we demonstrated TMZ-sensitization of a TMZ non-responder neurosphere in vitro by treating them with the FDA-approved pharmacological Hh-pathway inhibitor vismodegib. Altogether, our results indicate that the Hh-pathway impedes sustained TMZ-response in GBM and could be a potential therapeutic target to enhance TMZ-response in this malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep07915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300501PMC
January 2015

Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival.

Nat Commun 2014 Dec 17;5:5835. Epub 2014 Dec 17.

National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.

The arachidonic acid metabolism (AAM) pathway promotes tumour progression. Chemical inhibitors of AAM pathway prolong post-treatment survival of cancer patients. Here we test whether non-synonymous somatic mutations in genes of this pathway, acting as natural inhibitors, increase post-treatment survival. We identify loss-of-function somatic mutations in 15 (18%) of 84 treatment-naïve oral cancer patients by whole-exome sequencing, which we map to genes of AAM pathway. Patients (n = 53) who survived ≥ 12 months after surgery without recurrence have significantly (P = 0.007) higher proportion (26% versus 3%) of mutations than those who did not (n = 31). Patients with mutations have a significantly (P = 0.003) longer median disease-free survival (24 months) than those without (13 months). Compared with the presence of a mutation, absence of any mutation increases the hazard ratio for death (11.3) significantly (P = 0.018). The inferences are strengthened when we pool our data with The Cancer Genome Atlas (TCGA) data. In patients with AAM pathway mutations, some downstream pathways, such as the PI3K-Akt pathway, are downregulated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms6835DOI Listing
December 2014
-->