COVID-19 pandemic is a major human tragedy. Worldwide, SARS-CoV-2 has already infected over 3 million and has killed about 230,000 people. SARS-CoV-2 originated in China and, within three months, has evolved to an additional 10 subtypes. One particular subtype with a non-silent (Aspartate to Glycine) mutation at 614 th position of the Spike protein (D614G) rapidly outcompeted other preexisting subtypes, including the ancestral. We assessed that D614G mutation generates an additional serine protease (Elastase) cleavage site near the S1-S2 junction of the Spike protein. We also identified that a single nucleotide deletion (delC) at a known variant site (rs35074065) in a cis-eQTL of TMPRSS2, is extremely rare in East Asians but is common in Europeans and North Americans. The delC allele facilitates entry of the 614G subtype into host cells, thus accelerating the spread of 614G subtype in Europe and North America where the delC allele is common. The delC allele at the cis-eQTL locus rs35074065 of TMPRSS2 leads to overexpression of both TMPRSS2 and a nearby gene MX1. The cis-eQTL site, rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.

SARS-CoV-2 was first reported from China. Within three months, it evolved to 10 additional subtypes. Two evolved subtypes (A2 and A2a) carry a non-synonymous Spike protein mutation (D614G). We conducted phylodynamic analysis of over 70,000 SARS-CoV-2 coronaviruses worldwide, sequenced until July2020, and found that the mutant subtype (614G) outcompeted the pre-existing type (614D), significantly faster in Europe and North-America than in East Asia. Bioinformatically and computationally, we identified a novel neutrophil elastase (ELANE) cleavage site introduced in the G-mutant, near the S1-S2 junction of the Spike protein. We hypothesised that elevation of neutrophil elastase level at the site of infection will enhance the activation of Spike protein thus facilitating host cell entry for 614G, but not the 614D, subtype. The level of neutrophil elastase in the lung is modulated by its inhibitor α1-antitrypsin (AAT). AAT prevents lung tissue damage by elastase. However, many individuals exhibit genotype-dependent deficiency of AAT. AAT deficiency eases host-cell entry of the 614G virus, by retarding inhibition of neutrophil elastase and consequently enhancing activation of the Spike protein. AAT deficiency is highly prevalent in European and North-American populations, but much less so in East Asia. Therefore, the 614G subtype is able to infect and spread more easily in populations of the former regions than in the latter region. Our analyses provide a molecular biological and evolutionary model for the higher observed virulence of the 614G subtype, in terms of causing higher morbidity in the host (higher infectivity and higher viral load), than the non-mutant 614D subtype.

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.

A thickened, white patch — leukoplakia — in the oral cavity is usually benign, but sometimes (in ~9% of individuals) it progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues — leukoplakia, tumour, adjacent normal, and blood — from each of 28 patients suffering from gingivobuccal oral cancer. We performed multiomics analysis of the 112 collected tissues (four tissues per patient from 28 patients) and integrated information on progressive changes in the mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole‐exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Nonsynonymous somatic mutations in the CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co‐occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favour lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal‐instability (arm‐level deletions of 19p and q, focal‐deletion of DNA‐repair pathway genes and NOTCH1, amplification of EGFR) (77%), and increased APOBEC‐activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact immune‐dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T‐cells (56%), depletion of cytotoxic T‐cells (68%), and antigen‐presenting dendritic cells (72%), with a concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (range: 4–10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Oral cancer is highly prevalent in India and is the most frequent cancer type among Indian males. It is also very common in southeast Asia. India has participated in the International Cancer Genome Consortium (ICGC) and some national initiatives to generate large-scale genomic data on oral cancer patients and analyze to identify associations and systematically catalog the associated variants. We have now created an open, web-accessible database of these variants found significantly associated with Indian oral cancer patients, with a user-friendly interface to enable easy mining. We have value added to this database by including relevant data collated from various sources on other global populations, thereby providing opportunities of comparative geographical and/or ethnic analyses. Currently, no other database of similar nature is available on oral cancer. We have developed Database of GENomic Variants of Oral Cancer, a browsable online database framework for storage, retrieval and analysis of large-scale data on genomic variants and make it freely accessible to the scientific community. Presently, the web-accessible database allows potential users to mine data on ∼24 million clinically relevant somatic and germline variants derived from exomes (n = 100) and whole genomes (n = 5) of Indian oral cancer patients; all generated by us. Variant data from The Cancer Genome Atlas and data manually curated from peer-reviewed publications were also incorporated into the database for comparative analyses. It allows users to query the database by a single gene, multiple genes, multiple variant sites, genomic region, patient ID and pathway identities. Database URL: http://research.nibmg.ac.in/dbcares/dbgenvoc/

Introduction: Components of immune system communicate extensively in tumour micro environment. Normally, immune system engages with tumours to inhibit its further progression. Simultaneously, cancer cells learn cues derived from immune system to its own growth advantage. Cytokines are cell signaling messengers that affect disease pathogenesis, non-specific response to infection, specific response to antigen, etc. A battery of cytokines are produced in the tumour microenvironment, when released in response to infections and inflammations, can function to inhibit tumour development and progression. Cancer cells also release cytokines that promote growth, extenuate apoptosis and perform invasion and metastasis.Hypothesis: Alterations in cytokine signaling genes might help tumour to misguide immune system. The aim of the study is to identify such genomic alterations in cytokine genes that may drive major human cancers. Methods:We did extensive literature survey to prepare a list of known cytokine genes (n=776) which were validated in multiple databases. To know the baseline DNA variation in cytokine genes, we analyzed DNA variations in healthy human population from the 1000 Genome project dataset. Somatic mutational landscape for cytokine genes were analyzed in 32 different human cancer types (TCGA data). Significantly mutated genes were detected using MutSig2CV and Oncodrive FM analysis. Genes found significant in both analysis were tabulated. Standard statistical and bioinformatics analysis were done further to identify putative driver events. Result:We detected 9 significantly mutated cytokine genes across major tumor types. EDN1 was found to be most significantly mutated, in multiple tumour types; apart from genes like CDH1,

Whole genome copy number alterations, targeted gene-panel and RNA sequencing were used to investigate differences in high hyperdiploid (HH) B-cell acute lymphoblastic leukemia (ALL), with and without whole chromosome uniparental isodisomy (wUPD). Patients with wUPD demonstrated a higher modal number of chromosomes with gains of chromosome 5. Mutations in genes within epigenetic pathways with upregulation of genes involved in cellular response to stress and stimuli were seen in wUPD, in contrast to mutations in RAS/RTK pathways and upregulation of genes in RNA Polymerase III pathway in noUPD. AP-1 transcription factors and NUDT18, potentially implicated in thiopurine drug resistance, were upregulated in wUPD. wUPD was associated with female gender, higher presenting white cell count and lower end of induction minimal residual disease levels, though survival rates were similar in the two groups. Genome-wide differences in HH ALL with and without UPD suggest plausible biological explanations for the heterogeneity in therapeutic response.