The role of delta like non-canonical Notch ligand 1 (DLK1) in cancer

Delta like non-canonical Notch ligand 1 (DLK1) is a cleavable single-pass transmembrane protein and a member of the Notch/Delta/Serrate family. It is paternally expressed and belongs to a group of imprinted genes located on chromosome band 14q32 in humans and 12qF1 in mice. DLK1 is expressed in many human tissues during embryonic development but in adults expression is low and is mostly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells (notably hepatoblasts). However, DLK1 is expressed at a high frequency in many common malignancies (liver, breast, brain, pancreas, colon and lung). More recently, high levels of expression have been identified in endocrine related cancers such as ovarian and adrenocortical carcinoma. There is growing evidence that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells. Although the exact mechanism through which DLK1 functions is not fully understood, it is known to maintain cells in an undifferentiated phenotype and has oncogenic properties. These effects are partly exacted through interaction with the Notch signalling pathway. In this review, we have detailed the functional role of DLK1 within physiology and malignancy and posit a mechanism for how it exacts its oncogenic effects. In describing the expression of DLK1 in cancer and in healthy tissue, we have highlighted the potential for its use both as a biomarker and as a potential therapeutic target.

A de novo 10q11.23q22.1 deletion detected by whole genome mate-pair sequencing: a case report

Background Interstitial deletions of chromosome band 10q11-q22 was a genomic disorder distinguished by developmental delay, congenital cleft palate and muscular hypotonia. The phenotypes involved were heterogeneous, hinge on the variable breakpoints and size. Case presentation Here, we presented a patient with soft palate cleft, growth and development delay. The patient was a 2 years and 5 months girl who was not able to walk unless using a children’s crutches to support herself. Whole-exome sequencing (WES) and whole-genome mate-pair sequencing (WGMS) were both performed by next generation sequencing (NGS). A 20.76 Mb deletion at 10q11.23q22.1 (seq[GRCh37/hg19]del(10)(50,319,387-71,083,899) × 1) was revealed by the WGMS, which was verified as de novo by quantitative polymerase chain reaction (QPCR). Conclusion Children with 10q11-q22 deletions greater than 20 MB have never been reported before, and we are the first to report and provide a detailed clinical phenotype, which brings further knowledge of 10q11-q22 deletions.

An analysis on the divergence of Chironomid spp. based on the study of 18S rRNA and polytene chromosome organization in the species revealing the role of environment on speciation

Background Nine species of Chironomus evolved throughout the world were measured for their divergence with regard to their DNA sequences concerning 18S rRNA since it is conserved for a specific species. With the advancement of the field of molecular evolution, cytogenetics requires further correlation between molecular architecture and morphological features of a species to compare amongst others to decipher their role in speciation. Therefore, divergence of DNA sequences of the Chironomus were compared with differences in the polytene chromosome features of most of the species under this investigation to evaluate underlying correlation among them, if any, to finally establish a novel method of molecular classification broadly applicable in cytogenetics studies. Results When Chironomus javanus Kieffer was considered as a reference organism, an in silico pair-wise alignment of sequences for the 18S rRNA gene regions of the other eight different species of the same genus exhibited nucleotide sequence homology ranging from 67 to 98%. This divergence of the species under consideration might be due to environmental impact causing alteration of nitrogenous bases probably due to mismatch pairing in DNA replication. This may be suggested as a cause of evolution of species in nature. A concomitant study on the polytene chromosome band patterns of majority of these species belonging to this series also indicated a divergence ranging from 10% to 30%. Conclusions Sequence analysis based on 18S rRNA of nine species of Chironomus under this investigation shows a similarity in the polytene chromosome organization in most of the Chironomid species of the series. Hence, molecular divergence in the species is consistent with cytological difference among Chironomid species. Therefore, molecular data based on 18S rRNA and cytological characters based on the polytene chromosome features of the Chironomid species may be useful for their taxonomical recognition. Moreover, variations concerning two aspects of this study may be correlated to their environmental distinctions.

A UVB-responsive common variant at chr7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor gene (AHR)

Genome-wide association studies have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP, and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). As ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWAS identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor gene (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. As AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus, and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression, and altering melanocyte growth phenotypes upon exposure.

A Gene-Based Method for Cytogenetic Mapping of Repeat-Rich Mosquito Genomes

Long-read sequencing technologies have opened up new avenues of research on the mosquito genome biology, enabling scientists to better understand the remarkable abilities of vectors for transmitting pathogens. Although new genome mapping technologies such as Hi-C scaffolding and optical mapping may significantly improve the quality of genomes, only cytogenetic mapping, with the help of fluorescence in situ hybridization (FISH), connects genomic scaffolds to a particular chromosome and chromosome band. This mapping approach is important for creating and validating chromosome-scale genome assemblies for mosquitoes with repeat-rich genomes, which can potentially be misassembled. In this study, we describe a new gene-based physical mapping approach that was optimized using the newly assembled Aedes albopictus genome, which is enriched with transposable elements. To avoid amplification of the repetitive DNA, 15 protein-coding gene transcripts were used for the probe design. Instead of using genomic DNA, complementary DNA was utilized as a template for development of the PCR-amplified probes for FISH. All probes were successfully amplified and mapped to specific chromosome bands. The genome-unique probes allowed to perform unambiguous mapping of genomic scaffolds to chromosome regions. The method described in detail here can be used for physical genome mapping in other insects.

Effects of Ionizing Radiation on Chromosome Replication and its Modification by HDAC Inhibitors

Ionizing radiation causes lethal injuries either directly or indirectly inducing damage to the biological macromolecules, most importantly the genetic material or DNA. Cells transiently halt their cell cycle progression to provide sufficient time for repair machinery to act on for the repair of radiation-induced DNA damages. This may include delay in replication or S-phase of cell cycle besides activating other cell cycle checkpoints. Multiple replicons (replicon cluster equivalent to a chromosome band) along the length of a chromosome fire in a definite pattern for the timely completion of replication. Histone deacetylase inhibitors (HDACi) have been shown to alter the pattern of DNA replication origin activity including earlier replication in S-phase of normally late replicating chromosome bands. This may also indicate an acceleration of repair steps since DNA damage acts as an impediment for replication. Trichostatin A (TSA), a well-known HDACi, was studied for its effect on replication initiation using Indian Muntjac cell as a model. It was found that TSA treatment enhanced the replication rate and increased the number of replicon clusters firing at any given time per chromosome. It also compensated the decline of replication rate in irradiated cells, helped in their revival and brought them to the control level.

P53 and the Carcinoma of the Breast: A Review

TP53 is a gene and p53 is its product protein. Since its discovery many studies have looked into its function and its role in cancer. It is not only involved in the induction of apoptosis but is also, a key player, in cell cycle regulation, development, differentiation, gene amplification, DNA recombination, chromosomal segregation and cellular senescence and so, it is called “the guardian of genome”. The human TP53 gene spans 20kb on chromosome band 17p13.1. The biological functions of p53 are apoptosis, senescence and cell migration. The evolution of a normal cell towards a cancerous one is a complex process. Tumorogenesis is considered to endow, the evolving tumor with, self-sufficiency of growth signals, insensitivity to antigrowth signals, evasion from programmed cell death, unlimited replicative potentials and finally the ability to invade and metastasize. TP53 may be considered as the “ultimate tumor suppressor gene”. Its oncogenic activity is attributed to loss of function, dominant negative (DN) oncogenic properties and activities of mutant p53. In breast cancer its oncogenic function is due to p53 mutation, changes in- upstream regulatory pathways, in p53 transcriptional target genes, in p53 co-activators, and/or involvement of other family members of p53 family like p63 and p73. The p53 mutation is present in only in about 20% of breast cancers, but when present, they entail the worst prognosis. This interesting paper is a review and discussion about role of p53 in carcinoma breast.

Inflammatory Myofibroblastic Tumor of the Breast: A Case Report

Inflammatory myofibroblastic tumors (IMTs) of the breast are extremely uncommon lesions, usually labelled as a subgroup of inflammatory pseudotumors. They are composed of inflammatory cells and bland spindle cells without nuclear atypia. Nearly half of all IMTs of the breast include clonal translocation of the anaplastic lymphoma kinase (ALK) gene, located at the chromosome band 2p23, and generally present with a palpable lump, swelling, and pain. Herein, we present a 66-year-old female patient with pain, swelling and a palpable lump in her right breast. A 40×26 mm sized T1A hypointense and T2A hyperintense mass with slightly lobulated margins was detected at breast magnetic resonance imaging. A mass associated with an intramammary lymph node was evaluated in the upper inner quadrant of the right breast via mammography. The results were considered as BI-RADS 3. Breast-conserving surgery with sentinel lymph node biopsy was performed. During pathological evaluation, cytoplasm with poorly-defined margins, and large-nucleoli tumor cells with benign ducts between these tumor cells, were observed. Intensive inflammatory cell infiltration and sclerotic changes in different areas were also noted. The lesion stained positive for caldesmon, smooth muscle actin, vimentin, CD10, and S100; however, it was negative for ALK on immunohistochemistry. The patient remained disease-free after the surgical procedure.International Journal of Human and Health Sciences Vol. 04 No. 04 October’20 Page : 305-308

MON-917 Carney Complex Due to a Contiguous Gene Deletion Syndrome (17q24.2-17q24.3)

Background While genomic rearrangements of chromosome 17 are not uncommon, deletions of chromosome band 17q24.2-q24.3 are rare, and associated features include cardiac abnormalities, characteristic facial appearance, short stature, obesity, syndactyly, intellectual disability, seizures, delayed dentition, and features of Carney Complex. It has been suggested that the involvement of KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A genes contribute to this phenotype. A case of a child with a 3.7 Mb deletion at chromosome band 17q24.2-q24.3, as well as a 2.1 Mb gain at chromosome 17q22, is described. Clinical Case A now 6 year old female was born at 34 weeks gestational age with prenatal course complicated by oligohydramnios and intrauterine growth restriction. Birth weight was at the 9th percentile, and birth length was at the 92nd percentile. She was noted to have a patent ductus arteriosus (PDA), poor suck and swallow, and dysmorphic features. Chromosome microarray revealed a 3.7 Mb deletion at Chromosome 17q24.2-q24.3, involving KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A, as well as a 2.1 Mb gain at Chromosome 17q22, involving C17orf112 and KIP2B. At 6 years old, she continues to be small for weight (-4.5 SDs), BMI (-4.22 SDs), and height (-2.5 SDs), though with appropriate pre-pubertal linear growth velocity. She is minimally verbal and continues to receive physical, occupational and speech therapies. Examination showed dysmorphic facial features, including triangular face with pointed chin, prominent forehead with low-set ears, retro-micrognathia, almond-shaped eyes with up-slanting palpebral fissures, bulbous nose, thin lips, and irregularly-shaped teeth. She had bilateral 5th digit clinodactyly, tapering of the distal aspects of bilateral first digits of the hands, and syndactyly of bilateral 2nd/3rd digits of the feet. She had scant freckling over the nasal bridge and cheeks, as well as freckles of the left arm, left groin, and back. She had no clinical stigmata of hypercortisolism. Echocardiogram continues to show a PDA with no cardiac myxomas. Thyroid ultrasound was normal. However, she does have mild hypercalcemia, most recently 2.61 mmol/L (2.15-2.55), and mildly elevated alkaline phosphatase of 341 U/L (96-297). Conclusion This case highlights a child with many of the previously reported findings associated with 17q24.2-q24.3 deletions. However, she also was noted to have a 2.1 Mb gain at chromosome 17q22 involving C17orf112 and KIP2B genes, which have not yet been associated with a clinical phenotype. It is therefore unclear if her phenotype is partially explained by the chromosomal gain. Clinicians should suspect a contiguous gene deletion syndrome in a patient with Carney Complex and atypical features. Patients with this condition have also been described as “Carney Complex-plus”, a term that we do not recommend be used.