Surgical Tumor Resection Deregulates Hallmarks of Cancer in Resected Tissue and the Surrounding Microenvironment.

Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers. IMPLICATIONS: Surgery deregulates hallmarks of cancer in human tissue.

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation.

BACKGROUND AND AIM: Molecular mechanism of translocation and outcome in variant chronic myeloid leukaemia (vCML) has been a topic of debate. While several cytogenetic studies suggest a low response to Imatinib Mesylate, others demonstrate a similar disease course in both classical and vCML. Besides, many studies comprehensively also link tyrosine kinase domain (TKD) mutations with aggressive clinical outcome. Thus, we aim to study the molecular mechanism of translocation, identify the third partner chromosomes and comment on the disease course and clinical outcome. METHOD: We cytogenetically characterised 25 vCML cases to determine the third partner chromosome, mechanism of translocation and prognostic outcome. We also compared vCML cases with and without TKD mutation to most appropriately outline the clinical consequence and ascertain the potent cause of unresponsiveness to treatment. RESULTS: Third partner chromosome in variant translocation was defined by conventional and molecular cytogenetics. Although in our study most cases showed inadequate clinical response attributable to TKD mutation rather than variant translocation, we observed an inferior outcome in cases involving chromosome 5 as the third partner. CONCLUSION: Thus, we conclude that characterising and reporting new cases of variant translocations, involving various different chromosomes as third partner (with different breakpoints) by cytogenetics, will lead to a better understanding of the disease. To the best of our knowledge, this kind of delineate study has not been applied to precisely comment on the prospects of cytogenetically characterised vCML.

Importance of conventional cytogenetics in the identification of ins(19;X)(q13.1;p11.2q28) and t(1;11)(q10;p10), both, novel cytogenetic abnormalities in a pediatric AML case.

Acute Myeloid Leukemia (AML) is a heterogeneous disease with respect to morphology, immunophenotype, chromosomal abnormalities and genetic lesions. While a majority of AML cases harbour recurrent chromosomal abnormalities, several rare, apparently unique or novel aberrations may be identified by conventional cytogenetics. In fact, with the prognostic relevance of chromosomal abnormalities, and with the advent of new-age, target-specific therapy, identifying such aberrations becomes vital. In this study, we present a case of pediatric AML with ins(19;X)(q13.1;p11.2q28) and t(1;11)(q10;p10), both, novel, previously unreported chromosomal abnormalities in AML. Post induction, both these clonal cytogenetic abnormalities persisted. The documentation of this case will help determine the significance of these cytogenetic abnormalities. Also, this case exemplifies the importance of cytogenetics in the complete characterization and risk stratification of AML patients.

Investigating the clinical, hematological and cytogenetic profile of endoreduplicated hypodiploids in BCP-ALL.

Ploidy, besides known translocations in lymphoblasts, is a strong predictor of prognosis in B- cell progenitor acute lymphoblastic leukemia (BCP-ALL). While hyperdiploidy with >50 chromosomes shows a favourable outcome, hypodiploidy with <45 chromosomes have a dismal clinical outcome. However, there exists a small subset where both the hypodiploid and hyperdiploid clones are apparent either by cytogenetics or flow cytometry and are defined partially masked hypodiploids or mosaics based on the percentage of clonal population. These patients are essentially hypodiploids, and show the hyperdiploid clone as a consequence of endoreduplication of the primary hypodiploid clone- A phenomenon of successive replication of genome without mitosis (cytokinesis) resulting in increased ploidy. In the current study, we present the complete clinical, hematological and cytogenetic profile of 11 such newly diagnosed mosaics or partially masked hypodiploid BCP-ALL cases.

Isoderivative chromosome 17 with multiple copies of RARα-PML fusions and Tp53 deletion in a rare case of APML.

Acute Promyelocytic Leukemia (APML) is a malignancy of cells in myeloid lineage. It is a neoplasm described by proliferation and accumulation of immature neutrophils called promyelocytes in the bone marrow, inhibiting normal cell production, which results in lower numbers of blood cells circulating the body. A minor but significant proportion of patients with APML harbor complex and cryptic rearrangements. Presence of isoderivative 17 with t(15;17) is very rare. We report a case of adult APML with amplification of RARα/PML fusion protein, a consequence of isoderivative 17 with duplication of normal chromosome 15 and 17 and Tp53 deletion on derivative 17. Immunophenotyping by flow cytometry, presence of pancytopenia and epistaxis helped classify the patient as APML. FISH was used for confirmation of the same and indicated involvement of additional abnormalities.

dic(7;9)(p11.1;p11.1) and del(7)(q36) as a Primary Abnormality in Childhood B-cell Precursor ALL: A Case Report.

OBJECTIVES: B-cell acute lymphoblastic leukemia is the clonal proliferation of B-lymphoblasts, primarily in the blood and bone marrow. The morphology of these cells is largely of L1 or L2 type according to French-American-British (FAB) classification. Molecular cytogenetic testing remains the gold standard technique for genetic classification of ALL along with molecular tests. Here we describe a case of pediatric B-ALL with dic(7;9)(p11.1;p11.1) and deletion of CUL1 (7q36) as a primary abnormality. Although both 7p and 9p deletions are associated with poor prognosis, the patient responded well to standard risk induction therapy. The abnormalities were identified by conventional karyotype and fluorescence in situ hybridization. Response to treatment was assessed by monitoring minimal residual disease.