The mechanisms of human lymphoid chromosomal translocations and their medical relevance

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

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Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

Cancers ◽

10.3390/cancers13102359 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2359

Author(s):

Liliana Montella ◽

Lucia Altucci ◽

Federica Sarno ◽

Carlo Buonerba ◽

Stefano De Simone ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcomas ◽

Chromosomal Translocations ◽

Intrinsic Variability ◽

Poor Survival ◽

Genomic Alterations ◽

Future Directions ◽

Oncogenic Mutations ◽

Targeted Treatments ◽

Innovative Therapies

Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.

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Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas

Cell Death and Disease ◽

10.1038/s41419-021-03548-4 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Xiaohong Pu ◽

Qing Ye ◽

Jing Cai ◽

Xin Yang ◽

Yao Fu ◽

...

Keyword(s):

Targeted Therapy ◽

Bile Duct ◽

Kinase Inhibitors ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Chromosomal Translocations ◽

Small Bile Duct ◽

Druggable Targets ◽

Inhibitor Treatment ◽

Specific Inhibitors

AbstractChromosomal translocations involving fibroblast growth factor receptor 2 (FGFR2) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets. However, predicting the sensitivity of FGFR2 fusions to FGFR kinase inhibitors is crucial to the prognosis of the ICC-targeted therapy. Here, we report identification of nine FGFR2 translocations out of 173 (5.2%) ICC tumors. Although clinicopathologically these FGFR2 translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct. We show that the protein products of FGFR2 fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains (n = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain (n = 1); and the non-classical fusions that lack both the TK and Ig-like domains (n = 2). We demonstrate that cholangiocarcinoma cells engineered to express the classical and sub-classical fusions show sensitivity to FGFR-specific kinase inhibitors as evident by the suppression of MAPK/ERK and AKT/PI3K activities following the inhibitor treatment. Furthermore, the kinase-deficient mutant of the sub-classical fusion also lost its sensitivity to the FGFR-specific inhibitors. Taken together, our study suggests that it is essential to determine the breakpoint and type of FGFR2 fusions in the small bile duct subtype of ICC for the targeted treatment.

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Chromosomal translocations inactivating CDKN2A support a single path for malignant peripheral nerve sheath tumor initiation

Human Genetics ◽

10.1007/s00439-021-02296-x ◽

2021 ◽

Author(s):

Miriam Magallón-Lorenz ◽

Juana Fernández-Rodríguez ◽

Ernest Terribas ◽

Edgar Creus-Batchiller ◽

Cleofe Romagosa ◽

...

Keyword(s):

Peripheral Nerve ◽

Chromosomal Translocations ◽

Nerve Sheath Tumor ◽

Tumor Initiation ◽

Peripheral Nerve Sheath Tumor ◽

Nerve Sheath ◽

Single Path

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Pursuing Medical Relevance: A Crucial Role for the Clinical Laboratory Scientist--From a Focus on Analytical Performance to One on Medical Outcome. Proceedings of the 18th annual Arnold O. Beckman Conference on Clinical Chemistry. Charleston, South Carolina, February 5-6, 1995

Clinical Chemistry ◽

10.1093/clinchem/41.8.1209 ◽

1995 ◽

Vol 41 (8) ◽

pp. 1209-1210 ◽

Cited By ~ 1

Keyword(s):

South Carolina ◽

Crucial Role ◽

Clinical Laboratory ◽

Clinical Chemistry ◽

Analytical Performance ◽

Medical Outcome ◽

Laboratory Scientist ◽

Medical Relevance

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Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation

International Journal of Molecular Sciences ◽

10.3390/ijms22031146 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1146

Author(s):

Reinhard Ullmann ◽

Benjamin Valentin Becker ◽

Simone Rothmiller ◽

Annette Schmidt ◽

Horst Thiermann ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Line ◽

Copy Number ◽

Resistant Cell ◽

Resistant Cell Line ◽

Chromosomal Translocations ◽

Dna Copy Number ◽

Mutational Signatures ◽

Copy Number Changes ◽

And Oxidative Stress

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.

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