Cytogenetics and genetics of human cancer: methods and accomplishments

Cytogenetic and related changes in human cancer constitute part of a constantly developing and enlarging continuum of known genetic alterations associated with cancer development and biology. The cytogenetic component of this continuum has fulfilled much of its pioneering role and now constitutes a small but dynamic segment of the vast literature on cancer genetics, in which it has played an important if not initiating role. The goals of this article are (a) to address historical and methodological aspects of cancer cytogenetics; (b) to present information on diagnostic translocations in leukemias, lymphomas, bone and soft tissue tumors, and carcinomas; (c) to connect some of these chromosomal aberrations with their molecular equivalents; and (d) to describe anomalies in some solid tumors indicative of the complexity of the genomic alterations in cancer. We also look at a few of the more recent genomic developments in cancer and offer an opinion as to what all these findings add up to.     

Dicentric (17;20)(p11.2;q11.2): an uncommon cytogenetic abnormality in myeloid malignancies

We report on two patients with myeloid disorders and complex karyotypes including a dicentric chromosome, dic(17;20)(p11.2;q11.2), resulting in the loss of most of 17p and 20q. The presence of the centromeres of chromosomes 17 and 20 in the dic(17;20), as well as the loss of TP53, were confirmed by fluorescence in situ hybridization. Deletions of 17p and 20q are recurrent abnormalities in hematologic disorders, particularly myelodysplastic syndrome and acute myeloid leukemia). However, a dic(17;20) is an uncommon finding. According to the few reports in the literature, dic(17;20) is associated with an unfavorable prognosis. The key mechanism might be the loss of TP53 as well as other tumor suppressor genes in 20q that may have a critical role in tumor genesis.     

Twelve-Week Daily Consumption of ad hoc Fortified Milk with ω-3, D,and Group B Vitamins Has a Positive Impact on Inflammaging Parameters: A Randomized Cross-Over Trial

Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with ad hoc fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters. Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63–80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission. Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of erythrocyte membranes. Conversely, it reduced the amount of arachidonic acid, homocysteine, and ω-6/ω-3 ratio. Conclusion: Twelve-week daily consumption of ad hoc fortified milk has an overall positive impact on different health parameters related to inflammaging in the elderly.     

c-Jun N-terminal kinase is involved in mercuric ions-mediated interleukin-4 secretion in mast cells

BACKGROUND: Interleukin (IL)-4 plays a prominent role in immune response. Mercuric compounds upregulate IL-4 expression in animal tissues, and this upregulation plays a role in mercuric-mediated immunomodulation. Mercuric ions-mediated IL-4 expression was observed in vitro in T lymphocytes and mast cells. In the present study, we investigated molecular mechanisms responsible for this effect of mercuric ions in mast cells. METHODS: C1.MC/C57.1 mouse mast cells were exposed in vitro to increasing concentrations of Hg(2+) in the absence or presence of the specific c-Jun N-terminal kinase (JNK) inhibitor SP600125. The level of phosphorylated c-Jun in mast cells was determined by Western blotting, JNK activity assessed with in vitro kinase assay and the amount of secreted IL-4 determined by ELISA. RESULTS: We observed that Hg(2+) upregulated c-Jun phosphorylation on Ser 73 at concentrations which overlapped concentrations mediating IL-4 secretion. Phosphorylation of c-Jun in mast cells was associated with an increase in JNK activity. The specific JNK inhibitor SP600125 abolished both mercuric-induced c-Jun phosphorylation and IL-4 secretion in mast cells. CONCLUSIONS: These observations are consistent with the hypothesis that JNK is one of the signaling proteins mediating the effect of Hg(2+) on IL-4 expression in mast cells and is engaged in environmentally mediated immunomodulation.     

Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug‐resistant epilepsy

Focal cortical dysplasia is a common cause of medically refractory epilepsy in infancy and childhood. We report a neonate with seizures occurring within the first day of life. Continuous video‐EEG monitoring led to detection of left motor seizures and a right frontal EEG seizure pattern. Brain MRI revealed a lesion within the right frontal lobe without contrast enhancement. The patient was referred for epilepsy surgery due to drug resistance to vitamin B6 and four antiepileptic drugs. Lesionectomy was performed at the age of two and a half months, and histopathological evaluation confirmed the diagnosis of focal cortical dysplasia type IIb (FCD IIb). The patient is free of unprovoked seizures without medication (Engel Class I) and is normally developed at 36 months after surgery. The case study demonstrates that FCD IIb may cause seizures within the first day of life and that epilepsy surgery can be successfully performed in medically intractable patients with a clearly identifiable seizure onset zone within the first three months of life. Although radical surgery such as hemispherectomy and multi‐lobar resections are over‐represented in early infancy, this case also illustrates a favourable outcome with a more limited resection in this age group.     

Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance

The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3–9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted.