13号染色体异常与多发性骨髓瘤

 近年随着荧光原位杂交（FISH）等技术的应用,多发性骨髓瘤（MM）染色体异常检出率明显提高,其中13号染色体异常最为常见,约占50%。定位于13号染色体上的肿瘤抑制基因和微小RNA在MM的发病机制中发挥重要作用。在过去的10年里研究者普遍认为13号染色体缺失（△13）是MM的独立预后不良因素,但目前越来越多的研究证实其预后价值有赖于其他染色体的异常,且随着新型药物的不断应用,其不良预后可以被逆转。     

Chromosome 1q21 abnormalities in multiple myeloma

Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.Subject terms: Cancer genomics, Myeloma, Myeloma     

多发性骨髓瘤细胞遗传学异常及预后的研究进展

多发性骨髓瘤(MM)是一种不可治愈的血液系统恶性肿瘤,随着细胞遗传学检测技术的进步,发现细胞遗传学异常几乎发生于全部的MM患者.细胞遗传学异常不仅揭示了MM的本质,而且成为影响MM患者预后最重要的因素.文章就MM遗传学异常及其不同预后意义进行综述.     

Clinical implications of chromosomal abnormalities in multiple myeloma

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4;14), t(14;16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT.     

Chromosome 13 deletion/hypodiploidy and prognosis in multiple myeloma patients

The application of high-dose treatment with autologous stem cell transplant(s) has improved survival, when compared to standard treatment, in patients with multiple myeloma. However, this benefit is mostly enjoyed by specific patient subgroups characterized by the absence of high-risk disease features. High-risk features are, first and foremost, the detection of unfavorable cytogenetic abnormalities (chromosome 13 deletion, hypodiploidy and myelodysplastic-type abnormalities in an otherwise typical myeloma karyotype) prior to treatment; elevated serum lactate dehydrogenase and C-reactive protein levels at diagnosis and high β-2 microglobulin levels prior to transplant also convey poor prognosis, although they account for less variability of the observed outcome than the cytogenetic abnormalities. While high-dose treatment with autologous stem cell transplant(s) can cure a sizable minority of patients with low-risk disease features and significantly prolongs survival in others with similar characteristics, patients with high-risk features are virtually incurable and their survival benefit is much less pronounced. As the tremendous clinical variability of myeloma can now be traced to its underlying genetic abnormalities, routine cytogenetic analysis at diagnosis and relapse are absolutely indicated. Based on this stratification, high-risk patients are excellent candidates for novel therapeutic approaches, such as planned non-myeloablative allogeneic transplants following an autologous transplant.     

Microbiome changes in esophageal cancer: implications for pathogenesis and prognosis

Esophageal cancer(EC) is an aggressive malignancy with a poor prognosis. Various factors, including dietary habits, and antacid and antibiotic use, have been shown to influence the esophageal microbiome. Conversely, enrichment and diversity of the esophageal microbiome can also impact its function. Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC, thus suggesting the potential contribution of the esophageal microbiome to EC development. Additiona...     

Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis

In a chromosome study of 83 patients with myelodysplastic syndrome (MDS), 50 showed a clonally abnormal karyotype. The most frequent abnormalities were the whole or a partial loss of the long arm of chromosome 7 (-7 or 7q-) (14 patients) and a partial loss of the long arm of chromosome 5 (5q-) (11 patients). Twenty patients with 5q- and/or -7 or 7q- had a shorter survival (median, 5 months) than those with other abnormal karyotypes (22 months) or those with a normal karyotype (28 months). In this series 30 patients were examined cytogenetically on two or more occasions during the course of their illness. Ten patients showed a further karyotypic alteration from the initial findings, and, concomitantly, their disease progressed in severity including overt leukemia. These patients had a shorter survival (median, 2 months) after the chromosome reanalysis than the other 20 patients who did not have further karyotypic changes (21 months). Thus, the prognosis of patients with MDS can be predicted more accurately by reanalyzing the chromosomes after the initial analysis.     

Chromosome abnormalities in erythroleukemia

Erythroleukemia (EL) is a heterogeneous disease in terms of cell type affected, chromosome abnormalities found in the malignant clone, and clinical course. In this article, cases of erythroid EL from the recent medical literature are reviewed using cytogenetic criteria to distinguish such cases from those of myeloid EL. Although most patients with erythroid EL were elderly men, 20% of the cases occurred in the under-3 age group, where boys and girls were equally affected. Chromosomes 5 and 7 were found to be lost or partially deleted in two thirds of the adult patients only, but not in the pediatric patients; this suggests that EL is associated with cumulative mutagen exposure in adult patients only. It is proposed that cytogenetic criteria may be of use prospectively in distinguishing patients with erythroid EL from those with myeloid EL.     

Chromosome abnormalities in cancer

Karyotypic abnormalities have been described in more than 10,000 human neoplasms analyzed by means of chromosome banding. These aberrations are of three different kinds: primary abnormalities, which are essential in establishing the tumor; secondary abnormalities, which develop only after the neoplasm is established but which nevertheless may be important in tumor progression; and cytogenetic noise, which is the background level of nonconsequential aberrations. These latter changes are, in contrast to the primary and secondary aberrations, randomly distributed throughout the genome. The primary abnormalities, of which more than 100 have been identified, are strictly correlated with particular neoplastic disorders and even with histopathological subgroups within a given tumor type. To these purely cytogenetic data implicating specific genetic changes in carcinogenesis may now be added the growing evidence of molecular specificity emerging from recombinant DNA studies. It appears that both currently known classes of directly cancer-relevant genes, the dominant oncogenes and the recessive anti-oncogenes, are located at precisely those genomic sites that are visibly involved in neoplasia-associated chromosomal rearrangements. The molecular genetic data thus support the cytogenetic conclusion that the distribution of consistently cancer-associated breakpoints reflects the genomic position of genes that, either directly or through the control function they exert, are essential in the proliferation and differentiation of human cells.     

Hemostatic abnormalities in multiple myeloma and related disorders.

Patients with multiple myeloma, Waldenstr?m's macroglobulinemia, benign monoclonal gammopathy, and other B-cell disorders associated with high titer serum paraproteins can manifest unique hemostatic disorders. Most of these disorders predispose the patient to hemorrhage, especially following surgical procedures. Mechanisms can include: acquired von Willebrand syndrome, paraprotein-induced platelet function defects, factor X deficiency, and local tissue fragility associated with amyloidosis, abnormalities of the function of fibrin, circulating anticoagulants, and thrombocytopenia. The mainstay of therapy is the treatment of the underlying disease. Depending on clinical circumstances, additional therapies might include: plasmapheresis with appropriate factor replacement, arginine vasopressin, fibrinolysis inhibitors, and splenectomy. Less commonly, the paraprotein disorders are associated with thrombotic complications, especially in those cases in which the lupus anticoagulant is present.     

Chromosome translocations in multiple myeloma

Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-switched plasma cells (PC), usually arises from a common benign PC tumor called Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases with the stage of disease: 50% in MGUS, 60-65% in intramedullarly MM, 70-80% in extramedullary MM, and >90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many partners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3' enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malignant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell.     

Chromosome abnormalities in malignant histiocytosis

Chromosome and pathologic studies were performed on two patients (a 12-year-old boy and a 62-year-old woman) with malignant histiocytosis (MH). Both patients had chromosome abnormalities in their neoplastic cells: the boy's karyotype was 45,Xp+,-Y,9p+,18q-, and the woman's 48,XX,+16, inv(1),mar(5),6p-,10p+,12q+,i(18q),+i(18q). The boy had typical clinical and pathologic findings of MH, and died without achieving remission by chemotherapy. At the initial stage the woman had the clinical and hematologic findings of MH. Chemotherapy was given, but had no beneficial effects. At the terminal stage the bone marrow (BM) biopsy and aspirate, and the autopsy findings, were consistent with those of non-Hodgkin lymphoma, diffuse large cell type, although some histiocytes or abnormal cells in monocyte-macrophage lineage remained in the BM and the autopsied lymph nodes. This study and a review of data on six other cases have failed to establish any specific chromosome changes in MH.     

Chromosome abnormalities in early cancers

The chromosome changes in early cancer had been thought to be difficult to analyse because of the technical reasons and of the complex nature of the chromosomal abnormalities as compared with hematological diseases having simple diploid karyotype. Recent advances allowed to analyse the chromosomes of solid tumors by the improved technics for cell disaggregation, short term culture, and chromosome banding. Although some advanced solid cancers kept the simple near by diploid chromosomal features, many tumors such as cervical cancers reveal complex chromosomal changes already in the pre-invasive stage. Much more data must be collected to evaluate the role of chromosomal changes in benign and early malignant tumors.     

Cytogenetic abnormalities in multiple myeloma

There is an increasing understanding that chromosomal abnormalities play a major role in the pathogenesis of multiple myeloma. Furthermore, they seem to predict the clinical outcome of patients according to the specific abnormalities detected. It is likely that in the future, knowledge of the cytogenetic composition will be an integral part of the evaluation of myeloma patients.