Accepted Manuscript Retrospective evaluation for the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities Dandan Liu, Ph.D, M.D, Yong Zhang, Ph.D, M.D, Suning Chen, Ph.D, M.D, Jinlan Pan, Ph.D, M.D, Xuefeng He, Ph.D, M.D, Jianying Liang, M.D, Zixing chen, Ph.D, M.D PII:
S2210-7762(15)00045-9
DOI:
10.1016/j.cancergen.2015.03.013
Reference:
CGEN 378
To appear in:
Cancer Genetics
Received Date: 23 July 2014 Revised Date:
25 February 2015
Accepted Date: 30 March 2015
Please cite this article as: Liu D, Zhang Y, Chen S, Pan J, He X, Liang J, chen Z, Retrospective evaluation for the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities, Cancer Genetics (2015), doi: 10.1016/j.cancergen.2015.03.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page
Title： ：Retrospective evaluation for the clinical and laboratory data from 300 patients
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of various hematological malignancies with chromosome 3 abnormalities
Authors: Dandan Liu 1(Ph.D, M.D), Yong Zhang2(Ph.D, M.D), Suning Chen1 (Ph.D, M.D),
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Jinlan Pan 1 (Ph.D, M.D),
Jianying Liang1 (M.D), Zixing chen 1 (Ph.D, M.D)
Departments and institutions:
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Xuefeng He 1 (Ph.D, M.D),
1: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key
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Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China 2: The Jinan Military General Hospital, Jinan, 250031, P.R. China
Dandan Liu,
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Correspondence:
The First Affiliated Hospital of Soochow University,
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Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China; Telephone: 86-0512-67780459; Fax: 86-0512-65113556; E-mail: [email protected]
Founding source: This research was supported in part by grant from National Natural Science Foundation of China (Youth National Natural Science Foundation of China) (81100332). 1
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Author contributions: D.L. and Y.Z. contributed equally to this research: D.L. designed research, analyzed data, and wrote the paper. Y.Z. developed the idea, analyzed data.
X.H. performed experiments. J.L. performed experiments. Z.C. designed the research and analyzed data.
Conflict of interest:
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The authors have no conflicts of interest to disclose.
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J.P. provided sample from patients, performed experiments.
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S.C. designed experiments, analyzed data.
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Manuscript
Retrospective evaluation for the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities
Chen1
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Dandan Liu1, Yong Zhang2, Suning Chen1, Jinlan Pan1, Xuefeng He1, Jianying Liang1, Zixing
1: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China
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2: The Jinan Military General Hospital, Jinan, 250031, P.R. China
Abstract: This retrospective study was designed to evaluate the clinical and laboratory behaviors
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of chromosome 3 abnormalities by analyzing the morphological, cytogenetic and follow-up data from 300 patients of various hematological malignancies with chromosome 3 abnormalities. From the results, trisomy 3, translocation(3q) and del(3) were the abnormal types most frequently observed(＞10%) among the chromosome 3 abnormalities. In hematological malignancies, chromosome 3 abnormalities were most frequently seen in the patients with acute myeloid leukemia (AML) (24.7%) and myelodysplastic syndrome (MDS) (16%), followed by acute
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lymphocytic leukemia (ALL) (13.7%) and multiple myeloma (MM) (12.7%). In this series, it was likely that genomic losses were the most frequent genetic abnormalities in AML, ALL and HAL patients, while structural rearrangements were frequently seen in CML and MDS patients, and genomic gains in MM patients. Chromosome 3 abnormalities mainly occurred as a component of
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a complex abnormality (251/300) rather than a sole one (14/300). Survival analysis demonstrated statistical difference between the patients with trisomy 3 who had the better prognosis and patients
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with del(3) who had the worse prognosis in these series (p＜0.05). Patients with abnormalities in chromosome 3 may imply an unfavorable outcome in CML and ALL. Key words: Chromosome 3 abnormality; Hematological malignancies
Introduction In patients with hematologic malignancies, chromosome 3 abnormalities are observed less often than abnormaltiies involving chromosomes 5, 7 and 8. However, the abnormalities on chromosome 3 are increasingly highlighted in recent years after t(3;3)/inv(3) was defined as a
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reproducible abnormality in World Health Organization (WHO) Classification Criteria 2008[1]. Therefore, we performed a retrospective analysis from 300 first visit patients with chromosome 3 abnormalities in a patient database including over 45000 patients with hematological malignancies
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who were treated in recent 2.5 decades in our center. This analysis was conducted in attempt to clarify the distributions and characteristics of each subtype of chromosome 3 abnormalities in hematological malignancies and the possible relationship with these conditions.
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Materials and Methods
The clinical and laboratory data regarding the age, gender, diagnosis and outcome of the patients of hematological malignancies with chromosome 3 abnormalities who were treated in our
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center from 1985 to 2011 were retrospectively analyzed. For the analysis, the occurring pattern and distribution of the chromosome 3 abnormalities in the hematological malignancies and the incidence of these abnormalities in various hematological disorders were summarized. Additionally, the survival analysis was also performed for 96 of these patients who had full follow-up data. In order to compare the prognosis of hematological malignancy patients with
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chromosome 3 abnormalities to that of those without chromosome 3 abnormalities, these patients included 73 CML cases (34 with t(9;22) abnormalities alone and 39 with abnormal karyotypes other than in chromosome 3), 60 ALL cases (25 with normal karyotypes and 35 with abnormal karyotypes other than in chromosome 3) and 21 MM cases with normal karyotypes were used as
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control group.
Cytogenetic analysis was performed on bone marrow (BM) cells using direct method and/or
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24-h cultures. An R-banding assay was used for karyotypic analysis. Clonal karyotypic abnormalities were described according to the International System for Human Cytogenetic Nomenclature (ISCN, 2013) [2]. For the patients with abnormalities in the long arm of chromosome 3 (3q) regions whose bone marrow cells were available, EVI1 rearrangements were examined by fluorescence in situ hybridization (FISH). Statistical analysis was performed by Statistical Package for Social Science (SPSS) 16.0 software. The survival analysis was performed by Kaplan-Meier analysis. p10%). The involved hematological malignancies
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were summarized also in Table 4.
EVI1 rearrangement was detected in 31of 75patients with abnormalities in 3q regions and
available bone marrow data (M/F =1.58:1; 10 AMLs, 4 CMLs, 3 MDSs, 1 HAL, 5 MMs, 4 ALLs, 2 CLLs and 2 unknown disorders). Abnormalities in 3q regions included add(3q), t(3q), inv(3q), etc. Only 11 of 31 patients with EVI1 rearrangement had follow-up data. Of these, 7 patients (63.6%) showed poor prognosis, only 4 patients (36.4%) had favorable prognosis. In this series, 96 patients of chromosome 3 abnormalities with follow-up data were subject to a survival analysis. As shown in Figure 3, patients with simple abnormal chromosome 3 karyotypes had numerically better prognosis than those with complex abnormal chromosome 3 6
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karyotypes, which indicated the additional information of chromsome 3 abnormalities did not add to, nor change this outcome; although clinical outcomes of patients with genomic gains in chromosome 3 were also better than those with genomic losses or structural rearrangements in
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chromosome 3, no statistical difference was found between the subpopulations (p＞0.05). In contrast, patients with trisomy 3 had significantly better prognosis than those with del(3), who
exhibited the worse prognosis among the examined populations (p＜0.05). No statistic difference was found when we compared the prognosis between the group of patients with abnormalities in
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3p and those with abnormalities in 3q. From Figure 4, CML patients with abnormalities in chromosome 3 had the worst prognosis as compared with the CML patients with t(9;22)
abnormalities alone and those with abnormal karyotypes other than in chromosome 3 (p＜0.05).
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ALL patients with abnormalities in chromosome 3 demonstrated a significantly worse prognosis than that of ALL patients with normal karyotypes (p＜0.05), although no statistical difference was found when compared with the patients with abnormal karyotypes other than in chromosome 3. MM patients with abnormalities in chromosome 3 had a numerically worse prognosis than that of MM patients with normal karyotypes, although we failed to find statistical difference between of MM patients with abnormal
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these two groups (p＞0.05). Because the follow-up data
karyotypes other than in chromosome 3 was small, and the number of each subtype of AML patients of abnormalities in chromosome 3 with follow-up data was also not adequate, the
Discussion
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comparative analysis had not been performed on these two groups of patients.
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It is well-known that cytogenetic disorders are commonly observed in patients with
hematological malignances, and are usually irreversible. The chromosomal abnormality may result in an abnormal structure and/or functionality of the affected key genes, playing an important role in the onset or development of these diseases [3]. Particularly, some reproducible abnormalities are associated with the specific leukemia types. In recent years, the abnormalities on chromosome 3 have been increasingly highlighted since the chromosome 3 abnormality associated hematological disorders was firstly proposed in WHO Classification Criteria published in 2008. It could be revealed in this study that there were various chromosome 3 abnormalities seen in
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a variety of hematological malignancies. Of all the types of the chromosome 3 abnormalities except for trisomy 3, t(3q) (16.7%) was the most frequent abnormality to be observed. As reported in previous publications [4-6], the most frequent translocations involving chromosome 3 were
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t(3;3), t(3;12) and t(3;21). In this study, however, we observed that many chromosomes in the genome participated in the formation of translocation along with chromosome 3 in addition to chromosomes 1, 3, 7, 8, 12 and 21, which were commonly reported, including a substantial portion of translocations that were not or rarely reported previously [7-8].
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Also seen in other publications, this study demonstrated that the abnormalities in the long arm of chromosome 3 (abnormalities in 3q) were the most common chromosome 3 abnormalities
seen in AML and MDS patients [9-10]. Inv(3)(q21q26)\t(3;3)(q21;q26) is the most frequent
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abnormality detected in AML, MDS, CML patients and often leads to overexpression of EVI1 (Ecotropic virus integration site-1), which is located at chromosome 3q26 [11]. EVI1 rearrangement was also found in some other 3q26 abnormalities such as t(3;21), t(3;12), t(3;7), etc. The patients with 3q26/EVI1 rearrangements often have a dismal outcome. From this study, it was revealed that 3q26/EVI1 rearrangements were not only found in AML, MDS and CML, but also in
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ALL, MM and CLL patients. Among them, an unusual case with 5q- syndrome had been reported: for this patient, the condition was finally transformed to acute lymphocytic leukemia with a secondary cytogenetic abnormality of t(3;3)(q21;q26) and EVI1 rearrangement; this happened about 3 years after the initial diagnosis [12]. Therefore, the role of EVI1 in hematologic disease
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has to been further clarified in the future.
From Table 3A, in the patients with trisomy 3, MM accounted for the highest percentage
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(31.3%) out of all the malignancies evaluated. Similarly from Table 3B in patients with MM, trisomy 3, accounted for the highest percentage out of all the chromosome 3 abnormalities studied. In Schmidt-Wolf’s series including 130 patients with MM, the percentage of chromosomal gains on chromosomes 3 and 9 were greater than those of chromosomal losses as well as gains on other chromosomes [13]. Additionally, it should be highlighted that the CLL patients with trisomy 3 approximately accounted for more than one half (53.8%) of the CLL patients with overall chromosome 3 abnormalities (Table 3B). Wu et al. found that the trisomy 3 may be associated with a dismal outcome for patients with CLL [14]. In this retrospective study, there is a limitation on the comparison involving patients with 8
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MM and/or CLL: these two subpopulations often have chromosomally abnormal cell populations that may not grow in routine culture. Therefore, the FISH analysis is of good significance on these cases. However, as the data presented in this manuscript are all based on the results of routine
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chromosomal assessments, the balance of the baseline characteristics among the groups may be affected if FISH data was additionally included. The comparison based on FISH data is a large
work and worthwhile for future study.Of all the chromosome 3 abnormalities, it seemed that genomic losses was the most frequent abnormality seen in acute leukemia (AML, ALL and HAL);
while structural rearrangements was the most frequent one seen in patients with bone marrow blast
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＜20%（CML and MDS patients), and genomic gains was the most frequent abnormality seen in MM patients (Figure 2).
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As shown in Figure 3, patients with trisomy 3 had better prognosis, while those with del(3) had worse prognosis among the populations studied (p＜0.05). In combination with the data summarized in Table 3B, of the AML, HAL and MDS patients (especially HAL) who altogether had poor prognosis, the abnormality of del(3) accounted for greater proportion than that of trisomy 3. Among CLL or lymphoma patients, the abnormality of del(3) had the lower incidence than
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trisomy 3. These results indicated that genomic losses may have more adverse impact on the patients’ prognosis than genomic gains as the former often led to the functional defects of some critical genes. As shown in Figure 4, no matter CML, ALL or MM, the patients with abnormalites in chromosome 3 had a worse prognosis than those with normal karyotypes as well as those with
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abnormal karyotypes other than in chromosome 3. Moreover in CML, the patients with abnormalites in chromosome 3 had a worse prognosis than those with t(9;22) alone as well as As discussed, the
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those with abnormal karyotypes other than in chromosome 3 (p＜0.05).
presence of abnormalities in chromosome 3 may implied an unfavorable prognosis. As shown in Table 2, the sole abnormality of chromosome 3 was uncommon to see, only
accounting for 4.7% (14/300) of all the chromosome 3 abnormalities, while the complex abnormality involving ≥ 3 chromosomes (containing chromosome 3) may account for 83.7%
(251/300) of this population, suggesting the probability of the combined abnormalities involving chromosome 3 and one or more other chromosomes. The above findings may also be interpreted as that the chromosome 3 abnormality is a secondary manifestation or concomitant product of the
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abnormality of other chromosomes. Through the data in Table 4, it could be found that the chromosomes that are most frequently involved in the combined abnormalities with chromosome 3 are chromosomes 5, 7 and 12. Therefore, whether the chromosome 3 abnormalities are a primary
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or secondary factor in the complex abnormalities, it deserves to be further studied in the future.
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Acknowledgment This work was supported in part by grant from National Natural Science Foundation of China (Youth National Natural Science Foundation of China (81100332))
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Conflict-of-interest statement: The authors declare no competing financial interests.
References
[1] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. LARC, Lyon; 2008.
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[2] Shaffer LG, McGowan-Jordan J, Schmid M, editors. ISCN (2013): an international system for human cytogenetics nomenclature. Basel:Karger;2013. [3] Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev, 2004; 18:115-36.
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[4] De Braekeleer E, Douet-Guilbert N, Basinko A, Bovo C, Gueganic N, Bris ML, et al. Conventional cytogenetics and breakpoint distribution by fluorescent in situ hybridization in patients with malignant hemopathies associated with inv(3)(q21;q26) and t(3;3)(q21;q26). Anticancer Res, 2011; 31:3441-8. [5] Lee SA, Lim J, Kim M, Kim Y, and Han K. A case of t(3;3)(q21;q26.2) associated with severe multilineage dysplasia and multi-drug resistance in blastic crisis of chronic myelogenous leukemia. Korean J Lab Med, 2010; 30:595-9. [Article in Korean] [6] Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, et al. Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Blood, 1996; 88: 682-9. [7] Levaltier X, Penther D, Bastard C, and Troussard X. t(2;3)(p23;q26) in a patient with AML M2. Br. J. Haematol, 1996; 92: 1027. [8] Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij-Philipsen M, 10
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Geurts van Kessel A, et al. Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: Report of 21 new cases, clinical, cytogenetic and molecular genetic features. Leukemia, 2004; 18: 1108-14.
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[9] Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, and Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol, 2007; 136: 806-13.
[10] Lugthart S, Gro¨schel S, Beverloo HB, Kayser S, J.M. Valk P, van Zelderen-Bhola SL, et al. Clinical, Molecular, and Prognostic Significance of WHO Type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and Various Other 3q Abnormalities in Acute Myeloid Leukemia. JOC, 2010; 28: 3890-98.
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[11] Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol, 2007; 136: 806-13. [12] Liu D, Chen S, Pan J, Zhu M, Wu N, Zhu F, et al. Acquired EVI1 rearrangement involved in the transformation from 5q- syndrome to pre-B lymphocytic leukemia in a Chinese patient. Int J Hematol, 2012; 96:806–9.
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[13] Schmidt-Wolf IG., Glasmacher A, Hahn-Ast C, Juttner A, Schnurr T, Cremer F, et al. Chromosomal aberrations in 130 patients with multiple myeloma studied by interphase FISH: diagnostic and prognostic relevance. Cancer Genetics and Cytogenetics, 2006;167: 20–5.
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[14] Wu SJ, Lin CT, Huang SY, Lee FY, Liu MC, Hou HA, et al. Chromosomal abnormalities by conventional cytogenetics and interphase fluorescence in situ hybridization in chronic lymphocytic leukemia in Taiwan, an area with low incidence--clinical implication and comparison between the West and the East. Ann Hematol, 2013; 92:799-806.
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Chromosome
Genomic loss or gain of a region of
loss or gain
chromosome 3
add(3q)
del(3q)
add(3p)
del(3p)
Number
64
38
18
22
9
15
of cases
(21.3%)
(12.7%)
(6.0%)
(7.3%)
(3.0%)
Age
48.5
54
42.5
33
(median,
(14-83)
(15-79)
(17-77)
(11-75)
1.56:1
1.53:1
3.5:1
1:1
t(3p)
22
(5.0%)
(16.7%)
(1.7%)
(7.3%)
50
25
53
47
37
(26-72)
(17-76)
(14-84)
(21-50)
(13-80)
1.25:1
1.5:1
2.13:1
4:1
2.67:1
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＊ Other rare abnormalities include ins(3), idic(3), etc.
inv (3q)
5
range) （M:F） ）
t(3q)
50
(%)
Gender
Other abnormalities
of chromosome 3
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del(3)
Structural rearrangement
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trisomy 3
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Table 1. Distributions and characteristics of chromosome 3 abnormalities in the hematological malignancies in this series (n=300)
inv (3p)
in chromosome 3
der (3)
---
---
≥2 abnormalities
in chromosome 3 ﹟
23
11
23
(7.7%)
(3.7%)
(7.7%)
68
48
60
(34-79)
(38-87)
(26-78)
1.56:1
1.75:1
1.56:1
Abbreviations: t(3q)= translocation(3q); inv(3q)=inversion(3q); t(3p)= translocation(3p); inv(3p)= inversion(3p); der(3)=derivation(3).
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rare
abnormalities ＊
0
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient.
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other
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Table 2. The pattern of chromosome 3 abnormalities occurring in the individual hematological malignancies Ages
Gender
Abnormalities
Median (Range)
M/F
N (%) 36(23-71)
17(5.7%)
36(21-59)
AML
74(24.7%)
48.5(13-83)
HAL
6(2.0%)
27(21-60)
MDS
48(16.0%)
56(14-84)
MM
38(12.7%)
59(36-87)
10(3.3%)
58(15-70)
23(7.7%)
58(29-80)
CLL
13(4.3%)
63(46-63)
Lymphoma
12(4.0%)
51(23-64)
ALL
41(13.7%)
26(11-80)
Total
300(100%)
47(11-87)
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Others △ Unknown ▲
1.25:1
△ Others indicated hematological disorders not mentioned in this table.
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▲ Unknown indicated the patients without identified diagnosis.
Chromosome 3
Chromosome 3
abnormality
abnormal plus another
abnormality as a
chromosome
component in a
abnormality
complex abnormality
0(0.0%)
16(6.4%)
1.83:1
2(14.3%) 0(0.0%)
1(2.9%)
16(6.4%)
1.39:1
4(28.6%)
14(40.0%)
56(22.3%)
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18(6%)
CML-AP/BC
2:1
0(0.0%)
1(2.9%)
5(2.0%)
3:1
2(14.3%)
8(22.9%)
38(15.1%)
1.71:1
1(7.1%)
1(2.9%)
36(14.3%)
1:1
1(7.1%)
2(5.7%)
7(2.8%)
1.56:1
1(7.1%)
2(5.7%)
20(8.0%)
5.5:1
0(0.0%)
3(8.6%)
10(4.0%)
2.25:1
0(0.0%)
0(0.0%)
12(4.8%)
1.41:1
3(21.4%)
3(8.6%)
35(13.9%)
1.73:1
14(100.0%)
35(100.0%)
251(100.0%)
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CML-CP
Sole chromosome 3
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Chromosome
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Table 3A. Distributions of different hematological malignancies in each of the chromosome 3 abnormalities in this series del(3)
abnormalities in 3p p
abnormalities in 3q q
☆
※
der(3)
other rare
≥2 abnormalities
abnormalities ＊
chromosome 3﹟ ﹟
0 (0.0%)
0(0.0%)
6(13.0%)
10(10.5%)
0(0.0%)
1(9.1%)
1(4.3%)
CML-AP/BC
2 (3.1%)
2(5.3%)
4(8.7%)
5(5.3%)
2(8.7%)
2(18.2%)
0(0.0%)
AML
11(17.2%)
15(39.5%)
11(23.9%)
4(17.4%)
1(9.1%)
7(30.4%)
HAL
1(1.6%)
2(5.3%)
1(2.2%)
2(2.1%)
0(0.0%)
0(0.0%)
0(0.0%)
MDS
4(6.3%)
6(15.8%)
11(23.9%)
14(14.7%)
6(26.1%)
4(36.4%)
3(13.0%)
MM
20(31.3%)
0(0.0%)
1(2.2%)
6(6.3%)
4(17.4%)
2(18.2%)
5(21.7%)
Others △
0(0.0%)
1(2.6%)
2(4.3%)
4(4.2%)
1(4.3%)
0(0.0%)
2(8.7%)
Unknown ▲
6(9.4%)
3(7.9%)
1(2.2%)
8(8.4%)
2(8.7%)
1(9.1%)
2(8.7%)
CLL
7(10.9%)
0(0.0%)
2(4.3%)
2(2.1%)
1(4.3%)
0(0.0%)
1(4.3%)
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CML-CP
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trisomy 3
25(26.3%)
1(2.6%)
1(2.2%)
5(5.3%)
1(4.3%)
0(0.0%)
1(4.3%)
10(15.6%)
8(21.1%)
6(13.0%)
14(14.7%)
2(8.7%)
0(0.0%)
1(4.3%)
Total
64(100.0%)
38(100.0%)
23(100.0%)
11(100.0%)
23(100.0%)
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3(4.7%)
ALL
Lymphoma
46(100.0%)
95(100.0%)
in 3p indicated genomic losses or gains of the region of chromosome 3p and structural rearrangements of 3p, including del(3p), add(3p), t(3p) and inv(3p).
※ Abnormalities
in 3q indicated genomic losses or gains of the region of chromosome 3q and structural rearrangements of 3q, including del(3q), add(3q), t(3q) and inv(3q).
＊ Other rare abnormalities included ins(3), idic(3) etc.
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☆ Abnormalities
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient. △ Others indicated hematological disorders not mentioned in this table.
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▲ Unknown indicated the patients without identified diagnosis.
in
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Others △
Unknown ▲
CLL
Lymphoma
ALL
0(0.0%)
6(26.1%)
7(53.8%)
3(25.0%)
10(24.4%)
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Table 3B. Distributions of the different chromosome 3 abnormalities in each of the hematological malignancies in this series
1(10.0%)
3(13.0%)
0(0.0%)
1(8.3%)
8(19.5%)
2(20.0%)
1(4.3%)
2(15.4%)
1(8.3%)
6(14.6%)
6(15.8%)
4(40.0%)
8(34.8%)
2(15.4%)
5(41.7%)
14(34.1%)
6(12.5%)
4(10.5%)
1(10.0%)
2(8.7%)
1(7.7%)
1(8.3%)
2(4.9%)
0(0.0%)
4(8.3%)
2(5.3%)
0(0.0%)
1(4.3%)
0(0.0%)
0(0.0%)
0(0.0%)
7(9.5%)
0(0.0%)
3(6.3%)
5(13.2%)
2(20.0%)
2(8.7%)
1(7.7%)
1(8.3%)
1(2.4%)
74(100%)
6(100.0%)
38(100.0%)
10(100.0%)
23(100.0%)
13(100.0%)
12(100.0%)
41(100.0%)
CML-AP/BC
AML
HAL
MDS
MM
trisomy 3
0(0.0%)
2(11.8%)
11(14.9%)
1(16.7%)
4(8.3%)
20(52.6%)
del (3)
0(0.0%)
2(11.8%)
15(20.3%)
2(33.3%)
6(12.5%)
0(0.0%)
in
6(33.3%)
4(23.5%)
11(14.9%)
1(16.7%)
11(22.9%)
1(2.6%)
in
10(55.6%)
5(29.4%)
25(33.8%)
2(33.3%)
14(29.2%)
der(3)
0(0.0%)
2(11.8%)
4(5.4%)
0(0.0%)
other rare
1(5.6%)
2(11.8%)
1(1.4%)
1(5.6%)
0(0.0%)
18(100.0%)
17(100.0%)
abnormalities 3p ☆ abnormalities 3q ※
≥2
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abnormalities ＊
abnormalities in chromosome 3﹟
48(100.0%)
in 3p indicated genomic losses or gains of the region of chromosome 3p and structural rearrangements of 3p, including del(3p), add(3p), t(3p) and inv(3p).
※ Abnormalities
in 3q indicated genomic losses or gains of the region of chromosome 3q and structural rearrangements of 3q, including del(3q), add(3q), t(3q) and inv(3q).
＊ Other rare abnormalities included ins(3), idic(3) etc.
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☆ Abnormalities
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient.
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Total
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CML-CP
△ Others indicated hematological disorders not mentioned in this table. ▲ Unknown indicated the patients without identified diagnosis.
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Table 4. Distributions of combined chromosome abnormalities involving chromosome 3 and another chromosome in hematological malignancies (n=35) Chromosome
Total
1
2
5
6
7
8
9
11
number
CML-CP
0(0.0%)
CML-AP/BC
1(2.9%)
AML
14(40.0%)
HAL
1(2.9%)
MDS
8(22.9%)
MM
1(2.9%)
Others
2(5.7%)
Unknown
2(5.7%)
CLL
3(8.6%)
Lymphoma
0(0.0%)
ALL
3(8.6%)
3 (8.6%)
3
7
(8.6%)
2
(20.0%)
5
(5.7%)
2
(14.3%)
(5.7%)
1 (2.9%)
1
16
5
18
2
(2.9%)
(14.3%)
(5.7%)
*
*
*
22
1 (2.9%)
X
2
1
(5.7%)
（2.9%）
*
*
*
*
*
* *
*
*
* *
* *
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(100%)
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35
*
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n, %
12
*
*
*
* * *
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“*” indicates the designated chromosome participates in the formation of combined abnormalities presented in the listed condition.
*
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Characteristic of t(3;V)
Chromosome1
Chromosome1; 10.0%
Chromosome2 Chromosome3
Chromosome2; 5.0%
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ChromosomeX; 2.5%
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More than one chromosome translocation; 15.0%
Chromosome3; 7.5%
Chromosome22; 5.0%
Chromosome21; 2.5%
Chromosome4; 3.8%
Chromosome20; 1.3% Chromosome19; 1.3% Chromosome18; 1.3%
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Chromosome5; 7.5%
Chromosome17; 2.5% Chromosome16; 5.0%
Chromosome6; 2.5%
Chromosome15; 1.3%
Chromosome7; 2.5%
Chromosome14; 2.5%
Chromosome8; 2.5%
Chromosome13; 1.3%
Chromosome4 Chromosome5 Chromosome6 Chromosome7 Chromosome8 Chromosome9 Chromosome10 Chromosome11 Chromosome12 Chromosome13 Chromosome14 Chromosome15 Chromosome16 Chromosome17 Chromosome18 Chromosome19 Chromosome20 Chromosome21 Chromosome22 ChromosomeX 多条易位
Chromosome12; 8.8%
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Chromosome9; 2.5%
Chromosome10; 2.5%
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Chromosome11; 3.8%
Figure 1：Frequency of the chromosomes that participated in the formation of translocation t (3;V)： ：Chromosome 3 can interact with any of the chromosomes
(chromosomes 1 to 22) within the genome to form a translocation t (3;V), particularly involving chromosomes 1, 12, 3, 5, 16 and 22 (≥5.0%).
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35.0%
33.3%
27.5%
27.3%
25.0% 20.0%
24.0%
19.5% 17.6%
16.9% 16.0%
15.0%
13.2%
11.0%
10.4%
10.4%
4.0% 2.2% 1.1% 0.0%
CML-CP
5.3% 3.9%
4.0% 2.6% 1.1%
1.3% 1.3%
8.8%
3.9%
2.6% 1.3%
1.3% 1.3%
0.0%
CMLAP/BC
AML
HAL
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5.0%
8.8%
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9.3% 8.8%
10.0%
0.0%
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30.0%
genomic gains genomic losses structural rearrangements
MDS
MM
Other
Unknown
CLL
Lymphoma
ALL
Figure 2: Incidence of different type of abnormalities in chromosome 3. MM patients accounted
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for the highest percentage in the group of genomic gains; AML patients accounted for the highest percentage in the group of genomic losses and structural rearrangements. The genomic losses were most frequently observed in AML, ALL and HAL patients, while structural rearrangements were most frequently observed in CML and MDS patients and genomic gains in MM, CLL and lymphoma patients.
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3A
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3B
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3C
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Figure 3 Survival profiles of patients with different abnormalities in chromosome 3: 3A. From the survival analysis, patients with simple abnormal chromosome 3 karyotype had numerically better prognosis than patients with complex abnormal chromosome 3 karyotype; but no statistical difference was found between the two groups (p＞0.05). 3B. From the survival analysis, clinical outcomes of patients with genomic gains in chromosome 3 were better than those with genomic losses or structural rearrangement in chromosome 3, although no statistical difference was found (p＞0.05). 3C. From the survival analysis, patients with trisomy 3 had significantly better prognosis than those with del(3), who exhibited the worse prognosis among the examined populations (p＜0.05).
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4A
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4B
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4C
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Figure 4 ： 4A. Survival profiles of different hematologically malignant patients with abnormalities in chromosome 3: 4A. From the survival analysis, CML patients with abnormalities in chromosome 3 (CML-group 3, n=16) had the worst prognosis as compared with the CML patients with t(9;22) abnormalities alone (CML-group 1, n=34) and those with abnormal karyotypes other than in chromosome 3 (CML-group 2, n=39) (p＜0.05). 4B. From the survival analysis, ALL patients with abnormalities in chromosome 3 (ALL-group 3, n=16) demonstrated a significantly worse prognosis than that of ALL patients with normal karyotypes (ALL-group 1, n=25) (p＜0.05), although no statistical difference was found when compared with the patients with abnormal karyotypes other than in chromosome 3 (ALL-group 2, n=35) (p＞ 0.05). 4C. From the survival analysis, MM patients with abnormalities in chromosome 3 (MM-group 2, n=15) had a numerically worse prognosis than that of MM patients with normal karyotypes (MM-group 1, n=21), although no statistical difference was found between these two groups (p＞0.05). Because the follow-up data of MM patients with abnormal karyotypes other than in chromosome 3 was not adequate , the comparative analysis had not been performed on this group of patients.
S2210-7762(15)00045-9
DOI:
10.1016/j.cancergen.2015.03.013
Reference:
CGEN 378
To appear in:
Cancer Genetics
Received Date: 23 July 2014 Revised Date:
25 February 2015
Accepted Date: 30 March 2015
Please cite this article as: Liu D, Zhang Y, Chen S, Pan J, He X, Liang J, chen Z, Retrospective evaluation for the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities, Cancer Genetics (2015), doi: 10.1016/j.cancergen.2015.03.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page
Title： ：Retrospective evaluation for the clinical and laboratory data from 300 patients
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of various hematological malignancies with chromosome 3 abnormalities
Authors: Dandan Liu 1(Ph.D, M.D), Yong Zhang2(Ph.D, M.D), Suning Chen1 (Ph.D, M.D),
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Jinlan Pan 1 (Ph.D, M.D),
Jianying Liang1 (M.D), Zixing chen 1 (Ph.D, M.D)
Departments and institutions:
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Xuefeng He 1 (Ph.D, M.D),
1: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key
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Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China 2: The Jinan Military General Hospital, Jinan, 250031, P.R. China
Dandan Liu,
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Correspondence:
The First Affiliated Hospital of Soochow University,
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Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China; Telephone: 86-0512-67780459; Fax: 86-0512-65113556; E-mail: [email protected]
Founding source: This research was supported in part by grant from National Natural Science Foundation of China (Youth National Natural Science Foundation of China) (81100332). 1
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Author contributions: D.L. and Y.Z. contributed equally to this research: D.L. designed research, analyzed data, and wrote the paper. Y.Z. developed the idea, analyzed data.
X.H. performed experiments. J.L. performed experiments. Z.C. designed the research and analyzed data.
Conflict of interest:
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The authors have no conflicts of interest to disclose.
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J.P. provided sample from patients, performed experiments.
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S.C. designed experiments, analyzed data.
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Manuscript
Retrospective evaluation for the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities
Chen1
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Dandan Liu1, Yong Zhang2, Suning Chen1, Jinlan Pan1, Xuefeng He1, Jianying Liang1, Zixing
1: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, 188 Shizi Street, Suzhou 215006, P.R. China
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2: The Jinan Military General Hospital, Jinan, 250031, P.R. China
Abstract: This retrospective study was designed to evaluate the clinical and laboratory behaviors
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of chromosome 3 abnormalities by analyzing the morphological, cytogenetic and follow-up data from 300 patients of various hematological malignancies with chromosome 3 abnormalities. From the results, trisomy 3, translocation(3q) and del(3) were the abnormal types most frequently observed(＞10%) among the chromosome 3 abnormalities. In hematological malignancies, chromosome 3 abnormalities were most frequently seen in the patients with acute myeloid leukemia (AML) (24.7%) and myelodysplastic syndrome (MDS) (16%), followed by acute
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lymphocytic leukemia (ALL) (13.7%) and multiple myeloma (MM) (12.7%). In this series, it was likely that genomic losses were the most frequent genetic abnormalities in AML, ALL and HAL patients, while structural rearrangements were frequently seen in CML and MDS patients, and genomic gains in MM patients. Chromosome 3 abnormalities mainly occurred as a component of
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a complex abnormality (251/300) rather than a sole one (14/300). Survival analysis demonstrated statistical difference between the patients with trisomy 3 who had the better prognosis and patients
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with del(3) who had the worse prognosis in these series (p＜0.05). Patients with abnormalities in chromosome 3 may imply an unfavorable outcome in CML and ALL. Key words: Chromosome 3 abnormality; Hematological malignancies
Introduction In patients with hematologic malignancies, chromosome 3 abnormalities are observed less often than abnormaltiies involving chromosomes 5, 7 and 8. However, the abnormalities on chromosome 3 are increasingly highlighted in recent years after t(3;3)/inv(3) was defined as a
3
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reproducible abnormality in World Health Organization (WHO) Classification Criteria 2008[1]. Therefore, we performed a retrospective analysis from 300 first visit patients with chromosome 3 abnormalities in a patient database including over 45000 patients with hematological malignancies
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who were treated in recent 2.5 decades in our center. This analysis was conducted in attempt to clarify the distributions and characteristics of each subtype of chromosome 3 abnormalities in hematological malignancies and the possible relationship with these conditions.
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Materials and Methods
The clinical and laboratory data regarding the age, gender, diagnosis and outcome of the patients of hematological malignancies with chromosome 3 abnormalities who were treated in our
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center from 1985 to 2011 were retrospectively analyzed. For the analysis, the occurring pattern and distribution of the chromosome 3 abnormalities in the hematological malignancies and the incidence of these abnormalities in various hematological disorders were summarized. Additionally, the survival analysis was also performed for 96 of these patients who had full follow-up data. In order to compare the prognosis of hematological malignancy patients with
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chromosome 3 abnormalities to that of those without chromosome 3 abnormalities, these patients included 73 CML cases (34 with t(9;22) abnormalities alone and 39 with abnormal karyotypes other than in chromosome 3), 60 ALL cases (25 with normal karyotypes and 35 with abnormal karyotypes other than in chromosome 3) and 21 MM cases with normal karyotypes were used as
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control group.
Cytogenetic analysis was performed on bone marrow (BM) cells using direct method and/or
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24-h cultures. An R-banding assay was used for karyotypic analysis. Clonal karyotypic abnormalities were described according to the International System for Human Cytogenetic Nomenclature (ISCN, 2013) [2]. For the patients with abnormalities in the long arm of chromosome 3 (3q) regions whose bone marrow cells were available, EVI1 rearrangements were examined by fluorescence in situ hybridization (FISH). Statistical analysis was performed by Statistical Package for Social Science (SPSS) 16.0 software. The survival analysis was performed by Kaplan-Meier analysis. p10%). The involved hematological malignancies
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were summarized also in Table 4.
EVI1 rearrangement was detected in 31of 75patients with abnormalities in 3q regions and
available bone marrow data (M/F =1.58:1; 10 AMLs, 4 CMLs, 3 MDSs, 1 HAL, 5 MMs, 4 ALLs, 2 CLLs and 2 unknown disorders). Abnormalities in 3q regions included add(3q), t(3q), inv(3q), etc. Only 11 of 31 patients with EVI1 rearrangement had follow-up data. Of these, 7 patients (63.6%) showed poor prognosis, only 4 patients (36.4%) had favorable prognosis. In this series, 96 patients of chromosome 3 abnormalities with follow-up data were subject to a survival analysis. As shown in Figure 3, patients with simple abnormal chromosome 3 karyotypes had numerically better prognosis than those with complex abnormal chromosome 3 6
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karyotypes, which indicated the additional information of chromsome 3 abnormalities did not add to, nor change this outcome; although clinical outcomes of patients with genomic gains in chromosome 3 were also better than those with genomic losses or structural rearrangements in
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chromosome 3, no statistical difference was found between the subpopulations (p＞0.05). In contrast, patients with trisomy 3 had significantly better prognosis than those with del(3), who
exhibited the worse prognosis among the examined populations (p＜0.05). No statistic difference was found when we compared the prognosis between the group of patients with abnormalities in
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3p and those with abnormalities in 3q. From Figure 4, CML patients with abnormalities in chromosome 3 had the worst prognosis as compared with the CML patients with t(9;22)
abnormalities alone and those with abnormal karyotypes other than in chromosome 3 (p＜0.05).
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ALL patients with abnormalities in chromosome 3 demonstrated a significantly worse prognosis than that of ALL patients with normal karyotypes (p＜0.05), although no statistical difference was found when compared with the patients with abnormal karyotypes other than in chromosome 3. MM patients with abnormalities in chromosome 3 had a numerically worse prognosis than that of MM patients with normal karyotypes, although we failed to find statistical difference between of MM patients with abnormal
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these two groups (p＞0.05). Because the follow-up data
karyotypes other than in chromosome 3 was small, and the number of each subtype of AML patients of abnormalities in chromosome 3 with follow-up data was also not adequate, the
Discussion
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comparative analysis had not been performed on these two groups of patients.
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It is well-known that cytogenetic disorders are commonly observed in patients with
hematological malignances, and are usually irreversible. The chromosomal abnormality may result in an abnormal structure and/or functionality of the affected key genes, playing an important role in the onset or development of these diseases [3]. Particularly, some reproducible abnormalities are associated with the specific leukemia types. In recent years, the abnormalities on chromosome 3 have been increasingly highlighted since the chromosome 3 abnormality associated hematological disorders was firstly proposed in WHO Classification Criteria published in 2008. It could be revealed in this study that there were various chromosome 3 abnormalities seen in
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a variety of hematological malignancies. Of all the types of the chromosome 3 abnormalities except for trisomy 3, t(3q) (16.7%) was the most frequent abnormality to be observed. As reported in previous publications [4-6], the most frequent translocations involving chromosome 3 were
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t(3;3), t(3;12) and t(3;21). In this study, however, we observed that many chromosomes in the genome participated in the formation of translocation along with chromosome 3 in addition to chromosomes 1, 3, 7, 8, 12 and 21, which were commonly reported, including a substantial portion of translocations that were not or rarely reported previously [7-8].
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Also seen in other publications, this study demonstrated that the abnormalities in the long arm of chromosome 3 (abnormalities in 3q) were the most common chromosome 3 abnormalities
seen in AML and MDS patients [9-10]. Inv(3)(q21q26)\t(3;3)(q21;q26) is the most frequent
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abnormality detected in AML, MDS, CML patients and often leads to overexpression of EVI1 (Ecotropic virus integration site-1), which is located at chromosome 3q26 [11]. EVI1 rearrangement was also found in some other 3q26 abnormalities such as t(3;21), t(3;12), t(3;7), etc. The patients with 3q26/EVI1 rearrangements often have a dismal outcome. From this study, it was revealed that 3q26/EVI1 rearrangements were not only found in AML, MDS and CML, but also in
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ALL, MM and CLL patients. Among them, an unusual case with 5q- syndrome had been reported: for this patient, the condition was finally transformed to acute lymphocytic leukemia with a secondary cytogenetic abnormality of t(3;3)(q21;q26) and EVI1 rearrangement; this happened about 3 years after the initial diagnosis [12]. Therefore, the role of EVI1 in hematologic disease
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has to been further clarified in the future.
From Table 3A, in the patients with trisomy 3, MM accounted for the highest percentage
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(31.3%) out of all the malignancies evaluated. Similarly from Table 3B in patients with MM, trisomy 3, accounted for the highest percentage out of all the chromosome 3 abnormalities studied. In Schmidt-Wolf’s series including 130 patients with MM, the percentage of chromosomal gains on chromosomes 3 and 9 were greater than those of chromosomal losses as well as gains on other chromosomes [13]. Additionally, it should be highlighted that the CLL patients with trisomy 3 approximately accounted for more than one half (53.8%) of the CLL patients with overall chromosome 3 abnormalities (Table 3B). Wu et al. found that the trisomy 3 may be associated with a dismal outcome for patients with CLL [14]. In this retrospective study, there is a limitation on the comparison involving patients with 8
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MM and/or CLL: these two subpopulations often have chromosomally abnormal cell populations that may not grow in routine culture. Therefore, the FISH analysis is of good significance on these cases. However, as the data presented in this manuscript are all based on the results of routine
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chromosomal assessments, the balance of the baseline characteristics among the groups may be affected if FISH data was additionally included. The comparison based on FISH data is a large
work and worthwhile for future study.Of all the chromosome 3 abnormalities, it seemed that genomic losses was the most frequent abnormality seen in acute leukemia (AML, ALL and HAL);
while structural rearrangements was the most frequent one seen in patients with bone marrow blast
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＜20%（CML and MDS patients), and genomic gains was the most frequent abnormality seen in MM patients (Figure 2).
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As shown in Figure 3, patients with trisomy 3 had better prognosis, while those with del(3) had worse prognosis among the populations studied (p＜0.05). In combination with the data summarized in Table 3B, of the AML, HAL and MDS patients (especially HAL) who altogether had poor prognosis, the abnormality of del(3) accounted for greater proportion than that of trisomy 3. Among CLL or lymphoma patients, the abnormality of del(3) had the lower incidence than
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trisomy 3. These results indicated that genomic losses may have more adverse impact on the patients’ prognosis than genomic gains as the former often led to the functional defects of some critical genes. As shown in Figure 4, no matter CML, ALL or MM, the patients with abnormalites in chromosome 3 had a worse prognosis than those with normal karyotypes as well as those with
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abnormal karyotypes other than in chromosome 3. Moreover in CML, the patients with abnormalites in chromosome 3 had a worse prognosis than those with t(9;22) alone as well as As discussed, the
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those with abnormal karyotypes other than in chromosome 3 (p＜0.05).
presence of abnormalities in chromosome 3 may implied an unfavorable prognosis. As shown in Table 2, the sole abnormality of chromosome 3 was uncommon to see, only
accounting for 4.7% (14/300) of all the chromosome 3 abnormalities, while the complex abnormality involving ≥ 3 chromosomes (containing chromosome 3) may account for 83.7%
(251/300) of this population, suggesting the probability of the combined abnormalities involving chromosome 3 and one or more other chromosomes. The above findings may also be interpreted as that the chromosome 3 abnormality is a secondary manifestation or concomitant product of the
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abnormality of other chromosomes. Through the data in Table 4, it could be found that the chromosomes that are most frequently involved in the combined abnormalities with chromosome 3 are chromosomes 5, 7 and 12. Therefore, whether the chromosome 3 abnormalities are a primary
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or secondary factor in the complex abnormalities, it deserves to be further studied in the future.
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Acknowledgment This work was supported in part by grant from National Natural Science Foundation of China (Youth National Natural Science Foundation of China (81100332))
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Conflict-of-interest statement: The authors declare no competing financial interests.
References
[1] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. LARC, Lyon; 2008.
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[2] Shaffer LG, McGowan-Jordan J, Schmid M, editors. ISCN (2013): an international system for human cytogenetics nomenclature. Basel:Karger;2013. [3] Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev, 2004; 18:115-36.
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[4] De Braekeleer E, Douet-Guilbert N, Basinko A, Bovo C, Gueganic N, Bris ML, et al. Conventional cytogenetics and breakpoint distribution by fluorescent in situ hybridization in patients with malignant hemopathies associated with inv(3)(q21;q26) and t(3;3)(q21;q26). Anticancer Res, 2011; 31:3441-8. [5] Lee SA, Lim J, Kim M, Kim Y, and Han K. A case of t(3;3)(q21;q26.2) associated with severe multilineage dysplasia and multi-drug resistance in blastic crisis of chronic myelogenous leukemia. Korean J Lab Med, 2010; 30:595-9. [Article in Korean] [6] Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, et al. Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Blood, 1996; 88: 682-9. [7] Levaltier X, Penther D, Bastard C, and Troussard X. t(2;3)(p23;q26) in a patient with AML M2. Br. J. Haematol, 1996; 92: 1027. [8] Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij-Philipsen M, 10
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Geurts van Kessel A, et al. Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: Report of 21 new cases, clinical, cytogenetic and molecular genetic features. Leukemia, 2004; 18: 1108-14.
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[9] Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, and Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol, 2007; 136: 806-13.
[10] Lugthart S, Gro¨schel S, Beverloo HB, Kayser S, J.M. Valk P, van Zelderen-Bhola SL, et al. Clinical, Molecular, and Prognostic Significance of WHO Type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and Various Other 3q Abnormalities in Acute Myeloid Leukemia. JOC, 2010; 28: 3890-98.
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[11] Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol, 2007; 136: 806-13. [12] Liu D, Chen S, Pan J, Zhu M, Wu N, Zhu F, et al. Acquired EVI1 rearrangement involved in the transformation from 5q- syndrome to pre-B lymphocytic leukemia in a Chinese patient. Int J Hematol, 2012; 96:806–9.
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[13] Schmidt-Wolf IG., Glasmacher A, Hahn-Ast C, Juttner A, Schnurr T, Cremer F, et al. Chromosomal aberrations in 130 patients with multiple myeloma studied by interphase FISH: diagnostic and prognostic relevance. Cancer Genetics and Cytogenetics, 2006;167: 20–5.
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[14] Wu SJ, Lin CT, Huang SY, Lee FY, Liu MC, Hou HA, et al. Chromosomal abnormalities by conventional cytogenetics and interphase fluorescence in situ hybridization in chronic lymphocytic leukemia in Taiwan, an area with low incidence--clinical implication and comparison between the West and the East. Ann Hematol, 2013; 92:799-806.
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Chromosome
Genomic loss or gain of a region of
loss or gain
chromosome 3
add(3q)
del(3q)
add(3p)
del(3p)
Number
64
38
18
22
9
15
of cases
(21.3%)
(12.7%)
(6.0%)
(7.3%)
(3.0%)
Age
48.5
54
42.5
33
(median,
(14-83)
(15-79)
(17-77)
(11-75)
1.56:1
1.53:1
3.5:1
1:1
t(3p)
22
(5.0%)
(16.7%)
(1.7%)
(7.3%)
50
25
53
47
37
(26-72)
(17-76)
(14-84)
(21-50)
(13-80)
1.25:1
1.5:1
2.13:1
4:1
2.67:1
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＊ Other rare abnormalities include ins(3), idic(3), etc.
inv (3q)
5
range) （M:F） ）
t(3q)
50
(%)
Gender
Other abnormalities
of chromosome 3
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del(3)
Structural rearrangement
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trisomy 3
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Table 1. Distributions and characteristics of chromosome 3 abnormalities in the hematological malignancies in this series (n=300)
inv (3p)
in chromosome 3
der (3)
---
---
≥2 abnormalities
in chromosome 3 ﹟
23
11
23
(7.7%)
(3.7%)
(7.7%)
68
48
60
(34-79)
(38-87)
(26-78)
1.56:1
1.75:1
1.56:1
Abbreviations: t(3q)= translocation(3q); inv(3q)=inversion(3q); t(3p)= translocation(3p); inv(3p)= inversion(3p); der(3)=derivation(3).
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rare
abnormalities ＊
0
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient.
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other
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Table 2. The pattern of chromosome 3 abnormalities occurring in the individual hematological malignancies Ages
Gender
Abnormalities
Median (Range)
M/F
N (%) 36(23-71)
17(5.7%)
36(21-59)
AML
74(24.7%)
48.5(13-83)
HAL
6(2.0%)
27(21-60)
MDS
48(16.0%)
56(14-84)
MM
38(12.7%)
59(36-87)
10(3.3%)
58(15-70)
23(7.7%)
58(29-80)
CLL
13(4.3%)
63(46-63)
Lymphoma
12(4.0%)
51(23-64)
ALL
41(13.7%)
26(11-80)
Total
300(100%)
47(11-87)
EP
Others △ Unknown ▲
1.25:1
△ Others indicated hematological disorders not mentioned in this table.
AC C
▲ Unknown indicated the patients without identified diagnosis.
Chromosome 3
Chromosome 3
abnormality
abnormal plus another
abnormality as a
chromosome
component in a
abnormality
complex abnormality
0(0.0%)
16(6.4%)
1.83:1
2(14.3%) 0(0.0%)
1(2.9%)
16(6.4%)
1.39:1
4(28.6%)
14(40.0%)
56(22.3%)
M AN U
18(6%)
CML-AP/BC
2:1
0(0.0%)
1(2.9%)
5(2.0%)
3:1
2(14.3%)
8(22.9%)
38(15.1%)
1.71:1
1(7.1%)
1(2.9%)
36(14.3%)
1:1
1(7.1%)
2(5.7%)
7(2.8%)
1.56:1
1(7.1%)
2(5.7%)
20(8.0%)
5.5:1
0(0.0%)
3(8.6%)
10(4.0%)
2.25:1
0(0.0%)
0(0.0%)
12(4.8%)
1.41:1
3(21.4%)
3(8.6%)
35(13.9%)
1.73:1
14(100.0%)
35(100.0%)
251(100.0%)
TE D
CML-CP
Sole chromosome 3
SC
Chromosome
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Table 3A. Distributions of different hematological malignancies in each of the chromosome 3 abnormalities in this series del(3)
abnormalities in 3p p
abnormalities in 3q q
☆
※
der(3)
other rare
≥2 abnormalities
abnormalities ＊
chromosome 3﹟ ﹟
0 (0.0%)
0(0.0%)
6(13.0%)
10(10.5%)
0(0.0%)
1(9.1%)
1(4.3%)
CML-AP/BC
2 (3.1%)
2(5.3%)
4(8.7%)
5(5.3%)
2(8.7%)
2(18.2%)
0(0.0%)
AML
11(17.2%)
15(39.5%)
11(23.9%)
4(17.4%)
1(9.1%)
7(30.4%)
HAL
1(1.6%)
2(5.3%)
1(2.2%)
2(2.1%)
0(0.0%)
0(0.0%)
0(0.0%)
MDS
4(6.3%)
6(15.8%)
11(23.9%)
14(14.7%)
6(26.1%)
4(36.4%)
3(13.0%)
MM
20(31.3%)
0(0.0%)
1(2.2%)
6(6.3%)
4(17.4%)
2(18.2%)
5(21.7%)
Others △
0(0.0%)
1(2.6%)
2(4.3%)
4(4.2%)
1(4.3%)
0(0.0%)
2(8.7%)
Unknown ▲
6(9.4%)
3(7.9%)
1(2.2%)
8(8.4%)
2(8.7%)
1(9.1%)
2(8.7%)
CLL
7(10.9%)
0(0.0%)
2(4.3%)
2(2.1%)
1(4.3%)
0(0.0%)
1(4.3%)
SC
CML-CP
M AN U
trisomy 3
25(26.3%)
1(2.6%)
1(2.2%)
5(5.3%)
1(4.3%)
0(0.0%)
1(4.3%)
10(15.6%)
8(21.1%)
6(13.0%)
14(14.7%)
2(8.7%)
0(0.0%)
1(4.3%)
Total
64(100.0%)
38(100.0%)
23(100.0%)
11(100.0%)
23(100.0%)
TE D
3(4.7%)
ALL
Lymphoma
46(100.0%)
95(100.0%)
in 3p indicated genomic losses or gains of the region of chromosome 3p and structural rearrangements of 3p, including del(3p), add(3p), t(3p) and inv(3p).
※ Abnormalities
in 3q indicated genomic losses or gains of the region of chromosome 3q and structural rearrangements of 3q, including del(3q), add(3q), t(3q) and inv(3q).
＊ Other rare abnormalities included ins(3), idic(3) etc.
EP
☆ Abnormalities
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient. △ Others indicated hematological disorders not mentioned in this table.
AC C
▲ Unknown indicated the patients without identified diagnosis.
in
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Others △
Unknown ▲
CLL
Lymphoma
ALL
0(0.0%)
6(26.1%)
7(53.8%)
3(25.0%)
10(24.4%)
SC
Table 3B. Distributions of the different chromosome 3 abnormalities in each of the hematological malignancies in this series
1(10.0%)
3(13.0%)
0(0.0%)
1(8.3%)
8(19.5%)
2(20.0%)
1(4.3%)
2(15.4%)
1(8.3%)
6(14.6%)
6(15.8%)
4(40.0%)
8(34.8%)
2(15.4%)
5(41.7%)
14(34.1%)
6(12.5%)
4(10.5%)
1(10.0%)
2(8.7%)
1(7.7%)
1(8.3%)
2(4.9%)
0(0.0%)
4(8.3%)
2(5.3%)
0(0.0%)
1(4.3%)
0(0.0%)
0(0.0%)
0(0.0%)
7(9.5%)
0(0.0%)
3(6.3%)
5(13.2%)
2(20.0%)
2(8.7%)
1(7.7%)
1(8.3%)
1(2.4%)
74(100%)
6(100.0%)
38(100.0%)
10(100.0%)
23(100.0%)
13(100.0%)
12(100.0%)
41(100.0%)
CML-AP/BC
AML
HAL
MDS
MM
trisomy 3
0(0.0%)
2(11.8%)
11(14.9%)
1(16.7%)
4(8.3%)
20(52.6%)
del (3)
0(0.0%)
2(11.8%)
15(20.3%)
2(33.3%)
6(12.5%)
0(0.0%)
in
6(33.3%)
4(23.5%)
11(14.9%)
1(16.7%)
11(22.9%)
1(2.6%)
in
10(55.6%)
5(29.4%)
25(33.8%)
2(33.3%)
14(29.2%)
der(3)
0(0.0%)
2(11.8%)
4(5.4%)
0(0.0%)
other rare
1(5.6%)
2(11.8%)
1(1.4%)
1(5.6%)
0(0.0%)
18(100.0%)
17(100.0%)
abnormalities 3p ☆ abnormalities 3q ※
≥2
TE D
abnormalities ＊
abnormalities in chromosome 3﹟
48(100.0%)
in 3p indicated genomic losses or gains of the region of chromosome 3p and structural rearrangements of 3p, including del(3p), add(3p), t(3p) and inv(3p).
※ Abnormalities
in 3q indicated genomic losses or gains of the region of chromosome 3q and structural rearrangements of 3q, including del(3q), add(3q), t(3q) and inv(3q).
＊ Other rare abnormalities included ins(3), idic(3) etc.
EP
☆ Abnormalities
﹟ Defined as two or more abnormalities are concurrently seen on chromosome 3 in one patient.
AC C
Total
M AN U
CML-CP
△ Others indicated hematological disorders not mentioned in this table. ▲ Unknown indicated the patients without identified diagnosis.
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Table 4. Distributions of combined chromosome abnormalities involving chromosome 3 and another chromosome in hematological malignancies (n=35) Chromosome
Total
1
2
5
6
7
8
9
11
number
CML-CP
0(0.0%)
CML-AP/BC
1(2.9%)
AML
14(40.0%)
HAL
1(2.9%)
MDS
8(22.9%)
MM
1(2.9%)
Others
2(5.7%)
Unknown
2(5.7%)
CLL
3(8.6%)
Lymphoma
0(0.0%)
ALL
3(8.6%)
3 (8.6%)
3
7
(8.6%)
2
(20.0%)
5
(5.7%)
2
(14.3%)
(5.7%)
1 (2.9%)
1
16
5
18
2
(2.9%)
(14.3%)
(5.7%)
*
*
*
22
1 (2.9%)
X
2
1
(5.7%)
（2.9%）
*
*
*
*
*
* *
*
*
* *
* *
M AN U
(100%)
SC
35
*
TE D
n, %
12
*
*
*
* * *
AC C
EP
“*” indicates the designated chromosome participates in the formation of combined abnormalities presented in the listed condition.
*
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Characteristic of t(3;V)
Chromosome1
Chromosome1; 10.0%
Chromosome2 Chromosome3
Chromosome2; 5.0%
M AN U
ChromosomeX; 2.5%
SC
More than one chromosome translocation; 15.0%
Chromosome3; 7.5%
Chromosome22; 5.0%
Chromosome21; 2.5%
Chromosome4; 3.8%
Chromosome20; 1.3% Chromosome19; 1.3% Chromosome18; 1.3%
TE D
Chromosome5; 7.5%
Chromosome17; 2.5% Chromosome16; 5.0%
Chromosome6; 2.5%
Chromosome15; 1.3%
Chromosome7; 2.5%
Chromosome14; 2.5%
Chromosome8; 2.5%
Chromosome13; 1.3%
Chromosome4 Chromosome5 Chromosome6 Chromosome7 Chromosome8 Chromosome9 Chromosome10 Chromosome11 Chromosome12 Chromosome13 Chromosome14 Chromosome15 Chromosome16 Chromosome17 Chromosome18 Chromosome19 Chromosome20 Chromosome21 Chromosome22 ChromosomeX 多条易位
Chromosome12; 8.8%
EP
Chromosome9; 2.5%
Chromosome10; 2.5%
AC C
Chromosome11; 3.8%
Figure 1：Frequency of the chromosomes that participated in the formation of translocation t (3;V)： ：Chromosome 3 can interact with any of the chromosomes
(chromosomes 1 to 22) within the genome to form a translocation t (3;V), particularly involving chromosomes 1, 12, 3, 5, 16 and 22 (≥5.0%).
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35.0%
33.3%
27.5%
27.3%
25.0% 20.0%
24.0%
19.5% 17.6%
16.9% 16.0%
15.0%
13.2%
11.0%
10.4%
10.4%
4.0% 2.2% 1.1% 0.0%
CML-CP
5.3% 3.9%
4.0% 2.6% 1.1%
1.3% 1.3%
8.8%
3.9%
2.6% 1.3%
1.3% 1.3%
0.0%
CMLAP/BC
AML
HAL
M AN U
5.0%
8.8%
SC
9.3% 8.8%
10.0%
0.0%
RI PT
30.0%
genomic gains genomic losses structural rearrangements
MDS
MM
Other
Unknown
CLL
Lymphoma
ALL
Figure 2: Incidence of different type of abnormalities in chromosome 3. MM patients accounted
AC C
EP
TE D
for the highest percentage in the group of genomic gains; AML patients accounted for the highest percentage in the group of genomic losses and structural rearrangements. The genomic losses were most frequently observed in AML, ALL and HAL patients, while structural rearrangements were most frequently observed in CML and MDS patients and genomic gains in MM, CLL and lymphoma patients.
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M AN U
SC
RI PT
3A
AC C
EP
TE D
3B
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M AN U
SC
RI PT
3C
AC C
EP
TE D
Figure 3 Survival profiles of patients with different abnormalities in chromosome 3: 3A. From the survival analysis, patients with simple abnormal chromosome 3 karyotype had numerically better prognosis than patients with complex abnormal chromosome 3 karyotype; but no statistical difference was found between the two groups (p＞0.05). 3B. From the survival analysis, clinical outcomes of patients with genomic gains in chromosome 3 were better than those with genomic losses or structural rearrangement in chromosome 3, although no statistical difference was found (p＞0.05). 3C. From the survival analysis, patients with trisomy 3 had significantly better prognosis than those with del(3), who exhibited the worse prognosis among the examined populations (p＜0.05).
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M AN U
SC
RI PT
4A
AC C
EP
TE D
4B
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M AN U
SC
RI PT
4C
AC C
EP
TE D
Figure 4 ： 4A. Survival profiles of different hematologically malignant patients with abnormalities in chromosome 3: 4A. From the survival analysis, CML patients with abnormalities in chromosome 3 (CML-group 3, n=16) had the worst prognosis as compared with the CML patients with t(9;22) abnormalities alone (CML-group 1, n=34) and those with abnormal karyotypes other than in chromosome 3 (CML-group 2, n=39) (p＜0.05). 4B. From the survival analysis, ALL patients with abnormalities in chromosome 3 (ALL-group 3, n=16) demonstrated a significantly worse prognosis than that of ALL patients with normal karyotypes (ALL-group 1, n=25) (p＜0.05), although no statistical difference was found when compared with the patients with abnormal karyotypes other than in chromosome 3 (ALL-group 2, n=35) (p＞ 0.05). 4C. From the survival analysis, MM patients with abnormalities in chromosome 3 (MM-group 2, n=15) had a numerically worse prognosis than that of MM patients with normal karyotypes (MM-group 1, n=21), although no statistical difference was found between these two groups (p＞0.05). Because the follow-up data of MM patients with abnormal karyotypes other than in chromosome 3 was not adequate , the comparative analysis had not been performed on this group of patients.
