Sole abnormalities of chromosome 7 in myeloid malignancies: Spectrum, histopathologic correlates, and prognostic implications

Authors


  • Conflicts of interest: The authors declare no competing financial interests.

Abstract

Among 6,565 consecutive abnormal cytogenetic reports at our institution, 3,192 (49%) constituted sole abnormalities, of which 230 (7%) involved chromosome 7: monosomy 7 (n = 98), 7q- (n = 51), der(1;7)(q10;p10) (n = 44), balanced translocations (n = 15), ring 7 (n = 13), and 7p- (n = 9). The most frequent histopathologic correlates were myelodysplastic syndromes (MDS; 28%), acute myeloid leukemia (AML; 17%), secondary or therapy-related MDS/AML (13%), primary myelofibrosis (PMF; 7%), and chronic myelomonocytic leukemia (6%). Monosomy 7 was the most frequent in each one of these disease categories except PMF where 7q- was more frequent. In primary MDS, patients with der(1;7)(q10;p10) (n = 13), compared to those with monosomy 7 (n = 30) or 7q- (n = 15), were less likely (P = 0.04) to display excess blasts or multilineage dysplasia but overall and leukemia-free survival adjusted for these variables revealed no significant difference between the three groups (P = 0.57 and 0.81, respectively). The current study does not prognostically distinguish monosomy 7 from 7q- or der(1;7), in MDS. Am. J. Hematol. 87:684–686, 2012. © 2012 Wiley Periodicals, Inc.

Introduction

Bone marrow myeloid blast percentage, karyotype and presence or absence of multilineage dysplasia constitutes the three most important prognostic parameters in myelodysplastic syndromes (MDS) [1]. Of these, prognostic classification according to cytogenetic findings has undergone numerous revisions and the observations from different investigators, in this regard, have not been always consistent [2–9]. The international prognostic scoring system (IPSS) considers complex karyotype (=3 abnormalities) and chromosome 7 abnormalities as poor-risk karyotype in MDS and does not distinguish between monosomy 7 and other chromosome 7 abnormalities [8]. However, recent reports have suggested that MDS patients with 7q- or der(1;7)(q10;p10) might carry a better prognosis than those with monosomy 7 [9–13] whereas others have refuted such a distinction [14]. In many of these studies, prognostic assessment of chromosome 7 abnormalities was confounded by the inclusion of patients with additional other chromosome abnormalities and those with therapy-related MDS [9, 13, 14].

In the current study, we focused on sole chromosome 7 abnormalities to avoid confounding from other chromosomal abnormalities. Our objectives were to (i) describe the prevalence and spectrum of chromosome 7 abnormalities in an unselected cohort of cytogenetic studies performed at our institution over a 20-year period, (ii) describe the specific histopathologic diagnoses associated with these abnormalities, and (iii) assess interabnormality [i.e., monosomy 7 vs. 7q- vs der(1;7)(q10;p10)] prognostic differences in the context of primary MDS and after accounting for presence or absence of excess blasts or multilineage dysplasia.

Materials and Methods

Between the years 1989 and 2009, a total of 24,262 cytogenetic studies were performed on Mayo Clinic patients with suspected or known hematologic malignancies. Cytogenetic studies were performed utilizing short-term bone marrow cultures along with conventional G or R banding fluorescence [15]. Where possible, 20 metaphases were evaluated. The findings were described and reported according to the international society of cytogenetic nomenclature (ISCN) [16]. An abnormality was considered clonal when at least two metaphases had the same aberration in case of a structural abnormality or an extrachromosome and at least three metaphases for classification as a monosomy [16]. World Health Organization (WHO) criteria were used for disease classification [17]. The study was approved by the Mayo Clinic Internal Review Board and adhered to the tenets of the Declaration of Helsinki.

All patients with abnormal karyotype were reviewed to identify those with sole chromosome 7 abnormalities, further subclassified into seven operational groups: monosomy 7, 7q-, der(1;7)(q10;p10), balanced translocations, 7p-, ring 7 alone, ring 7 with monosomy 7 or 7q-. All statistical analyses considered parameters at time of first referral to the Mayo Clinic, which in most instances was the time of initial diagnosis. Differences in the distribution of continuous variables between categories were analyzed by Mann–Whitney or Kruskal–Wallis test. Patient groups with nominal variables were compared by chi-squared test. The primary endpoints for prognostic assessment were overall and leukemia-free survival and were calculated from the date of cytogenetic testing using Kaplan–Meier plots. Cox proportional hazard regression model was used for multivariable analysis. P values <0.05 were considered significant. The Stat View (SAS Institute, Cary, NC) statistical package was used for all calculations.

Results and Discussion

Consecutive patients (n = 24,262) were included in the current analysis. An abnormal karyotype was seen in 6,565 cases (27%). Of these 3,192 (49%) were sole abnormalities and 900 (14%) had abnormalities involving chromosome 7. Among the latter, 230 (26%) had sole abnormalities of chromosome 7 including monosomy 7 (n = 98; 43%), 7q- (n = 51; 22%), der(1;7)(q10;p10) (n = 44; 19%), balanced translocations (n = 15; 7%), 7p- (n = 9; 4%), ring 7 (n = 9; 4%), and ring 7 with monosomy 7 or 7q- (n = 4; 2%). The most frequent histopathologic diagnoses were MDS (28%), acute myeloid leukemia (AML; 17%), secondary or therapy-related MDS/AML (13%), primary myelofibrosis (PMF; 7%), and chronic myelomonocytic leukemia (CMML; 6%). Monosomy 7 was the most frequent in each one of these clinicopathologic categories except PMF where 7q- was more frequent. Table I summarizes the myeloid histopathologic diagnoses that were associated with the aforementioned sole chromosome 7 abnormalities and considers 199 cases (out of the total 230) with at least two instances of a specific myeloid diagnosis with chromosome 7 abnormality.

Table I. Hematologic Myeloid Malignancies With At Least Two Cases With Sole Abnormality of Chromosome 7
 Total (N = 199)Monosomy 7 (N = 91)7q- (N = 46)Der 7 (N = 36)Balanced translocation 7 (N = 10)7p- (N = 5)Ring 7 (N = 8)Ring 7 and 7q- or monosomy 7 (N = 3)
  1. *Primary

  2. Abbreviations: MDS, myelodysplastic syndromes; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, RA with excess blasts; AML, acute myeloid leukemia; MPN, myeloproliferative neoplasms; ET, essential thrombocythemia; PMF, primary myelofibrosis; Post PVMF, post polycythemia vera myelofibrosis; Post ETMF, Post ET myelofibrosis; CNL, chronic neutrophilic leukemia; MPN-U, MPN unclassifiable; t-AML, therapy related AML; t-MDS, therapy related MDS; CMML, chronic myelomonocytic leukemia; JMML, juvenile myelomonocytic leukemia; and SM, systemic mastocytosis.

MDS*653015134021
MDS with unilineage dysplasia247591020
 RARS41110001
 RCMD127410000
 RAEB2515523000
AML*3920923221
 M075100010
 M172500000
 M296100011
 M451101200
 M521001000
 M631110000
 M742011000
 Unclassified22000000
MPN34513111310
 ET20110000
 PMF174641110
 Post-PV MF91340100
 Post-ET MF20110000
 CNL10000100
 MPN-U30210000
t-AML or t-MDS2211550010
CMML1310200001
 < 5% blasts44000000
 ≥ 5% blasts96200001
Non-diagnostic103221020
Post MDS or MPN AML or MDS87010000
Aplastic anemia or hypocellular MDS41021000
JMML22000000
SM/MDS22000000

The number of study patients with primary MDS was large enough (n = 65) to further investigate disease-specific phenotypic and prognostic correlates. The most common sole chromosome 7 abnormalities in MDS were monosomy 7 (n = 30), 7q- (n = 15) and der(1;7)(q10;p10) (n = 13), accounting for 58 of the total 65 patients. At presentation, MDS patients with der(1;7)(q10;p10), compared to those with monosomy 7 or 7q-, were less likely to display excess blasts or multilineage dysplasia (P = 0.04) and more likely to display higher hemoglobin (P = 0.01) but the three groups were otherwise largely similar in other clinical or laboratory features (Table II). All 58 MDS patients with sole monosomy 7, 7q- or der(1;7)(q10;p10) were followed to death (median 14 months; range, 0–112). Overall and leukemia-free survival comparisons, adjusted for the presence of either excess blasts or multilineage dysplasia, revealed no significant difference between the three groups (P = 0.57 and 0.81, respectively). The absence of a significant survival difference was also apparent in a univariate analysis (Fig. 1; P = 0.14). Of note, overall survival analysis considered all 58 patients whereas leukemia-free survival analysis considered 29 of the 58 patients in whom the presence or absence of leukemic transformation before death could be ascertained.

Figure 1.

Overall survival data of 58 patients with primary MDS and sole chromosome 7 abnormalities, stratified by the specific cytogenetic abnormality displayed: monosomy 7 vs. 7q- vs. der(1;7)(q10;p10). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Table II. Presenting Clinicopathologic Features of 58 Patients With Myelodysplastic Syndromes and Sole Chromosome 7 Abnormalities
 Total (N = 58)Monosomy 7 (N = 30)Del 7 (q) (N = 15)Der 7 (N = 13)P value
  1. Abbreviations: MDS, myelodysplastic syndromes; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, RA with excess blasts.

Median age in years (range)68.5 (13.1–94.5)66.6 (38.6–88.3)72.3 (56.2–94.5)62.4 (13.1–87.0)0.06
Number of males (%)41 (71%)19 (63%)11 (73%)11 (85%)0.36
MDS subcategory    0.12
MDS with unilineage dysplasia21 (36.2%)7 (23.3%)5 (33.3%)9 (69.3%) 
RARS3 (5.2%)1 (3.3%)1 (6.7%)1 (7.7%) 
RCMD12 (20.7%)7 (23.3%)4 (26.7%)1 (7.7%) 
RAEB22 (37.9%)15 (50%)5 (33.3%)2 (15.4%) 
Presence of excess blasts or multilineage dysplasia; n (%)    0.04
Both absent24 (41.4%)8 (26.7%)6 (40%)10 (76.9%) 
Multilineage dysplasia present without excess blasts12 (20.7%)7 (23.3%)4 (26.7%)1 (7.7%) 
Excess blasts present22 (37.9%)15 (50%)5 (33.3%)2 (15.4%) 
Median hemoglobin (g/dL)9.38.99.611.40.01
Median WBC (×109/L)3.43.14.22.60.13
Median platelet count (×109/L)9677168960.07
Median follow up (months)14 (0–112)13.3 (0–55)14.9 (2–52)11.6 (2–112)0.61

Previous reports in MDS have suggested that 7q- or der(1;7) is prognostically better than monosomy 7 [9–13]. However, these studies mostly used univariate analysis in their evaluation of survival: Hasse et al. [9] (a tendency toward better survival with 7q- compared to monosomy 7), Pozdnyakova et al. [10] (better survival with 7q- or der(1;7) compared to monosomy 7), and Cordoba et al. [11] (better survival with 7q- compared to monosomy 7). Multivariable analysis was utilized in the study by Sanada et al. [13] (better survival with der(1;7) compared to either 7q- or monosomy 7) but the results were confounded by the inclusion of patients with therapy-related MDS and those with multiple chromosome abnormalities. Most recently, Schanz et al. [12] reported that 7q- was more favorable with regards to overall survival as compared to monosomy 7, when each was considered as a single abnormality, but their observation was internally inconsistent in that 7q- and monosomy 7 were considered equivalent for defining double abnormalities. On the other hand, Slovak et al. [14] found no significant survival difference between der(1;7) and either monosomy 7 or 7q- in MDS patients of whom some were therapy-related.

Taken together, we conclude that the results of most previous studies that suggest prognostic variation among MDS patients with specific chromosome 7 abnormalities are undermined by not only the inclusion of patients with therapy-related MDS or additional chromosome abnormalities but also by the lack of multivariable analysis that accounts for other risk factors such as the presence of excess blasts or multilineage dysplasia. The current study attempts to address these issues and its results suggest similar overall and leukemia-free survival among primary MDS patients with isolated abnormalities of monosomy 7, 7q-, or der(1;7).

Author Contributions

FTNH and AT performed all data collection, statistical analysis, and wrote the article. EPN, RK, and DVD reviewed all cytogenetic abnormalities. CAH reviewed hematopathology. SR helped in collection of information. AP contributed patients and helped in statistical analysis. All authors approved the final draft of the article.

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