Deletions and losses in chromosomes 5 or 7 in adult acute lymphocytic leukemia: incidence, associations and implications.

Deletions or losses in chromosomes 5 or 7 are recurrent non-random abnormalities in acute myeloid leukemia (AML), and are associated with prior exposure to carcinogens or leukemogenic agents, and with poor prognosis. Their occurrence and significance in adult acute lymphocytic leukemia (ALL) is not well described. The aim of the study was to evaluate the incidence, associations and implications of chromosome 5 or 7 abnormalities in adult ALL. Patients with newly diagnosed ALL referred to MD Anderson Cancer Center between 1980 and 1996 were analyzed. Characteristics and outcome of patients with or without chromosome 5 or 7 abnormalities were compared by standard statistical methods. Thirty-one of 468 patients (6.6%) had chromosome 5 or 7 abnormalities. Loss of chromosome 5 occurred in six cases, three of them had both chromosome 5 and 7 abnormalities. Deletion or loss of chromosome 7 occurred as a single abnormality in three patients; in 28 patients it was associated with other abnormalities. The most significant cytogenetic association was with the Philadelphia chromosome (Ph) abnormality occurring in nine patients (29%). Compared with patients without the abnormalities, patients with chromosome 5 or 7 abnormalities tended to express CD34 more frequently (74% vs 54% P = 0.07), to be older (age >60 years 29% vs 18% P = 0.14), and to be associated with Ph (29% vs 11% P = 0.004). With therapy, the complete response (CR) rate with chromosome 5 or 7 abnormalities was lower (64% vs 79% P = 0.038) but the survival rate was similar (3-year survival rate 32% vs 36% P = 0.14). When the 22 patients without Ph were considered separately, the CR and survival rates were similar among patients with or without chromosome 5 or 7 abnormalities. Abnormalities in chromosome 5 or 7 are not specific for AML, and may occur in ALL. Unlike in AML, chromosome 5 or 7 abnormalities in ALL were not predictive of worse prognosis, which is accounted for mostly by the association with Ph.     

Correlation of chromosome abnormalities with patient characteristics, histologic subtype, and induction success in children with acute nonlymphocytic leukemia

Cytogenetic analyses of bone marrow cells were performed in 195 children with acute nonlymphocytic leukemia (ANLL) at diagnosis, as part of Childrens Cancer Study Group Study No. 251. Ninety-six patients (49%) exhibited clonal abnormalities, including trisomy 8 in 18 patients, t(8;21) in 11, t(15;17) in seven, loss of a sex chromosome in seven, monosomy 7 in seven, and the Philadelphia chromosome in four. Clonal abnormalities were found significantly more often in younger patients. Furthermore, recurring cytogenetic abnormalities tended to correlate with specific ages. For example, t(8;21) was associated significantly with children over four years of age, while -7 associated with overall loss of genetic material from the long arm of chromosome 7 (7q) and 11q- were associated significantly with younger children. Recurring chromosome abnormalities also correlated with specific ANLL histologic subtypes, such as t(8;21) with acute myelogenous leukemia and t(15;17) with acute promyelocytic leukemia. Presence or absence of cytogenetic abnormalities was compared with the ability of patients to achieve remission. Individuals exhibiting clonal abnormalities in bone marrow cells had an equally likely chance of achieving remission (74%) as those individuals with normal karyotypes (75%). Nonrandom chromosome abnormalities associated with a high induction success rate included +8 with a 94% induction success rate (P = .13) and t(8;21) with a 91% success rate (P = .46). Patients exhibiting the -7 abnormality associated with overall loss of 7q had a significantly less successful induction outcome, with only 28% achieving remission (P = .02); three of seven patients with t(15;17) died during induction therapy.     

High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative.

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.     

Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia

BACKGROUND: The purpose of the current study was to evaluate the cytogenetic features of the hypodiploid leukemic cells of pediatric patients with this rare subgroup of acute lymphoblastic leukemia (ALL). In addition, the authors determined whether subdivision of the hypodiploid category served a prognostic purpose for these patients. METHODS: The authors evaluated the cytogenetic records of 979 patients with ALL admitted to St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 1999. RESULTS: Of 67 patients (6.8%) whose leukemic cells contained a modal number (MN) of chromosomes less than or equal to 45 (i.e., hypodiploid leukemic cells), 57 had an MN of 45 and 10 had an MN of less than 45. In 19 patients, cells with an MN of 45 had a whole chromosome missing (42%), which was a sex chromosome in 12 patients (63%). Leukemic cells with an MN of 45 contained dicentric chromosomes (n = 33) formed from chromosome 9p (55%), 12p (18%), or both (21%). The ETV6-CBFA2 fusion was present in 39% of 28 evaluable B-lineage cases with an MN of 45. The event-free survival rate (EFS) for patients with hypodiploid leukemic cells of MN less than 45 (5-year EFS = 20.0% +/- 10.3%) was significantly (P < 0.001) lower than that for patients with leukemic cells of MN greater than or equal to 45 (5-year EFS = 74.9% +/- 1.6%). CONCLUSIONS: Low hypodiploidy (MN < 45) should be recognized as a high-risk feature in pediatric ALL. Only two hypodiploid groups (MN < 45 and MN = 45) may be necessary in prognostic assessments.     

Trisomy 8 as sole anomaly or with other clonal aberrations in acute myeloid leukemia: impact on clinical presentation and outcome

One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age >or=60 years (P<0.0001) and association with unfavorable karyotype (P=0.03) were of poor prognostic value for CR achievement. Age >or=60 years (P<0.0001) and antecedents of dysmyelopoiesis (P=0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics (P=0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.     

DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma.

PURPOSE: To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy. PATIENTS AND METHODS: The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities. RESULTS: The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis-positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P =.01); CR + nCR, 25% v 11% (P =.01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P =.84); CR + nCR, 17% v 15% (P =.73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P <.0001); CR + nCR, 27% v 6% (P <.0001). CONCLUSION: Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.     

Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.

PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. PATIENTS AND METHODS: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS). RESULTS: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 x 10(9) cells/L v 16 x 10(9) cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P =.005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P =.04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P <.0001), an increasing WBC count (P <.0001), poor-risk cytogenetics (P =.005), and T-lineage (P =.01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P <.0001 and P =.0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P =.002) and EFS (P =.0002) in B-lineage ALL and for EFS (P =.05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents. CONCLUSION: This study's findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.     

Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere.

Dicentric chromosomes are observed in many malignant diseases including myelodysplasia (MDS) and acute myeloid leukemia (AML) and have often been observed in a subset of these diseases, namely therapy-related MDS (t-MDS) and AML (t-AML). Using fluorescence in situ hybridization (FISH) with centromere-specific probes, we investigated the frequency and type of dicentric chromosomes in 180 consecutive patients with t-MDS and t-AML and in 231 consecutive patients with de novo MDS and AML, whose karyotypes had been studied previously by conventional G-banding. Twenty-seven out of 180 patients with t-MDS or t-AML presented dicentric chromosomes compared to only seven out of 231 patients with de novo disease (P = 0.00003). A dic(1q;7p) was observed in 10 cases, a dic(5p;17q) was observed in six cases, whereas various isodicentric chromosomes were observed in six cases. Excluding these six cases with isodicentrics, all 25 patients with dicentric chromosomes had involvement of at least one of the chromosome arms 1q, 5p, or 7p resulting in monosomy for 5q or 7q, and/or trisomy for 1q. Patients with dicentric chromosomes presented significantly more often as t-MDS compared to patients without dicentrics (P = 0.046), and the presence of a dicentric chromosome was significantly related to previous therapy with alkylating agents (P = 0.026). Thus, only one out of 27 patients with a dicentric chromosome had not previously received an alkylating agent. A specific susceptibility to breakage at the centromere after exposure to alkylating agents is suggested and may explain the frequent loss of whole chromosomes, in particular chromosomes 5 and 7 in t-MDS and t-AML, if the breaks are not followed by rejoining. Leukemia (2000) 14, 105-111.     

Histopathological, cytogenetic, and molecular characterization of renal cortical tumors.

We used cytogenetic and restriction fragment length polymorphism (RFLP) analysis methods to define genetic alterations and also correlate the changes with histopathology in renal cortical tumors. The study series is comprised of 50 renal tumors in 4 histological categories: (a) clear cell, nonpapillary, renal cell carcinoma (RCC) (n = 32); (b) nonclear cell, nonpapillary RCC (n = 10); (c) papillary RCC (n = 3); and (d) oncocytic tumors (n = 5). Successful karyotypes were obtained from 28 tumors (56%), of which 17 (61%) were abnormal. Abnormalities of chromosome 3p were seen in 9 tumors, which included unbalanced translocations and terminal or interstitial deletions. Abnormalities of chromosome 5 were identified in 11 tumors, 8 of which were due to unbalanced translocations between 3p and 5q, resulting in an extra copy for the region 5q22----ter. In addition, trisomy or tetrasomy of chromosome 17 was seen in 6 (5 with normal chromosome 3 and one with 3p deletion), trisomy or more copies of chromosome 7 in 8 (4 with 3p deletion, 2 with trisomy or tetrasomy 17, and 2 with trisomy alone), and trisomy 12 in 3 (all with trisomy 17) tumors. Furthermore, relative deficiency of chromosome 17p was seen in 3 (all with deletion 3p) and chromosome 18 in 4 (all with deletion 3p) tumors. RFLP analysis with four chromosome 3 specific probes detected 3p deletions in 19 tumors with the most common breakpoint located between 3p14-21. The 19 3p deletions detected by RFLP included tumors that also showed rearrangement of 3p by cytogenetics (n = 4) and those that showed normal karyotypes (n = 3) in addition to cytogenetic failures (n = 12). Deletions of 17p were seen in 5 of 31 informative cases. Thus, deletions of 3p were seen in a total of 24 tumors by cytogenetic and/or RFLP analysis, 21 of which were clear cell, nonpapillary RCC, whereas 3 had a minor clear-cell component. Oncocytic and nonclear, nonpapillary tumors, on the other hand, did not demonstrate 3p deletions by either technique, whereas trisomy 17 was seen in 3 of the 3 papillary tumors. The loss of alleles from chromosome 17p and 18 and an increased dosage of gene or genes on chromosomes 5q and 7 as seen in high-stage tumors of various histological subtypes may be associated with progression of disease.     

Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.

BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P =.02) and time to recurrence (P =.01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P =.02) and time to recurrence (P =.004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P =.006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P =.003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P =. 002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P =.002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.     

Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.     

Trisomy 13 in acute leukemia.

Trisomy 13 occurring as a sole cytogenetic abnormality has recently been demonstrated to have adverse prognostic significance in acute leukemia. Trisomy 13 is seen primarily in an older male population, and has been reported in treatment-associated acute leukemia and acute leukemia evolved from myelodysplastic syndromes, as well as in de novo leukemia. The 36 cases of acute leukemia with trisomy 13 reported to date include 26 AML, 6 AUL, 2 ALL and 2 mixed lineage patients. Immunophenotyping studies have demonstrated an undifferentiated phenotype or biphenotypic markers in most cases. Trisomy 13 is associated with a low complete remission rate and with brief remission duration. The role of the additional copy of chromosome 13 in the pathogenesis of these cases of acute leukemia and the gene(s) of importance on chromosome 13 are yet to be determined.     

Trisomy 13 in Acute Leukemia

Trisomy 13 occurring as a sole cytogenetic abnormality has recently been demonstrated to have adverse prognostic significance in acute leukemia. Trisomy 13 is seen primarily in an older male population, and has been reported in treatment-associated acute leukemia and acute leukemia evolved from myelodysplastic syndromes, as well as in de novo leukemia. The 36 cases of acute leukemia with trisomy 13 reported to date include 26 AML, 6 AUL, 2 ALL and 2 mixed lineage patients. Immunophenotyping studies have demonstrated an undifferentiated phenotype or biphenotypic markers in most cases. Trisomy 13 is associated with a low complete remission rate and with brief remission duration. The role of the additional copy of chromosome 13 in the pathogenesis of these cases of acute leukemia and the gene(s) of importance on chromosome 13 are yet to be determined.     

Trisomy 21 as the sole acquired chromosomal abnormality in children with acute lymphoblastic leukemia.

Most studies of cytogenetic abnormalities in leukemia patients have focused on structural chromosomal rearrangements. Less attention has been paid to the role of single numerical abnormalities in the complex mechanisms of leukemia pathogenesis. We therefore studied 11 cases of acute lymphoblastic leukemia (ALL) with trisomy 21 as the sole chromosomal abnormality, representing 1.8% of 601 completely banded cases of ALL seen during a 10-year period. Bone marrow cells from all but one of these cases also had normal karyotypes, representing 8 to 77% of the completely analyzed metaphases. Each of the five cases tested lacked evidence of trisomy 21 mosaicism of constitutional origin in peripheral blood samples. The presenting features of these five girls and six boys were heterogeneous but tended to reflect lower-risk ALL: median age, 3.3 years (range 1-18 years), median leukocyte count, 11.6 x 10(9)/l (range 1.8-82 x 10(9)/l), white race, and a B-cell precursor immunophenotype. Complete remissions were readily induced in all 11 patients. With follow-up ranging from 1+ months to 6.4+ years, the only relapses have been extramedullary (testis and central nervous system) in two patients, both of whom have since achieved second remissions of greater than 76 and greater than 65 months. Trisomy 21 as the sole chromosomal abnormality in childhood ALL appears related to favorable presenting risk features and may represent a good prognosis subset within the group of patients with 47-50 chromosomes.     

The characteristics and outcome of patients with late relapse acute myelogenous leukemia

The characteristics and outcome of 58 patients with acute myelogenous leukemia (AML) who experienced relapse after a first remission duration longer than 18 months (late-relapse AML) were analyzed and compared with those of 278 patients with earlier relapses. Late-relapse AML was associated with a lower incidence of antecedent hematologic disorder, leukocytosis, and elevated creatinine and lactic acid dehydrogenase (LDH) levels. A favorable karyotype (inversion of chromosome 16; translocations between chromosomes 8 and 21, or 15 and 17) was more frequent in patients whose first remission was 12 months or longer compared with less than 12 months (30% v 10%; P less than .0001). An unfavorable karyotype (chromosome 5 and 7 abnormalities, trisomy 8, other changes) was more frequent in the latter category (16% v 42%; P less than .0001). Thirty-seven of the 58 patients (64%) with late-relapse AML achieved complete remission (CR). The incidence of CR increased significantly with an increased first remission duration from less than 12, 12 to 18, and greater than 18 months (17% v 41% v 64%; P less than .0001), while the incidence of resistant disease was significantly lower (59% v 36% v 19%; P less than .0001). When effective antileukemic regimens were considered, remission rates were also significantly increased by the duration of first remission (24% v 48% v 72%; P less than .001). Compared with patients with earlier relapse, those with late-relapse AML had a longer median survival from salvage therapy (3.5 v 12 months; P less than .01), and longer median second remission durations (3.5 v 11 months; P less than .01). We conclude that late-relapse AML has unique clinical, cytogenetic, and prognostic characteristics, and remains extremely sensitive to chemotherapy with a potential cure fraction. The duration of first remission is an important prognostic parameter in AML relapse and may be useful in the design and analysis of future salvage programs.     

Acquired chromosome 11q deletion involving the ataxia teleangiectasia locus in B-cell non-Hodgkin's lymphoma: correlation with clinicobiologic features.

PURPOSE: To study the clinicobiologic significance of acquired 11q deletions involving the ataxia teleangiectasia locus (ATM+/-) in B-cell non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Fifty-three indolent lymphomas and 82 aggressive lymphomas were studied by conventional cytogenetic analysis and by fluorescence in situ hybridization using an 11q22-23 probe recognizing ATM sequences. Pertinent clinical data were collected. RESULTS: A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas). Dual-color hybridization studies showed ATM deletion to be possibly a secondary aberration in three patients with MCL. Ten out of 15 ATM+/- patients had a complex karyotype, 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status), and +12, 13q14 deletion, and 17p13 deletion were seen in seven, four, and five cases, respectively. Patients with ATM+/- more frequently had a complex karyotype (P =.01) and the AA karyotype (P =.04) compared with patients without ATM+/-. With the exception of a poor performance status (P =.001), no correlation was found between ATM+/-, initial clinical variables, and complete remission rate; whereas a highly significant association was found with shorter survival (P <.0001). This cytogenetic lesion maintained its prognostic importance in multivariate analysis (P =.0004), along with performance status (P =.0006), serum lactate dehydrogenase level (P =.03), splenomegaly (P =.01), and histologic grade (P =.03). When analyzing indolent lymphomas and aggressive lymphomas separately, ATM+/- maintained its prognostic importance as an independent variable in both histologic groups (P =.0001 and P =.016, respectively). CONCLUSION: Though possibly not representing a primary genetic lesion in the majority of cases, the acquired ATM+/- status has clinicobiologic importance in NHL, possibly representing a major cytogenetic determinant of outcome.     

Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia.

PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12-14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12-14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12-14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P =.04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P =.25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P =.72). CONCLUSION: Aberrations of 13q12-14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.     

慢性淋巴细胞白血病的分子遗传学特点

目的 了解慢性淋巴细胞白血病（CLL）的分子遗传学特性。方法运用间期荧光原位杂交（FISH）技术对60例初发的B细胞CLL（B-CLL）患者进行12号染色体3体（＋12）、del（13q14）和del（17p13）检测。结果60例患者中,41例（68．3％）至少有一种分子遗传学异常,2例（3．3％）具有2种染色体异常。12例（20．0％）有＋12异常,其畸变细胞率在4．0％-34．0％之间;24例（40．0％）有del（13q14）异常,其畸变细胞率在22．0％～93．0％之间,其中3例有2条染色体del（13q14）异常;7例（11．7％）有del（17p13）异常,其畸变细胞率在6．0％～68．0％之间。不同Binet分期中,3种分子遗传学异常差异无统计学意义。结论FISH是一种在分析CLL染色体数目和结构异常方面较为快速、准确和敏感的方法,可为CLL的研究提供较为准确的分子遗传学信息。