Resistance to 1-Beta-d-arabinofuranosylcytosine and hypersensitivity to bleomycin in ataxia-telangiectasia B-lymphoblastoid cell-lines

Three ataxia telangiectasia (AT) B-lymphoblastoid cell lines (B-LCLs) were examined for the chromosome aberrations induced by a DNA replication and repair inhibitor, 1-beta-D-arabinofuranosylcytosine (ara-C), and the effects of ara-C on the frequencies of chromosome aberrations caused by bleomycin (BLM). All these AT cell lines exhibited resistance to ara-C compared with normal and Bloom syndrome (BS) cells. In contrast with normal and BS cells, ara-C did not enhance chromosome aberrations produced by BLM in AT cells, although these cells showed hypersensitivity to BLM. After treatment with 1 X 10(-5) M ara-C for 24 h, total frequencies of chromosome aberrations in AT cells were 0.095-0.115/cell, which is about 6 times lower than those in normal (0.625/cell) and BS cells (0.775/cell). Following combination treatment with tetrahydrouridine (THU) and ara-C, we found that the frequencies of chromosome aberrations in AT B-LCLs were greatly increased compared with treatment with ara-C alone. Furthermore, when AT cells were pretreated with THU in combination with ara-C, then treated with BLM, a great synergistic enhancement of chromosome aberrations was observed. Because THU is an exclusive inhibitor of cytidine deaminase, these results strongly indicate that in AT B-LCLs there could be overproduction of cytidine Jeaminase, which is responsible for ara-C resistance. On the other hand, combination of THU and deoxycytidine (dCyd) significantly reduced chromosome aberrations induced by BLM in AT cells, although dCyd alone had no effect on bleomycin-induced chromosome aberrations. Break point distributions on chromosome bands following treatment with BLM or ara-C plus THU, alone or in combination, were examined and are discussed.     

Prognostic significance of karyotype at diagnosis in childhood acute lymphoblastic leukemia [corrected]

Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. The disease is heterogeneous. The leukemic cells in childhood ALL patients show various karyotypic abnormalities, express diverse phenotypes, and respond variably to treatment. Identification of prognostic factors will make it possible to predict treatment outcome and to identify the patients that require different therapeutic approaches. The important prognostic implications of chromosome number and of the presence of several well defined structural chromosomal aberrations have been established by several groups. We analyzed 145 children with ALL at diagnosis for cytogenetic features. In 135 cases cytogenetic analysis was successful. Of these, 101 showed abnormal karyotype (70%). Structural chromosomal rearrangements were detected in 71 out of 135 cases investigated (53%), i.e. 71% of the cytogenetically abnormal cases. These cytogenetic findings were correlated with clinical outcome. In our series the ploidy of the karyotype appeared to be of prognostic importance. Our findings concerning karyotype, phenotype, and treatment outcome of this subgroup were in most cases in agreement with earlier reports from other investigators. We observed an increased risk for central nervous system relapse in childhood ALL patients with abnormalities involving the short arm of chromosome 12 in combination with pre-B or common ALL phenotype.     

Acute cytogenetic effects of antineoplastic drugs on peripheral blood lymphocytes in cancer patients chromosome aberrations and micronuclei

AIMS AND BACKGROUND: The aim of the present study was to evaluate the individual sensitivity of cancer patients to different antineoplastic drugs administered in standard protocols by assessing their acute cytogenetic effects on peripheral blood lymphocytes. METHODS AND STUDY DESIGN: In 12 patients undergoing cancer chemotherapy, acute cytogenetic effects on peripheral blood lymphocytes were evaluated by analysis of structural chromosome aberrations and micronuclei. All patients were given antineoplastic drugs, mainly as polychemotherapy. The frequencies of both cytogenetic biomarkers determined after the first chemotherapy cycle were compared with their pre-treatment (baseline) values. RESULTS: All chemotherapy protocols employed induced clear cytogenetic effects in both tests studied. The results obtained indicate interindividual variations between cytogenetic damage in peripheral blood lymphocytes among cancer patients. Statistically significant increases in the total number of structural chromosome aberrations and micronuclei in lymphocytes analyzed after chemotherapy compared to pre-therapy samples were observed in almost all patients studied. The highest level of chromosome damage as well as the highest incidence of micronuclei was observed following administration of the ACOP protocol (adriamycin, cyclophosphamide and vincristine). The proportions of signal-positive and signal-negative micronuclei were evaluated using DAPI staining, while silver staining revealed Ag-NOR+ and Ag-NOR- micronuclei. In some patients the incidence of signal-positive and Ag-NOR+ micronuclei after treatment was increased, indicating a more pronounced susceptibility of particular chromosomes to damage caused by antineoplastic drugs. CONCLUSIONS: With regard to the results obtained we may conclude that both parameters used in the present study on peripheral lymphocytes are sensitive biomarkers and can be successfully employed for biomonitoring of acute cytogenetic effects induced by antineoplastic drugs in standard clinical protocols for cancer treatment.     

Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia.

PURPOSE: To prospectively compare cytogenetic and molecular cytogenetic analysis for the detection of the most relevant chromosome abnormalities in a large series of patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred forty consecutive adult patients with AML entered onto the multicenter treatment trial AML HD93 were studied. Chromosome banding and fluorescence in situ hybridization (FISH) applying a comprehensive set of genomic DNA probes were performed in a single reference laboratory. RESULTS: Two cases of inv(16), three cases of t(11q23), and three cases of t(8;21)var were only detected by molecular cytogenetics. By FISH, aberrations were identified in three cases with normal karyotypes: inv(16), -Y (in a patient with low metaphase yield on chromosome banding) and a 12p microdeletion. Additional aneuploidies, in particular +8q and +11q, were diagnosed by FISH; however, virtually all these aberrations occurred in patients with complex karyotypes or as an additional abnormality in leukemias with an AML-specific translocation. Finally, aberrations were detected by FISH in eight of 14 patients with no assessable metaphases. CONCLUSION: In most cases of AML, conventional cytogenetic study reliably detects chromosomal abnormalities, and this method should not be replaced by FISH. FISH should be used as a complementary method for the detection of more subtle abnormalities, such as inv(16) and t(11q23), in all patients with newly diagnosed AML and for suspected t(8;21)var. Furthermore, molecular cytogenetics using this comprehensive set of DNA probes provides a valuable diagnostic tool for patients with poor chromosome morphology, low or no yields of metaphase cells, or both.     

Cytogenetic effects of chemotherapy and cranial irradiation on the peripheral blood lymphocytes of children with malignant disease.

Results of a cytogenetic analysis of peripheral blood lymphocytes of children with leukemia after massive chemotherapy and cranial irradiation, and of children with nephrosis after coritisone therapy and cyclophosphamide are presented. Prolonged intensive chemotherapy results in a significant rise in the number of chromatid aberrations after twelve months, and of chromosomal aberrations after 24 months of therapy. After cranial irradiation a sharp rise in chromosome aberrations is present for about three months. This drops after one year to levels present in cases with chemotherapy alone.     

Cytogenetic and immunohistochemical analysis of lymphoepithelioid cell lymphoma (Lennert's lymphoma): further substantiation of its T-cell nature

In 1968 a special variant of Hodgkin's disease, epithelioid cellular lymphogranulomatosis--later on termed lymphoepithelioid cell lymphoma/Lennert's lymphoma--was defined. There are increasing indicators that Lennert's lymphoma is of T-cell origin. Seven cases of Lennert's lymphoma are studied with cytogenetic as well as immunohistochemical techniques. Six of them have cytogenetic abnormal clones always including aberrations of chromosome No. 3 (+3, break in q22, dup q22----q24). In all cases band 3q22 is either broken or duplicated. Immunohistochemically it is clearly demonstrated that the proliferating cells are of T-cell nature (Ki67+, Leu4+, Leu1+). Under consideration in the literature it can be stated in conclusion that (1) lymphoepithelioid cell lymphoma (Lennert's lymphoma) with aberrations has to be designated as malignant lymphoma, (2) immunohistochemical double labeling proved the T-cell nature of this lymphoma, (3) there are remarkable similarities between the chromosomal patterns of lymphoepithelioid cell lymphoma, lymphogranulomatosis X/angioimmunoblastic lymphadenopathy and probably Hodgkin's disease: many normal mitoses and abnormalities of chromosome No. 3, especially trisomy. It is discussed that abnormalities of chromosome No. 3 involving band q22 are an indicator of a common genetic background of these lymphomas.     

应用FISH技术对我国早期从事医用X线工作者的细胞遗传学评价

目的:对受到长期、低剂量率照射的我国早期从事医用X线工作者辐射损伤的远期效应进行细胞遗传学观察和评价.方法:用4号和7号全染色体探针和荧光原位杂交技术,分析25名早期X线工作者和10名对照者外周血淋巴细胞染色体畸变,并用Giemsa染色验证.结果:直观地表现出正常靶染色体和多种畸变.X线工作者的易位占其染色体总畸变的84 %;其他各种畸变率分别为插入(Ins)1.9%、双着丝粒(Dic)4.5%、无着丝粒断片(Ace)9.7 %;X线工作者的染色体易位率和总畸变率均明显高于对照组(P＜0.005).结论:早期医用X线工作者外周血淋巴细胞的染色体畸变以易位为主.     

The benzene metabolites hydroquinone and catechol act in synergy to induce dose-dependent hypoploidy and -5q31 in a human cell line

Chronic exposure to high concentrations of benzene is associated with an increased incidence of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Studies of patients occupationally exposed to benzene show a pattern of cytogenetic aberrations involving loss of all or part of chromosomes 5 and/or 7 as well as trisomy 8 and we have previously reported that hydroquinone (HQ) induces deletions of 5, 7 and 8. Benzene metabolism is a requirement for bone marrow toxicity and the phenolic metabolites, HQ and catechol (CAT), have been implicated in benzene hematotoxicity. A research project was designed to determine whether CAT by itself and in conjunction with HQ could directly induce loss of chromosome 5 and/or 7 and gain of chromosome 8. Using fluorescence in situ hybridization with chromosome-specific 5, 7, and 8 probes we demonstrate that 5 to 150 uM CAT does not produce chromosomal aberrations, however CAT and 25 uM HQ can act in synergy to induce dose dependent loss of these chromosomes. In addition HQ/CAT selectively induces -5q which is not observed for HQ only. These results demonstrate for the first time that CAT/HQ act in synergy to induce specific chromosome loss found in secondary MDS/AML.     

The Benzene Metabolites Hydroquinone and Catechol Act in Synergy to Induce Dose-Dependent Hypoploidy and -5q31 in a Human Cell Line

Chronic exposure to high concentrations of benzene is associated with an increased incidence of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Studies of patients occupationally exposed to benzene show a pattern of cytogenetic aberrations involving loss of all or part of chromosomes 5 and/or 7 as well as trisomy 8 and we have previously reported that hydroquinone (HQ) induces deletions of 5, 7 and 8. Benzene metabolism is a requirement for bone marrow toxicity and the phenolic metabolites, HQ and catechol (CAT), have been implicated in benzene hematotoxicity. A research project was designed to determine whether CAT by itself and in conjunction with HQ could directly induce loss of chromosome 5 and/or 7 and gain of chromosome 8. Using fluorescence in situ hybridization with chromosome-specific 5, 7, and 8 probes we demonstrate that 5 to 150 uM CAT does not produce chromosomal aberrations, however CAT and 25 uM HQ can act in synergy to induce dose dependent loss of these chromosomes. In addition HQ/CAT selectively induces -5q which is not observed for HQ only. These results demonstrate for the first time that CAT/HQ act in synergy to induce specific chromosome loss found in secondary MDWAML.     

Recurrent cytogenetic aberrations in histologically benign,invasive meningiomas of the sphenoid region

Meningiomas that arise in the sphenoid region (MSR) often display growth patterns leading to widespread invasion and destruction of the surrounding structures. Consequently, there is still estimated recurrence rate up to 30% with MSR. Conventional cytogenetic studies have failed to reveal aberrations characteristic of invasive meningiomas. Here we investigated 10 invasive and 5 non-invasive MSR using the array-based comparative genomic hybridization (array-CGH) with the GenoSensor Array 300. Mean number of aberrations detected per tumor was significantly greater for invasive meningiomas—67.4 compared with 40.5 for non-invasive MSR. Additionally, invasive MSR disclosed frequent losses on 1p, 6q, 14q and gains on 15q and 20, which were identified previously as molecular hallmarks of stepwise meningioma progression. Thus, the presence of a complex cytogenetic profile and progression-associated chromosomal aberrations in benign MSR is associated with their increased invasive potential. Inasmuch as no reliable adjuvant therapy for recurrent meningiomas is available thus far, revealed genomic aberrations can provide a potential targets for drug discovery and therapeutic intervention in a future.     

Nonrandom chromosome changes in malignant melanoma

Chromosome aberrations were analyzed in 4 cases of malignant melanoma (MM) after disaggregation of the tumors with collagenase and short-term culture. In all cell cultures, the MM cells displayed a typical triangular spindle form. The chromosome number was near-diploid in one case and near-triploid in three cases. A total of 27 abnormal chromosomes were identified with the Giemsa banding technique. By far, the most common types of abnormalities were translocations, followed by deletions and isochromosomes. Chromosomes 1, 6, and 7 were found to be most frequently involved in structural aberrations. Markers originating from chromosomes 1 and 6 were found in all four cases, and abnormalities of chromosome 7 were found in three. Each marker chromosome was unique for a given case; no common markers for two or more cases were found. Based on the present results and an analysis of reports on the chromosomal constitution of MM cells in the literature, we suggest that abnormalities involving chromosomes 6 and 7 may be a characteristic feature of MM. Aberrations of chromosome 1, although common in MM, may be part of a general cytogenetic feature in human neoplasia.     

A case-control analysis of lymphocytic chromosome 9 aberrations in lung cancer

Cytogenetic aberrations on chromosome 9 have been reported to be one of the most frequent genetic changes in lung tumorigenesis. Although many of these changes have been detected in lung carcinoma specimens, there is growing evidence showing the concordance between chromosomal alterations in primary lung tumors and peripheral blood lymphocytes (PBLs). We investigated whether spontaneous aberrations on chromosome 9 in PBLs are associated with the presence of lung cancer and with a family history of cancer. A personal interview, to construct a detailed epidemiologic profile including family history of cancer, was conducted on 174 lung cancer cases and 162 matched controls. One hundred metaphases from PBLs of each subject were analyzed for chromosome 9 aberrations using the whole chromosome painting technique. Overall, the mean proportion of individuals with chromosome 9 abnormalities in their PBLs was significantly higher in cases (96.0%) than in controls (60.5%) (p < 0.05). After adjustment by age, gender, ethnicity, family size, and pack-years, there was a 16.63-fold significantly elevated odds ratio (OR) for lung cancer associated with chromosome 9 aberrations. When subjects were categorized by frequencies of the chromosome 9 lesions, we observed significantly increased odds ratios of 11.13 (4.66, 26.58) and 27.45 (11.15, 67.54) for individuals with 1 chromosome 9 aberration and >/=2 chromosome 9 aberrations, respectively. By performing family history analyses, we further observed that control individuals with chromosome 9 aberrations were more likely to report a family history of any cancer (OR = 1.67 [0.84, 3.32]) and lung cancer (OR = 2.49 [0.81, 7.67]). Our findings suggest that chromosome 9 aberrations in PBLs might be considered a marker of lung cancer predisposition and may be associated with familial aggregation of cancer.     

17p Anomalies in Lymphoid Malignancies: Diagnostic and Prognostic Implications

Eighteen patients with lymphoid malignancies and abnormalities of the short arm of chromosome 17 were evaluated, in order to analyse whether this anomaly was associated with a particular subgroup of lymphoid malignancies. The patients suffered from acute lymphoblastic leukemia, high-grade non-Hodgkin's lymphoma or plasma cell leukemia. No 17p anomaly was found in any patient with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma. In four cases the aberration of the short arm of chromosome 17 was the sole cytogenetic abnormality, in fourteen patients additional chromosomal aberrations were found. Five out of 18 cases were Burkitt's lymphoma/leukemia showing the typical rearrangement of 8q24. In cases with a karyotype evolution the 17p anomaly was always a late event. Concerning the clinical outcome of the patients with abnormalities of the short arm of chromosome 17 eight of nineteen patients died within 90 days after the diagnosis of the 17p anomaly only three were alive at the last follow up (26 months to 40 months after diagnosis of a 17p aberration). Rearrangements of 17p, especially as secondary cytogenetic events, seem to be associated with a poor clinical outcome in lymphoid malignancies.     

Recurrent chromosomal aberrations in INK4a/ARF defective primary lymphomas predict drug responses in vivo

Predicting responsiveness to anticancer therapy based on molecular findings at diagnosis is important to optimize treatment decisions. Although clinical outcome correlates with distinct mutations in some cancer entities, treatment responses within these lesion-stratified subgroups still remain heterogeneous, underscoring the need for additional prognosticators. We previously demonstrated that defined genetic defects at the INK4a/ARF locus, which encodes the tumor suppressors p16INK4a and ARF, not only accelerated lymphomagenesis in the Emu-myc transgenic mouse but also interfered with treatment sensitivity. In this study, we take a nonbiased genome-wide approach to examine whether the responsiveness of these lymphomas can be further stratified based on cytogenetic information at diagnosis. Indeed, using spectral karyotyping, comparative genomic hybridization, and fluorescence in situ hybridization in 38 primary lymphomas, we find recurrent cytogenetic alterations that refine the predictive value of INK4a/ARF lesions on drug responses in vivo: gain of chromosome 14, which was never detected in INK4a/ARFnull lymphomas, defined an ARFnull subgroup with superior treatment outcome. Gain of chromosome 6 was identified as a recurrent chromosomal aberration that predisposed ARFnull tumors to their subsequent INK4a loss during therapy. These data illustrate how cytogenetic information from cancer specimens might complement established prognostic markers and may improve anticancer treatment strategies.     

Chromosome instability as an indicator of malignant progression in laryngeal mucosa.

PURPOSE: Routine histologic examination cannot predict whether premalignant laryngeal lesions will progress toward invasive growth. The acquisition of changes in chromosome constitution has been suggested to be essential for driving tumor progression by enhancing mutagenic mechanisms. The aim of the present study was to determine whether chromosomal changes occur in the subsequent stages of early laryngeal carcinogenesis and, if so, whether these changes can be of prognostic value. MATERIALS AND METHODS: Numerical aberrations for chromosomes 1 and 7 were detected in tissue sections from archival material using an improved in situ hybridization protocol. In total, eight benign laryngeal lesions, 37 premalignant laryngeal lesions, and 16 specimens containing histologically normal epithelia adjacent to laryngeal squamous cell carcinomas were studied. Both the histologic and the cytogenetic classifications were correlated with progression to laryngeal cancer. RESULTS: No evidence for chromosome alterations was obtained in the control group, nor in histologically normal epithelia adjacent to laryngeal squamous cell carcinomas, nor in all but one hyperplastic lesion (n = 11). In contrast, 14 of 15 dysplastic lesions and nine of 11 carcinomas-in-situ contained numerical chromosomal aberrations. Tetrasomy was present in the majority of the dysplastic lesions. An unstable chromosome content (indicated by the presence of chromosome imbalances and/or polyploidization) in the premalignant lesion strongly predicted its malignant progression. CONCLUSION: Our results show that laryngeal tumor development involves chromosome tetraploidization. The further change from a stable to an unstable chromosome constitution is of importance for malignant progression.     

Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities

BackgroundAbnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset.Patients and MethodsThrough the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts).ResultsSpecific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3–MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P = .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P = .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs.ConclusionPatients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.     

Cytogenetic abnormalities in Langerhans cell histiocytosis.

We present the cytogenetic investigations of five histiocytic tumour lesions from children. In four cases there was a confirmed diagnosis of Langerhans cell histiocytosis (LCH) and one case of histiocytosis that did not fulfil all the criteria for true LCH. All five cases showed cytogenetic abnormalities, including the first report of an abnormal clone in LCH. The clone showed a t(7;12)(q11.2;p13) translocation and was detected in only a small percentage of cells. This case and a further three also contained non-clonal abnormalities and an increase in chromosome breakage. The fifth case, the only one in which no acquired abnormalities were seen, had a constitutional paracentric inversion of chromosome 13q.     

Chromosomal aberrations accumulate in polyploid cells of high-grade squamous intraepithelial lesions (HSIL)

Persistant infection with human papillomavirus (HPV) of the uterine cervix is related with cytological atypia (SIL), the oncogenic potential of which is unclear in a given time point of monitoring. HPV-induced genetic instability result in polyploidization as well as in low frequency random chromosome aberrations in squamous cells. In the present work we analyzed whether highly polyploid/aneuploid cells reflect genomic changes at the chromosomal level. 13 samples with the cytological diagnosis of HSIL were analyzed for HPV type and nuclear DNA content measured by laser scanning cytometry (LSC). Hyperdiploid cells with >5c and with >9c DNA content were further analyzed for numerical aberrations of the chromosomes 3 and 17 by fluorescence in situ hybridization (FISH) following repositioning. Cells with >5c DNA content were found more frequently than cells with >9c DNA content (5-98 and 1-44 cells, respectively). The FISH analysis demonstrated frequent polysomies, however, the rate of aneusomy (other than 2, 4, 8 or 16 chromosome copies) was significantly higher in cells with >9c DNA content than in cells with >5c DNA content or the normal diploid cells. The imbalance of chromosome 3 and 17 copy number was also increased in cells with >9c DNA content. Moreover, in three out of the 13 analyzed HSIL samples, recurrent abnormal chromosome 3/17 ratio was demonstrated in a significant part of the cells, indicating a common origin of these cells. Highly polyploid/aneuploid cells in HSIL accumulate cytogenetic aberrations detectable by FISH analysis. These cells may reflect early changes with tumorigenic potential in a very concentrated fashion.     

碳离子辐照诱导人外周血淋巴细胞染色体畸变的时间和剂量效应

目的：研究碳离子辐照诱导淋巴细胞染色体畸变的时间和剂量效应。方法：以加速的碳离子为辐射源,吸收剂量分别为2、4Gy的碳离子辐照人外周血淋巴细胞后,分别培养48、72、84h后收集细胞,用姊妹染色单体区别染色法分析淋巴细胞第一次分裂中期染色体畸变,以研究畸变的时间效应;吸收剂量为0、0.5、1、2、3、4Gy的碳离子辐照人外周血淋巴细胞后,培养48h,用常规染色体技术研究碳离子辐照诱导淋巴细胞染色体畸变的剂量效应。结果：辐照后分别培养48、72和84h得到的双着丝粒和着丝粒环畸变（＂双＋环＂畸变）频率没有明显差异;在0.5～4Gy剂量范围内,＂双＋环＂畸变的量效关系符合线性关系：Y=0.0005＋0.689D。结论：在本实验辐照条件下,碳离子辐射诱导淋巴细胞染色体畸变不存在时间效应,可以用48h的培养时间来研究碳离子的生物学效应,并发现染色体＂双＋环＂畸变随剂量的增加而呈线性增加。