22例急性白血病患者染色体脆性部位分析

对22例急性白血病患者和15例正常人外周血淋巴细胞染色体脆性部位进行了观察分析。实验结果表明:病人组的染色体结构畸变率和脆性部位检出率均显著高于正常对照组。经C显带定位的断点中检出脆性部位43种表达211次,有26种和癌断裂点对位,有8种与癌基因位点一致。以上结果提示脆性部位和染色体的断裂重排有相关性,在急性白血病的发病机理上可能起重要作用。     

喉癌及鼻腔鼻窦癌患者淋巴细胞染色体脆性部位的研究

用ＴＣ１９９培养基及原位显带的方法，对３７例喉癌、鼻腔鼻窦癌及２０例正常人染色体脆性部位进行分析。结果表明癌症患者脆性部位表达率显著高于正常人，且其表达的脆性部位与癌相关断裂点及癌基因位点密切相关。     

食管癌遗传病因的研究：Ⅴ.林县食管癌高癌家族成员淋巴...

The chromosome fragile sites of cultured peripheral lymphocytes from 40 members of 4 high risk cancer families and 10 members of 4 low risk cancer families in Linxian County were analysed. The results showed that 46 fragile sites in 7045 lymphocytes expression at 502 times (7.13%) were found in high risk cancer families and 8 fragile sites in 1053 lymphocytes expression at 26 times (2.47%) were found in low risk cancer families. There was a significant difference between the two groups (P less than 0.01). In 46 fragile sites carried by 40 members of high risk cancer families, 27 were common, 5 rare, 12 provisional and 2 new fragile sites. Among them, the fragile sites at 1p22-p36 and 4q21-q31 were detected in members of high risk cancer families and in patients with esophageal cancer, meanwhile, uniform breakpoint in chromosome deletion and rearrangement was also found in 4 esophageal cancer cell lines. Therefore, the author conjectures that these fragile sites at 1p13-p36 and 4q21-q31 may be fragile site-specific for high risk cancer families and patients with esophageal cancer, and they may be breakpoint-specific for esophageal cancer cells. These fragile sites may play an important role in esophageal carcinogenesis in high risk cancer families.     

Chromosome fragile sites in patients with multiple primary tumors and familial forms of breast cancer]

An analysis was carried out of chromosomal site-fragility in patients with primary multiple tumors and familial breast cancer. A possible correlation is discussed between fragile sites, breakpoints in chromosome rearrangements in cancer patients and the localization of oncogenes mapped in chromosomal regions involved in said rearrangements.     

Variant Philadelphia translocations in chronic myeloid leukemia: correlation with cancer breakpoints, fragile sites and oncogenes

Four cases of variant Philadelphia (Ph1) translocations were found in 72 patients (5.5%) with Ph1-positive chronic myeloid leukemia (CML). One previously unreported case was a simple variant translocation, namely, 46,XY,t(11;17)(q13;p13),t(17;22)(q25;q22); 46,XY,t(1;21)(q32;q11),t(11;17)(q13;p13), t(17;22)(q25;q11). Complex variant translocations were observed in three cases, namely, 46,XY,t(5;9;22)(q31;q34;q11),46,XX,t(8;9;22) (q22;q34;q11) and 46,XX,t(9;15;22) (q34;q15;q11). The chromosomal breakpoints in the cases of variant Ph1 translocations were the following: 1q32, 5q31, 8q22, 11q13, 15q15, 17p13, 17q25 and 21q11. Eight of the eight (100%) breakpoints were located in Giemsa-negative bands. Furthermore, seven of the eight (87%) variant Ph1 breakpoints correspond to the breakpoints present in consistent cancer arrangements. Three of the eight (38%) correspond to fragile sites and four of the eight (50%) correspond to oncogenes.     

Fragile sites are targets of diverse mutagens and carcinogens

Using a high-resolution chromosome banding technique with cultured human lymphocytes and caffeine as a mutagen enhancer, 16 different mutagens and carcinogens were found to induce 110 recurrent fragile sites. All agents produced chromosome breaks and the majority of the 110 recurrent break sites involved were elicited by at least half of all agents, even though they act through different molecular mechanisms. Two of the agents used are known to induce hypersensitive chromatin sites in regulatory regions of active genes. Of the 110 mutagen-sensitive fragile sites, 50 coincide with the location of 50 of 75 specific cancer chromosome breakpoints (67%) and 21 with the location of 26 of 36 oncogenes (72%). The expression of so many similar fragile sites following exposure of cultured cells to diverse mutagens, and the high correlation of these sites with cancer chromosome breakpoints and oncogenes, suggests that they can be general targets of mutagenic action.     

Relationship between chemical-induced fragile sites and chromosomal breakpoints in malignant cells in children.

Many fragile sites in the human genome occur at or near chromosomal breakpoints reportedly involved in translocations of DNA material in neoplastic cells. This fact has led some investigators to postulate that fragile sites have a pathogenic role in human neoplasia. To learn whether caffeine-induced fragile sites relate to breakpoints found in the neoplastic cells of an individual patient, we studied lymphocytes from the peripheral blood of 32 patients in remission from malignant disease. Lymphocytes were cultured in medium containing either 5-Fluoro-2'-deoxyuridine (FdU) or FdU plus caffeine, and G-banded metaphases were examined for nonrandom breaks. Analyses of completely G-banded malignant cell chromosomes from 31 of the 32 patients were available for comparison. In only once case, a 5-year-old child with acute lymphoblastic leukemia, did a caffeine-induced fragile site (1q44) coincide with a breakpoint in the neoplastic cells [dup(1)(q21-->q44)]. Our findings suggest that chromosomal abnormalities in childhood malignancies cannot generally be explained by the presence of FdU- or FdU plus caffeine-induced fragile sites.     

Relationship Between Chemical-Induced Fragile Sites and Chromosomal Breakpoints in Malignant Cells in Children

Many fragile sites in the human genome occur at or near chromosomal breakpoints reportedly involved in translocations of DNA material in neoplastic cells. This fact has led some investigators to postulate that fragile sites have a pathogenic role in human neoplasia. To learn whether caffeine-induced fragile sites relate to breakpoints found in the neoplastic cells of an individual patient, we studied lymphocytes from the peripheral blood of 32 patients in remission from malignant disease. Lymphocytes were cultured in medium containing either 5-Fluoro-2'-deoxyuridine (FdU) or FdU plus caffeine, and G-banded mataphases were examined for nonrandom breaks. Analyses of completely G-banded malignant cell chromosomes from 31 of the 32 patients were available for comparison. In only once case, a 5-year-old child with acute lymphoblastic leukemia, did a caffeine-induced fragile site (1q44) coincide with a breakpoint in the neoplastic cells [dup(1)(q21 $ q44)]. Our findings suggest that chromosomal abnormalities in childhood malignancies cannot generally be explained by the presence of FdU- or FdU plus caffeine-induced fragile sites.     

胃良恶性疾病外周血淋巴细胞染色体脆性位点表达与胃癌的发生

目的：探讨胃良恶性疾病外周血淋巴细胞染色体脆性位点与胃癌发生的关系。方法：采用低叶酸培养条件，比较胃癌（１５例）与慢性浅表性胃炎和胃溃疡（各１５例）患者的外周血淋巴细胞染色体脆性位点表达率，差异有非常显著性意义。结果：胃癌组阳生个体表达例数有统计学意义的７个脆性位点５个与癌断裂点、癌基因居染色体同一区带，涉及到７个癌基因，表明与癌基因同位或相邻的脆性位点活跃表达在胃癌发生中起了极重要的作用。同一胃     

Chromosome Fragility of Lymphocytes from Breast Cancer Patients in Relation to Epidemiologic Data

The chromosomal fragility of peripheral blood lymphocytes from 50 women, undergoing operations for breast tumors (47 carcinomas, 2 intraductal papillomatoses and 1 malignant lymphoma) was studied to ascertain the association between chromosome fragility and epidemiologic data, such as a family or personal history of cancer, hormonal status, etc. Under conditions of folic acid and thymidine depletion, the average number of gaps and breaks on the patients' lymphocyte chromosome was 6.02±5.28 and that in the control medium was 2.0±2.0 while those of healthy controls were 5.8±5.5 and 1.36±1.22. These gaps and breaks were mostly seen in group A chromosomes (4.1±2.6) in 24 patients, including the 2 with benign tumors and the 1 with the lymphoma as well as 11 healthy controls. They were frequent in group B (3.0±0) in 3 patients, in group C (4.3±2.9) in 11 patients, and in groups D (2.0±1.0) and E (3.0±1.0) in 3 patients from each. This different distribution of gaps and breaks correlated neither with the patients' age nor with their tumor's histology, but patients having a late menarche were distributed in non-A groups. There was low inducibility of breaks in patients with a family history of breast cancer and/or relatively rare cancers. The availability of common fragile sites for studying an individual's susceptibility to cancer is discussed. One patient showed a bromodeoxyuridine-requiring heritable 10q25 fragile site. Another, with triple primary cancers, showed a constitutional translocation of t(5;19)(q15;q13).     

Chromosome fragility of lymphocytes from breast cancer patients in relation to epidemiologic data

The chromosomal fragility of peripheral blood lymphocytes from 50 women, undergoing operations for breast tumors (47 carcinomas, 2 intraductal papillomatoses and 1 malignant lymphoma) was studied to ascertain the association between chromosome fragility and epidemiologic data, such as a family or personal history of cancer, hormonal status, etc. Under conditions of folic acid and thymidine depletion, the average number of gaps and breaks on the patients' lymphocyte chromosome was 6.02 +/- 5.28 and that in the control medium was 2.0 +/- 2.0 while those of healthy controls were 5.8 +/- 5.5 and 1.36 +/- 1.22. These gaps and breaks were mostly seen in group A chromosomes (4.1 +/- 2.6) in 24 patients, including the 2 with benign tumors and the 1 with the lymphoma as well as 11 healthy controls. They were frequent in group B (3.0 +/- 0) in 3 patients, in group C (4.3 +/- 2.9) in 11 patients, and in groups D (2.0 +/- 1.0) and E (3.0 +/- 1.0) in 3 patients from each. This different distribution of gaps and breaks correlated neither with the patients' age nor with their tumor's histology, but patients having a late menarche were distributed in non-A groups. There was low inducibility of breaks in patients with a family history of breast cancer and/or relatively rare cancers. The availability of common fragile sites for studying an individual's susceptibility to cancer is discussed. One patient showed a bromodeoxyuridine-requiring heritable 10q25 fragile site. Another, with triple primary cancers, showed a constitutional translocation of t(5;19)(q15;q13).     

鼻咽癌患者染色体断裂热点与SCE高发位点、脆性部位、原癌基因位点的相关研究

采用在染色体标本上同时显示ＳＣＥ及Ｇ带带型的方法，对鼻咽癌患者染色体断裂热点与ＳＣＥ高发位点、染色体脆性部位及原癌基因位点之间的相关性进行了分析。结果表明：患者的ＳＣＥ频率、染色体畸变率均显著的高于对照组（Ｐ＜０．０１），患者的染色体断裂点和ＳＣＥ位点都主要分布在染色体的Ａ、Ｂ、Ｃ、Ｄ组和浅带上，且两者所累及的染色体号存在着明显的相关（ｒ＝０．９５７６，Ｐ＜０．０１），患者的１５个断裂热点与ＳＣＥ高发位点的一致率为５３．３３％，与脆性部位的一致率为８０％，与原癌基因位点的一致率为４０％     

Chromosomal fragile site FRA16D and DNA instability in cancer

It has been proposed that common aphidicolin-inducible fragile sites, in general, predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Although this appears to be the case for the fragile site FRA3B and may be the case for FRA7G, it is not yet clear whether this association is a general property of this class of fragile site. The major aim of the present study was to determine whether the FRA16D chromosomal fragile site locus has a role to play in predisposing DNA sequences within and adjacent to the fragile site to DNA instability (such as deletion or translocation), which could lead to or be associated with neoplasia. We report the localization of FRA16D within a contig of cloned DNA and demonstrate that this fragile site coincides with a region of homozygous deletion in a gastric adenocarcinoma cell line and is bracketed by translocation breakpoints in multiple myeloma, as reported previously (Chesi, M., et al., Blood, 91: 4457-4463, 1998). Therefore, given similar findings at the FRA3B and FRA7G fragile sites, it is likely that common aphidicolin-inducible fragile sites exhibit the general property of localized DNA instability in cancer cells.     

Roles of FHIT and WWOX fragile genes in cancer

It was hypothesized as early as 1986, that the recently discovered common fragile sites could facilitate recombination events, such as deletions and translocations, that result in clonally expanded cancer cell populations with specific chromosome alterations in specific cancer types. A natural extension of this hypothesis is that the clonal expansion must be driven by alteration of genes at recombination breakpoints whose altered functions actually drive clonal expansion. Nevertheless, when the FHIT gene was discovered at FRA3B, the most active common chromosome fragile region, and proposed as an example of a tumor suppressor gene altered by chromosome translocations and deletions, a wave of reports suggested that the FHIT gene was altered in cancer simply because it was in a fragile region and not because it had contributed to the clonal expansion, thus turning the original hypothesis upside down. Now, after nearly ten years and more than 500 FHIT reports, it is apparent that FHIT is an important tumor suppressor gene and that there are genes at other fragile regions that contribute significantly to development of cancer. A second fragile gene with a demonstrated role in cancer development is the WWOX gene on chromosome 16q; alterations to the WWOX gene contribute to development of hormone responsive and other cancers. Results of our recent studies of these two fragile tumor suppressor genes were summarized at the first Fragilome meeting in Heidelberg, Feb. 2005.     

进展期胃癌和胃淋巴瘤的MSCT影像学鉴别

目的：分析探讨多层螺旋CT（MSCT）在进展期胃癌和胃淋巴瘤鉴别诊断中的价值。方法对46例进展期胃癌和34例胃淋巴瘤患者的MSCT平扫和增强扫描影像学资料进行分析,比较两种肿瘤在胃侵犯部位、胃壁胃黏膜及胃腔改变、周围组织及器官的浸润或转移、中上腹部淋巴结转移等方面的差异。结果进展期胃癌组多部位侵犯14例,增强扫描不均匀强化28例,胃黏膜中断、破坏24例,胃腔狭窄、近侧胃腔扩张14例,腹主动脉周围下部淋巴结转移18例;胃淋巴瘤组多部位侵犯24例,增强扫描不均匀强化7例,胃黏膜中断、破坏5例,胃腔狭窄、近侧胃腔扩张3例,腹主动脉周围下部淋巴结转移23例;两组上述指标差异均有统计学意义（P＜0.05或P＜0.01）。进展期胃癌组和胃淋巴瘤组在胃壁厚度、肿瘤外侵和器官转移、平均淋巴结转移的部位数等差异无统计学意义（P＞0.05）。结论 MSCT可清晰显示进展期胃癌和胃淋巴瘤的侵犯部位、侵犯程度的不同,对于二者的鉴别具有重要价值。     

鼻咽癌患者和EB病毒IgA/VCA抗体阳性者染色体脆性部位研究

分析58例鼻咽癌患者和54例IgA/VCA抗体阳性者的染色体脆性部位,并与正常人对照,发现鼻咽癌患者染色体畸变率明显高于其他两组。从非随机的脆性部位断裂点分析中,提出脆性部位5P~(13)、5P~(14)和8P~(24)及其相应部位癌基因激活可能与鼻咽癌发生有关;非脆性部位断裂点1P~(11)、1 cen、2P~(23)和5P~(34)及相应部位癌基因激活也可能对肿瘤的发生起作用。而出现频率较高的脆性部位3P~(14)3P~(14)则与肿瘤的发生没有特异相关。     

Preferential integration of a transfected marker gene into spontaneously expressed fragile sites of a breast cancer cell line

Common fragile sites are non-randomly distributed unstable chromosomal regions thought to be hot spots for recombination. They appear as gaps, breaks and triradial figures when cells are cultured under conditions that inhibit replication or repair of DNA. The removal of replication-inhibitory challenges is followed by repair activation to restore the DNA damage at the fragile site. The breast cancer cell line MDA-MB-436 has a spontaneous and non-random expression pattern of fragile sites that appear to be related to the complex pattern of chromosomal rearrangements. The high frequency of which fragile sites are spontaneously activated should make MDA-MB-436 cells a powerful tool to study in greater detail the DNA sequences of a multiplicity of fragile sites. Here, we have explored if the DNA at spontaneously activated fragile sites in MDA-MB-436 cells can be genetically tagged by the repair-mediated insertion of an exogenously supplied drug resistance gene. The cells were transfected with pSV2Neo, stably transfected clones were selected with neomycin, and the sites of pSV2Neo integration were determined by fluorescent in situ hybridization. Eighty-eight of 100 isolated clones had a non-random distribution of a total of 112 pSV2Neo integrations. Of these, 95 integrations (85%) coincide with the position at which non-random gaps and breaks appear in the MDA-MB-436 cells. Forty-nine (44%) of the 112 integrations appeared to be at position of known fragile sites, 46 (41%) were at the non-random chromosomal sites not previously described as "true" fragile sites. It is possible, however, that these non-random instabilities signal of genomic regions equivalent to fragile sites, that either have not previously been detected due to low level expression or that are activated in a tissue- or cell-type-specific manner. Collectively, our results show a preferential integration of exogenous DNA into fragile sites and other non-random regions of high genomic instability in MDA-MB-436 cells. This approach has provided a platform for the efficient targeted cloning and characterization of a substantial number of both common fragile sites and other non-random instability regions possibly related to breast cancer, and possibly also to other types of cancer.     

Cytogenetics of non-Hodgkin's lymphoma

In the non-Hodgkin's lymphoma (NHL), recurring cytogenetic abnormalities have been identified, and significant correlations among them and morphology, immunophenotyping, and parameters of clinical outcome have been recognized. The structural involvement of the 14q32 band is substantially more frequent than are other common abnormalities, which include del(6q), i(17q), +3, +7, +12, +18, and +21. Twenty-two recurring translocations have been identified. Almost three-fourths of all breakpoints in NHL occur at sites to which lineage-determining, transformation-related genes, or fragile sites have been mapped. Besides the well-known association of the t(14;18) (q32;q21) with the follicular histologies and t(8;14)(q24;q32) with small non-cleaved cell lymphoma, several other associations between recurring cytogenetic abnormalities and morphologic subtypes have been found. Similarly, several associations between cytogenetic abnormalities and the B or T immunophenotype have been delineated. Trisomy 3 or duplications of 3p predict a favorable clinical outcome; trisomy 2 or duplication 2p and abnormalities of chromosome 17 predict a poor prognosis. Common sequential changes include a (second) 14q32 break and abnormalities of chromosomes 1 and 2. Continuing work in these areas will serve to identify more clearly those regions of the genome important to transformation, differentiation, clinical aggressiveness, and progression in NHL.     

Increased fragile sites and sister chromatid exchanges in bone marrow and peripheral blood of young cigarette smokers

Cigarette smoking is considered to be the single most important acquired cause of cancer mortality. Studies of chromosome aberrations, sister chromatid exchanges, and fragile sites in peripheral blood or bone marrow are useful methods to detect the effects of the environmental mutagens or carcinogens found in cigarette smoke. The effects of smoking on the immature cells in the bone marrow have not been studied. Here, we examine the peripheral blood and bone marrow in 18 smokers (15 females and 3 males) with a median age of 25 years (range, 21-40) and an average cigarette use corresponding to 6 pack years. In both bone marrow cells and peripheral blood lymphocytes, we were able to show a significantly increased frequency of sister chromatid exchanges in smokers with a 5 or more cigarette pack year history, but not in those who smoked less than 5 pack years. We also found a higher frequency of sister chromatid exchanges in peripheral blood lymphocytes than in bone marrow cells. In addition, the peripheral lymphocytes of smokers demonstrated (a) a significantly higher frequency of fragile sites, (b) an increased number of metaphases with extensive breakage; and (c) elevated expression of fragile sites at the cancer breakpoints 3p14.2, 11q13.3, 22q12.2, and 11p13-p14.2 and at the oncogene sites bcl 1, erb B, erb A, and sis. Our results suggest that chromosomal DNA of peripheral blood lymphocytes is sensitive to cigarette smoking. Studies of the chromosomal changes in these cells provide an index of the mutagenic damage caused by these exogenous agents in individual patients and the ability of individuals to repair that damage, and might predict susceptibility to malignant events.     

Spontaneous unusual expression of frequency of chromosome aberrations and common fragile in human lymphocytes of colorectal cancer patients induced by Aphidicolin

Chromosomal fragile sites are distributed all over the human genome. Aphidicolin mediated expression frequency of common fragile sites and other chromosomal changes were evaluated in prometaphase/metaphase chromosomes obtained from peripheral blood lymphocytes of colorectal cancer patients. The present study reveals first time high incidence i.e. 6 % of aphidicolin induced chromosome breaks / gaps designated as "common fragile sites" in cell population of clinically diagnosed patients of colorectal cancer patients in Nepalese population. These chromosomal changes including structural and numerical were compare to clinically healthy normal individual of same sex / age groups, act as controls for statistical analysis. The frequency of chromosomal aberration in cancer patients were significantly higher (p<0.001) when compare to normal individuals. The increased genetics instability probably either due to nutritional factor i.e. lack of folic acid component in diet--an essential component required for DNA synthesis or unknown environmental factor for such genetic disorder. The present study indicates aphidicolin high frequency of induced chromosome aberrations and "common fragile sites" because of late replication of DNA in mitosis in colorectal cancer patients suggesting these sites could be used as suitable marker for determining genetic predisposition in cancer patients.