1/18. Cytogenetic study of eight new cases of radiation-induced solid tumors.radiation-induced tumors were selected according to the criteria defined by Cahan (1948) for sarcomas. Cell cultures and/or xenografts in nude mice were performed with biopsies obtained from second primary tumors. Karyotypes of eight tumors were established after R-banding. After comparison with literature data on 15 other cases, two distinct cytogenetic patterns could be distinguished. One was characterized by polyclonal karyotypes, of which a large proportion were simple and carriers of balanced translocations. Another one was characterized by monoclonal chromosome alterations observed in highly aneuploid and complex karyotypes, in which many deletions were observed. These two different patterns could be related to the modality of metaphase harvesting. Polyclonal karyotypes were preferentially observed after long-term cultures, and monoclonal karyotypes after short-term cultures or xenografts. The following scheme of radiation oncogenesis is proposed: a) induction of recessive gene mutations including that of tumor suppressor genes; b) accumulation of genomic alterations in the irradiated tissue with aging, including deletions or mutations of normal alleles from mutated tumor suppressor genes; and c) loss of tumor suppressor gene function and initiation of a multistage tumor development and progression. Polyclonal abnormalities are assumed to exist in noncancerous cells which acquired radiation-induced chromosome aberrations.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
2/18. Cytogenetic heterogeneity and clonal evolution in synchronous bilateral breast carcinomas and their lymph node metastases from a male patient without any detectable BRCA2 germline mutation.Two synchronous bilateral breast carcinomas and their matched lymph node metastases from a 70-year-old man were cytogenetically analyzed. All four tumors were near-diploid, and except for the primary tumor from the right breast, had a 45,X,-Y clone in common. The loss of the y chromosome was, however, common to all four tumors, whereas metaphase cells from peripheral blood lymphocytes showed a normal 46, XY chromosome complement. The primary tumor from the right breast was monoclonal, with loss of the y chromosome and gain of 1q, whereas its metastasis had two related clones: the 45,X,-Y clone, and the other a more complex version of the clone in the primary tumor, with inv(3), -14, and del(16)(q13) as additional changes. The primary tumor from the left breast was polyclonal with three unrelated clones: 45,X,-Y/45,XY,-18/47,XY, 20, two of which were present in its metastasis. dna flow cytometric studies showed diploidy for both primary tumors. No mutation in the BRCA2 gene was found on analysis of dna from peripheral blood lymphocytes. The present findings show that del(16)(q13) is a recurrent finding among male breast carcinomas and that some of the primary cytogenetic abnormalities, as well as the pattern of chromosomal changes during the progression of sporadic breast carcinoma in the male, are similar to those in the female. In addition, the loss of the y chromosome in the tumors but not in peripheral blood lymphocytes, suggests a possible role for this abnormality in the pathogenesis of male breast carcinoma.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
3/18. Triple philadelphia chromosomes with major-bcr rearrangement in hypotriploid erythroleukaemia.The philadelphia (Ph) chromosome is observed in approximately 1% of patients with acute myeloblastic leukaemia (AML), especially subtypes M1 and M2 in the French-American-British classification. We describe here a cytogenetic and molecular investigation of a rare case with Ph-positive AML M6 (erythroleukaemia). A 63-yr-old woman was diagnosed as having erythroleukaemia. Leukaemic cells were positive for CD4 and CD7 as well as CD13, CD33, CD34 and HLA-DR. They were analyzed by G-banding, fluorescence in situ hybridization (FISH), Southern blot and reverse transcriptase polymerase chain reaction analyses. The karyotypes at diagnosis were as follows: 61, XX, -X, -1, -2, -3, -4, -5, -7, t(9;22)(q34;q11)x 2, -15, -16, -17, -18, 19, 21, 22 [3]/61, idem, -22, der(22)t(9;22) [36]. FISH with BCR/ABL probes showed that 39% and 57% of interphase nuclei had double and triple BCR/ABL fusion signals, respectively. Chromosome analysis in complete remission showed a normal karyotype in all 20 metaphases, confirming the diagnosis as Ph positive-acute leukaemia. FISH at relapse showed that 92% of interphase nuclei had triple fusion signals. Rearrangement of major breakpoint cluster region (M-bcr) in the BCR gene and coexpression of p210-type (b2a2) and p190-type (e1a2) BCR/ABL fusion transcripts due to alternative splicing were also detected. We conclude that clonal evolution from double to triple Ph chromosomes may be implicated in the disease progression. Considering other two reported cases, Ph-positive erythroleukaemia appears to be correlated with coexpression of myeloid/T-lymphoid markers and hyperdiploidy with double or triple Ph chromosomes, although breakpoints in the BCR gene are heterogenous.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
4/18. Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants.Five infants (two girls and three boys) from four families all had severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
5/18. Double minutes containing amplified bcr-abl fusion gene in a case of chronic myeloid leukemia treated by imatinib.Amplification of the bcr-abl fusion gene has recently been associated with resistance to imatinib therapy in chronic myeloid leukemia (CML). A 55-yr-old man was diagnosed with philadelphia (Ph) chromosome-positive CML. Resistance to interferon treatment and occurrence of blastic phase lead to the decision of imatinib therapy. After two autologous stem cell transplantation, the patient reverted to chronic phase with a decrease in the proportion of Ph chromosome-positive cells under imatinib. A second blastic phase occurred 4 months after transplantation, of which the patient died. Cytogenetic studies, including fluorescent in situ hybridization, showed a (9;22)(q34;q11) translocation and one bcr-abl fusion gene during the whole evolution, but for the last 2 months. Bcr-abl gene amplification (over 25 copies) was noted while banding cytogenetics showed a karyotype of 55-62 chromosomes with multiple double minutes (dmin). To the best of our knowledge, dmin containing amplified bcr-abl gene has never been reported in patients with CML. Therefore, although we cannot exclude that the gene amplification was strictly associated with disease progression, our data may suggest that the amplification resulted in resistance to imatinib.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
6/18. endoreduplication in conjunction with tumor progression in an aneuploid laryngeal squamous cell carcinoma.We report the case of a 58-year-old man who presented with a squamous cell carcinoma pT1a G2 of the left vocal cord. Six months after histologically verified complete resection, the patient experienced an endolaryngeal and extralaryngeal local recurrence pT4 pN2b G2. We applied dna flow cytometry (FCM) and comparative genomic hybridization (CGH) on both primary and recurrent tumor. The primary tumor and the endolaryngeal compartment of the relapse was an aneuploid cell clone with a FCM dna index of 1.42 and 1.44, respectively. The extralaryngeal compartment showed a shift featuring a dna index of 2.78. In the primary tumor and in both compartments of the recurrence there was an identical pattern of complex chromosomal imbalances as detected in CGH (CGH karyotype: rev ish enh [8q24.2-q24.3, 10q26.1-q26.3, 11q24-q25, 12q24.2-q23.33,X], dim [4q, 13q14.3-q31], amp[1p36.1-p36.2]). Hence, the recurrence was not associated with further gains and losses of chromosomal material. However, in the anterior part of the recurrence, the aneuploid tumor cell genome had completely doubled, obviously due to endoreduplication. Immunohistochemical analysis of several cell-cycle regulators revealed altered expression of checkpoint proteins, pointing to a complex disturbance in cell-cycle regulation.- - - - - - - - - - ranking = 4keywords = progression (Clic here for more details about this article) |
7/18. Plasmablastic transformation of multiple myeloma.We describe morphological, immunophenotypic, and cytogenetic characterization of a case of multiple myeloma (MM) that showed plasmablastic transformation at the terminal phase with a picture resembling acute leukemia. The plasmablasts expressed monotypic cytoplasmic immunoglobulin together with myeloid and megakaryocytic markers at disease transformation. Conventional cytogenetic study of bone marrow cells showed coexistence of hypodiploid and hyperdiploid cells, with the former being the predominant clone as evidenced by an interphase fluorescence in situ hybridization study. The clinical course in our case shows that plasmablastic transformation should be considered in the differential diagnoses of disease progression in MM. Whether de novo plasmablastic myeloma and plasmablastic transformation can be distinguished as a progression from underlying MM merits further investigation, especially in terms of biologic features and relevance to prognosis.- - - - - - - - - - ranking = 2keywords = progression (Clic here for more details about this article) |
8/18. An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma.This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
9/18. Two clonal occurrences of tetrasomy 21 in an atypical chronic myeloid leukemia with wild-type RUNX1 alleles. Additional support for a gene dosage effect of chromosome 21 or RUNX1 in leukemia.Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder with no specific genetic lesion. Here we demonstrate clonal occurrences of tetrasomy for the long arm of chromosome 21 in a patient with aCML, and a thorough review of the literature provides evidence that this chromosomal anomaly is a so far not recognised recurrent finding in aCML. Further, the timely association of the occurrence of the tetrasomy 21q with acceleration of the leukemia suggests a role for chromosome 21 in leukemic disease progression. The chromosome 21 gene most strongly implicated in both normal and abnormal hematopoiesis is RUNX1. Also, RUNX1 haploinsufficiency due to RUNX1 point mutations characterises the familial platelet disorder with propensity to develop leukemia, and thromboytopenia was a leading feature in the present case. Therefore, an extensive molecular analysis of RUNX1 was performed. However, these analyses did not reveal a mutation, and the results support a gene dosage effect for RUNX1 in myeloid disease similar to observations in lymphoid disease. patients with aCML and a tetrasomy 21 may form a karyotypically and phenotypically defined subgroup of aCML.- - - - - - - - - - ranking = 1keywords = progression (Clic here for more details about this article) |
10/18. Distribution of aneuploid cell populations in ulcerative colitis with dysplasia or cancer.flow cytometry was used to detect the presence and assess the distribution of aneuploid cell populations in eight proctocolectomy specimens from patients with ulcerative colitis. Mucosal samples were taken according to a systematic protocol for flow cytometry, the surrounding tissue was examined histologically, and the distributions of flow cytometric and histologic abnormalities were "mapped" within each resected colon. Two resection specimens that were negative for dysplasia lacked aneuploid cell populations. Four resection specimens with final case diagnoses of dysplasia or Dukes' stage A carcinoma had 1-5 regions of aneuploidy or increased 4N (G2/tetraploid) cell populations located in discrete areas of the colon. Two specimens with dysplasia or Dukes' stage C carcinoma each had 14-15 different, often overlapping, regions of aneuploidy or increased 4N (G2/tetraploid) cell populations involving large portions of the colonic mucosa. Analysis of the dna content of the invasive portion of the tumor from the specimen with a Dukes' stage C carcinoma showed a single aneuploid cell population. The results show that single or multiple aneuploid cell populations are often present in colons resected for ulcerative colitis with dysplasia or early cancer. The distribution of these aneuploid cell populations suggests that each represents a clone of cells that has expanded to occupy a discrete region of colonic mucosa. Additional genetic errors may result in multiple aneuploid cell populations that may be associated with an increased risk of developing cancer. These data, therefore, are consistent with the hypothesis that genomic instability and clonal evolution are associated with the progression to dysplasia and carcinoma in ulcerative colitis. Because flow cytometry can measure aneuploid cell populations in colonoscopic mucosal biopsies, it may prove to be complementary to histology for detecting patients with ulcerative colitis who are at risk for neoplastic progression.- - - - - - - - - - ranking = 2keywords = progression (Clic here for more details about this article) |
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