Cancer Genetics and Cytogenetics

Editorial Board

2010-02-01

Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations

2010-02-01

Abstract: Chronic myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET) and primary myelofibrosis (PMF), result from interactions between initiating growth factor mutations and secondary genomic changes. Codon 617 mutation of the JAK2 kinase is found in 40–50% of ET/PMF, whereas the mutation of codon 515 in the JAK2-linked thrombopoietin receptor MPL is found in approximately 20% of JAK2-unmutated cases of ET and PMF. Using quantitative mutation assays, we compared patterns of clinical and cytogenetic progression in MPL-mutated MPN (n=21) to those with JAK2 V617F mutation (n=383) or neither mutation (n=109). Among patients with MPL mutations, ET was seen in 9 and PMF in 12. Median mutation levels in pretreatment ET samples were significantly higher for MPL-mutated cases (60%) than for JAK2-mutated cases (24%; P=0.01), as was presentation with anemia. Differential genomic changes included +9 in JAK2-mutated cases and chromosome 1 alterations in MPL-mutated ones, implicating dosage effects related to gene copy number. Decreases in the levels of MPL mutation were seen in sequential marrow samples from some patients under treatment with biologic therapies, but not in those treated with kinase inhibitors, consistent with selective response of the MPL-mutated clone similar to the responses seen in JAK2-mutated MPN.

Analysis of poly(ADP-ribose) polymerase-1 (PARP1) gene alteration in human germ cell tumor cell lines

2010-02-01

Abstract: The poly(ADP-ribose) polymerase-1 protein (PARP-1) functions in DNA repair, maintenance of genomic stability, induction of cell death, and transcriptional regulation. We previously analyzed alterations of the PARP1 gene in 16 specimens of human germ cell tumors, and found a heterozygous sequence alteration that causes the amino acid substitution Met129Thr (M129T) in both tumor and normal tissues in a single patient. In this study, aberration of the PARP1 gene and protein was further analyzed in human germ cell tumor cell lines. We found a nonheterozygous sequence alteration that causes the amino acid substitution Glu251Lys (E251K) located at a conserved peptide stretch of PARP-1 in cell line NEC8. Sequencing of 95 samples from Japanese healthy volunteers revealed that all the samples were homozygous for the wild-type alleles at M129T and E251K. The M129T allele is thus suggested to be a rare single-nucleotide polymorphism (SNP). We observed a decrease in auto-poly(ADP-ribosyl)ation activity of PARP-1 proteins harboring M129T or E251K amino acid substitution, but the difference was not statistically significant. The levels of PARP-1 and poly(ADP-ribosyl)ation were heterogeneous among germ cell tumor cell lines. The SNPs of the PARP1 gene, as well as differences in the levels of PARP-1 and poly(ADP-ribosyl)ation of proteins, may influence germ cell tumor development and responses to chemotherapy and radiotherapy.

Tissue factor pathway inhibitor 2 (TFPI2) is frequently silenced by aberrant promoter hypermethylation in gastric cancer

2010-02-01

Abstract: Aberrant methylation of promoter CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in cancer. TFPI2, a Kunitz-type serine proteinase inhibitor, has been identified as a putative tumor-suppressor gene from genome-wide screening for aberrant methylation, using a microarray combined with the methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dCyd) in various types of tumors. We assessed the methylation status of TFPI2 and investigated its expression pattern in human primary gastric cancer (GC) tissues and in GC cell lines. Hypermethylation of the promoter CpG island, which was observed in more or less all of GC cell lines, was prevalent in a high proportion of primary GC tissues (15/18, or 83%), compared with noncancerous (4/18, or 22%) or normal (0/3, or 0%) stomach tissues, and expression of TFPI2 mRNA was reduced in 7 of the 17 primary GC tissues (41%). Moreover, immunohistochemical analyses showed decreased levels of TFPI-2 protein, compared with adjacent noncancerous tissues in 8 of the 20 primary GC tissues examined (40%). TFPI2 mRNA expression was restored in gene-silenced GC cells after treatment with 5-aza-dCyd. Aberrant methylation of TFPI2 promoter CpG island occurred not only in GC cells but also in primary GC tissues at a high frequency, suggesting that epigenetic silencing of TFPI2 may contribute to gastric carcinogenesis.

E-cadherin–160 C/A promoter polymorphism and risk of pancreatic carcinoma in Chinese population

Yang Fei, Jian Hu, Shengli Liu, Xushun Liu, Feng Wang, Jieming Gong — 2010-02-01

Abstract: Recent studies have implicated E-cadherin–160C/A single-nucleotide polymorphism (SNP) in susceptibility to and early onset of some cancers. We investigated the role of E-cadherin–160 C/A SNP in Chinese pancreatic carcinoma patients without dominant family history by genotyping 254 patients and 101 controls. The risk of cancer for CC genotype individuals was less than half that of AA individuals [odds ratio (OR) = 0.41; 95%confidence interval (95%CI) = 0.18–0.96]. Furthermore, patients with the CC and CA genotypes whose tumors were stages III (T4NxM0) and IV (TxNxM1) (OR = 0.38; 95%CI = 0.17–0.83), poorly differentiated (OR = 0.28; 95%CI = 0.09–0.84), and left-sided (OR = 0.45; 95%CI 0.21–0.98) were associated with significantly lower risk than AA patients. Young (60 years old or younger) AA patients had a 5-year lower mean age at onset than CC/CA patients (P = 0.02). Young male AA patients had worse disease-specific survival than CC/CA patients (P = 0.002). Thus, contrary to Canadians and Portuguese, the AA (rather than CC) genotype is associated with increased susceptibility and advanced pancreatic carcinoma in Chinese patients, suggesting a more complex relationship between the SNP and pancreatic carcinoma risk, possibly modulated by population differences.

Three-way translocation involving MLL, MLLT1, and a novel third partner, NRXN1, in a patient with acute lymphoblastic leukemia and t(2;19;11) (p12;p13.3;q23)

2010-02-01

Abstract: Translocations involving mixed lineage leukemia (MLL) gene at 11q23 are associated with de novo acute leukemia as well as therapy-related acute leukemia. More than 100 different translocations involving MLL have been described in acute leukemia, with more than 60 translocation partner genes characterized on the molecular level. In addition to various simple translocations affecting MLL, there are also complex forms involving three or more chromosomes. Here, we describe a novel three-way translocation of t(2;19;11)(p12;p13.3;q23) in a patient with acute lymphoblastic leukemia (ALL). In this translocation, the distal 19p13.3 joins the proximal 11q23 on der(11), whereas the distal 11q23 is translocated to 2p12. Three-way translocations involving 11q23 are often difficult to detect with cytogenetic means alone. In the present case, however, the chromosomes involved in the three-way translocation were readily identifiable by GTG banding. The MLL–MLLT1 fusion products from the derivative chromosome 11 were detected by reverse transcriptase–polymerase chain reaction (RT-PCR), and two splicing variant forms were confirmed by cloning and sequencing. Furthermore, the novel third partner gene, NRXN1, was detected by systematic breakpoint analysis using long-distance inverse-PCR methods (LDI-PCR). The apparent three-way translocation thus identified is noteworthy because few studies have reported complex rearrangements involving 11q23 and 19p13.3 in acute leukemias.

Epigenetic inactivation of retinoid X receptor genes in non-small cell lung cancer and the relationship with clinicopathologic features

Su Man Lee, Ji Yun Lee, Jin Eun Choi, Shin Yup Lee, Jae Yong Park, Dong Sun Kim — 2010-02-01

Abstract: Retinoid X receptors (RXRs) are nuclear receptors for retinoids that play a critical role in the regulation of growth and differentiation in normal and tumor cells. Deregulation of RXR expression has been reported in non-small cell lung cancer (NSCLC); however, the mechanism underlying the impaired expression of RXRs in lung cancer is not known. Aberrant methylation of promoter CpG islands is known to be a major mechanism for inactivation of tumor suppressor genes. We investigated the methylation status of the RXR genes in 139 surgically resected NSCLCs and correlated the results with the clinicopathologic characteristics of the patients. Methylation in the tumors was detected in all three genes: RXRA, 5.7%; RXRB, 4.3%; RXRG, 23.7%. Reverse transcriptase–polymerase chain reaction analysis showed that RXRG methylation correlates with mRNA expression. Methylation of the RXRG gene was not significantly associated with the prognosis of patients. When the patients were categorized by smoking status, however, the effect of RXRG methylation on prognosis was significantly different between never- and ever-smokers (P=0.003, test for homogeneity). Specifically, RXRG methylation was associated with a significantly worse survival in never-smokers; a trend to better survival outcome was observed for ever-smokers, although not statistically significant. This finding suggests that methylation-associated downregulation of the RXRG gene may play a differential role in the carcinogenesis of NSCLCs according to smoking status, but further studies are needed to confirm this.

Role of STAT3 decoy oligodeoxynucleotides on cell invasion and chemosensitivity in human epithelial ovarian cancer cells

Xiaolei Zhang, Peishu Liu, Bo Zhang, Ancong Wang, Meixiang Yang — 2010-02-01

Abstract: Recent studies have reported that STAT3 activation is associated with poor prognosis in human epithelial ovarian cancer. STAT3 has been proposed to play an important role in ovarian cancer metastasis and chemoresistance. This mechanism, however, is still not thoroughly understood. In this study, to investigate the role of STAT3 on ovarian cancer cells, we used decoy oligodeoxynucleotide (ODN) technology to regulate STAT3 in SKOV3 and OVCAR3 cells in vitro. Cell invasive power and chemo-sensitivity were assessed in the cells transfected with STAT3 decoy ODN and control ODN. Western blot analysis was used to examine the expression of EMMPRIN, P-gp, and Akt. Results showed that STAT3 decoy ODN inhibited cancer cell invasive power and enhanced sensitivity to paclitaxel for SKOV3 and OVCAR3 cells. The mechanism involved the inhibition of EMMPRIN, P-gp, and pAkt by STAT3 decoy ODN. These three proteins were probably the target proteins of STAT3. These findings suggest that STAT3 is a key factor for ovarian cancer metastasis and chemoresistance. STAT3 decoy ODN may prove to be a beneficial therapeutic agent, especially for invasive or chemoresistant ovarian cancer.

Clinical significance of transient receptor potential vanilloid 2 expression in human hepatocellular carcinoma

2010-02-01

Abstract: Transient receptor potential vanilloid 2 (TRPV2), one of the members of TRP (transient receptor potential) superfamiliy of ion channels, has been suggested to contribute to pain associated with inflammation or neuropathy. To investigate its role in hepatocarcinogenesis, we examined the expression of TRPV2 in human hepatocellular carcinoma (HCC) samples and analyzed the association of TRPV2 expression with its clinical significance. TRPV2 expression in 55 HCC patients was examined by immunohistochemistry, and the correlation between TRPV2 levels and clinicopathologic parameters was analyzed. Thirteen paired HCC specimens and their nontumor counterparts were investigated by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Quantitative RT-PCR and Western blotting analysis revealed that expression of TRPV2 at both the mRNA and protein levels were increased in cirrhotic livers compared with chronic hepatitis, whereas that also occurred in moderately and well-differentiated tumors compared with that of poorly differentiated tumors. Immunohistochemistry of the 55 HCC samples showed that the expression of TRPV2 increased when going from normal liver or chronic hepatitis to cirrhosis. Increased TRPV2 expression was observed in tissues of liver cirrhosis (31/37, 83.8%). In HCC, increased expression of TRPV2 was identified in 16/55 (29%) cases. Clinicopathologic assessment suggested a significant association between TRPV2 expression and portal vein invasion and histopathologic differentiation (P = 0.036 and 0.001, respectively). Our data suggest that TRPV2 plays a role in human hepatocarcinogenesis and might be a prognostic marker of patients with HCC.

Coexistence of alternative MLL–SEPT9 fusion transcripts in an acute myeloid leukemia with t(11;17)(q23;q25)

2010-02-01

Abstract: We present the characterization at the RNA level of an acute myeloid leukemia with a t(11;17)(q23;q25) and a MLL rearrangement demonstrated by FISH. Molecular analysis led to the identification of two coexistent in-frame MLL-SEPT9 fusion transcripts (variants 1 and 2), presumably resulting from alternative splicing. Real-time quantitative RT-PCR analysis showed that the relative expression of the MLL-SEPT9 fusion variant 2 was 1.88 fold higher than the relative expression of MLL-SEPT9 fusion variant 1. This is the first description of a MLL-SEPT9 fusion resulting in coexistence of two alternative splicing variants, each of which previously found isolated in myeloid leukemias.

Light pulses administered during the circadian dark phase alter expression of cell cycle associated transcripts in mouse brain

R. Ben-Shlomo, C.P. Kyriacou — 2010-02-01

Abstract: The circadian mode of cell division has been known for more than a century, but the association between circadian rhythms and mitosis is not yet clear. Synchronization of circadian oscillators with the outside world is achieved because light, or other external temporal cues, have acute effects on the levels of the clock's molecular components. Thus, an important question is whether environmental signals also affect transcription levels of cell machinery genes in a similar manner? In a microarray analysis, we have tested the influence of light pulses on the expression of transcripts in the mouse brain. Light pulses consistently affect transcription levels of genes that are essential and directly control the cell cycle mechanism, as well as levels of genes that are associated with the various cell cycle checkpoints. The changes in the levels and the direction of these changes could possibly lead to cell cycle arrest. We also found consistent changes in transcription levels of genes that are associated with tumorigenesis and are directly implicated with enhanced proliferation and metastasis.

Molecular cytogenetic studies characterize a near-triploid complex karyotype in a child with acute lymphoblastic leukemia

2010-02-01

Abstract: High hyperdiploidy with modal chromosome numbers between 50 and 65 is common in childhood acute lymphoblastic leukemia (ALL), occurring in 25–30% of the cases. This chromosomal constitution is associated with a very good prognosis. By contrast, near triploidy and tetraploidy are found in <1% of childhood ALL. Given the sparseness of this group, the associated chromosomal abnormalities and their prognostic implications have not yet been studied in detail. Here, we describe clinical and molecular cytogenetic findings in a child with ALL who had a near-triploid complex karyotype, with loss and gain of chromosomes, including extra copies of the same derivative chromosomes. These findings suggest a random nondisjunction mechanism for near triploidy in the present case.

Concomitant and successive amplifications of MYC in APL-like leukemia

Hélène Bruyère, Heather Sutherland, Katherine Chipperfield, Monika Hudoba — 2010-02-01

Abstract: A 61-year-old male patient presented with very high blood white cell count, left shift of granulocytes to blasts, as well as low hemoglobin and platelets. The bone marrow aspirate and biopsy were consistent with an acute myeloid leukemia (AML). Blasts presented with large azurophilic inclusions and prominent Auer rods resembling acute promyelocytic leukemia (APL). Cytogenetic analysis revealed a deletion 9p and double-minute chromosomes. Fluorescence in situ hybridization showed amplification of the MYC probe and the absence of a RARA rearrangement. The patient achieved complete morphologic and cytogenetic remission 1 month after allogenic transplant, but relapsed 1 month later. Cytogenetics showed MYC amplification as a homogeneously staining region inserted into the long arm of one chromosome 9 and as a ring structure. At least five other acute promyelocytic leukemia-like cases without translocation 15;17, but with double minutes, have been reported in the literature. Only one of these had no RARA rearrangement. This report presents a second patient with APL-like bone marrow morphology, absence of RARA rearrangement, and MYC amplification. In this case, the amplification happened in various concomitant or successive forms.

Deletion 6p as the sole chromosome abnormality in a patient with therapy-related myelodysplastic syndrome: case report and review of the literature

2010-02-01

Rearrangement or deletion of 6p in hematologic malignancies is an unusual finding . The majority of cases appear to be associated with therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML), where deletion 6p is present in the context of a complex karyotype that frequently includes −5/del(5q) or −7/del(7q) . To our knowledge, deletion 6 p has not previously been reported as a sole abnormality in t-MDS or t-AML.

Translocation(X;2)(q26;q11.2) in a patient with acute myeloid leukemia M2 evolved from essential thrombocytemia

2010-02-01

Translocation (X;2)(q26;q11) has been reported only once in the literature in a case of childhood acute myeloid leukemia (AML) . Interestingly, in that particular case the patient had a cryptic translocation of MLL associated. We report here a second case of a 71 year-old male patient with essential thrombocytemia (ET) that 15 months later developed AML with a t(X;2)(q26;q11) as a sole abnormality at diagnosis. The patient was diagnosed with ET in August 2007 and was referred to our hospital because of thrombocytosis. A peripheral blood sample examination showed Hb 15.6g/dL, PLT 900 x 109/L and WBC 11x 109/L, with 65% neutrophils 23% lymphocytes, 12% monocytes. Bone marrow aspirate showed hypercellularity, with megakaryocytes notably increased. A diagnosis of ET was made at that time.

Cytogenetic heterogeneity in biphasic synovial sarcoma associated with telomere instability

2010-02-01

We have read with great interest the recent article by Iliszko et al. in which the authors described their cytogenetic findings on seven new cases of synovial sarcomas (SS), as well as pooled data on 12 previously described cases. They found that complex tumor-specific translocations involving chromosomes X and 18 were present in 2.5–11.7% of SS karyotypes (average 6.5%). As for DNA content, their series included a few tumors displaying hyperdiploidy, hypertriploidy, and hypertetraploidy, a noteworthy finding, given that most published SS cases with t(X;18) fall within the diploid range . Here, we describe some particular cytogenetic findings on a new case of biphasic SS, which provide additional insight on this exciting topic.

High sensitivity of BRCA1-associated tumors to cisplatin monotherapy: report of two cases

2010-02-01

Many forms of preclinical evidence suggest outstanding sensitivity of BRCA1-related tumors to platinum compounds. However, relevant clinical data are limited by the report of Byrski et al. , who observed a 100% response rate in 10 breast cancer patients undergoing neoadjuvant cisplatin monotherapy. Here we present two more cases supporting the high efficacy of cisplatin in BRCA1 carriers.

Malignant transformation of an untreated congenital sacrococcygeal teratoma: a amplification at 8q and 12p detected by comparative genomic hybridization

2010-02-01

Sacrococcygeal teratomas are frequent congenital neoplasms showing an incidence of approximately 1:35,000–40,000 live births and a female-to-male ratio of approximately 4:1 . Malignant transformation has been found in approximately 1% of teratoma patients , frequently comprising squamous cell carcinoma, but also adenocarcinomas, sarcomas, and other malignancies. Thus, teratomas are suggested to be regarded as tumors with malignant potential, which calls for accurate treatment and long-term follow-up . Little is known about untreated teratomas.

Erratum

2010-02-01

Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR. Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC—DUX4 fusion gene event. Cancer Genet Cytogenet 2009;195:1-11.

Erratum

2010-02-01

Miyoung Kim, Seon-Hee Yim, Nam-Sun Cho, Seong-Ho Kang, Dae-Hyun Ko, Bora Oh, Tae Young Kim, Hyun Jung Min, Cha Ja She, Hyoung Jin Kang, Hee Yung Shin, Hyo-Sup Ahn, Sung Soo Yoon, Byoung Kook Kim, Hai-Rim Shin, Kyu Sup Han, Han Ik Cho, Dong Soon Lee. Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study. Cancer Genet Cytogenet 2009;195:59-65.

2010-02-01

Cancer Genetics and Cytogenetics

Editorial Board

Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations

Analysis of poly(ADP-ribose) polymerase-1 (PARP1) gene alteration in human germ cell tumor cell lines

Tissue factor pathway inhibitor 2 (TFPI2) is frequently silenced by aberrant promoter hypermethylation in gastric cancer

E-cadherin–160 C/A promoter polymorphism and risk of pancreatic carcinoma in Chinese population

Three-way translocation involving MLL, MLLT1, and a novel third partner, NRXN1, in a patient with acute lymphoblastic leukemia and t(2;19;11) (p12;p13.3;q23)

Epigenetic inactivation of retinoid X receptor genes in non-small cell lung cancer and the relationship with clinicopathologic features

Role of STAT3 decoy oligodeoxynucleotides on cell invasion and chemosensitivity in human epithelial ovarian cancer cells

Clinical significance of transient receptor potential vanilloid 2 expression in human hepatocellular carcinoma

Coexistence of alternative MLL–SEPT9 fusion transcripts in an acute myeloid leukemia with t(11;17)(q23;q25)

Light pulses administered during the circadian dark phase alter expression of cell cycle associated transcripts in mouse brain

Molecular cytogenetic studies characterize a near-triploid complex karyotype in a child with acute lymphoblastic leukemia

Concomitant and successive amplifications of MYC in APL-like leukemia

Deletion 6p as the sole chromosome abnormality in a patient with therapy-related myelodysplastic syndrome: case report and review of the literature

Translocation(X;2)(q26;q11.2) in a patient with acute myeloid leukemia M2 evolved from essential thrombocytemia

Cytogenetic heterogeneity in biphasic synovial sarcoma associated with telomere instability

High sensitivity of BRCA1-associated tumors to cisplatin monotherapy: report of two cases

Malignant transformation of an untreated congenital sacrococcygeal teratoma: a amplification at 8q and 12p detected by comparative genomic hybridization

Erratum

Erratum

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