Recurrent chronic myeloid leukemia with t (9;22;16) (q34; q11; p13) treated by nilotinib: A case report.

RATIONALE: Variant Philadelphia chromosome translocations involving chromosomes other than chromosomes 9 and 22 have been reported in 5% to 10% of patients with chronic myeloid leukemia (CML). Here, a case of CML with a t (9, 22, 16) (q34; q11; p13) translocation, which has never been described, is reported. PATIENT CONCERNS: A 59-year-old female with dry cough, referred to our hospital, exhibited hepatosplenomegaly, high basophil count, and high platelet count at admission without any other known chronic diseases. DIAGNOSES: The patient was diagnosed with CML with the translocation t (9;22;16) (q34; q11; p13). The patient was treated with imatinib, a first-generation tyrosine kinase inhibitor (TKI), discontinuously, achieving a complete hematological response for 7 years. Since November 8, 2017, the patient had recurrent fever, and her platelet count rose to 1422 × 10/L. Subsequently, the E279K mutation in the BCR-ABL kinase region was detected. OUTCOMES: According to a previous report, this mutation confers sensitivity to nilotinib, a second-generation TKI. In the end, the patient received treatment with nilotinib and showed a complete hematological response. LESSONS: The present study reports a rare case of CML with Ph chromosome and a t (9;22;16) (q34; q11; p13) translocation. For such cases about CML with variant Philadelphia chromosome translocations or BCR-ABL kinase region mutation, TKI may still be valuable.

[Chromosomal aberrations--the cause of spontaneous abortions]. / Aberracje chromosomowe jako przyczyna poronien samoistnych.

UNLABELLED: The genetic factor remains the most frequent cause of spontaneous abortions. Examination of the fetal tissue from spontaneous miscarriages shows that 75% of them were caused by abnormal karyotype. Other reasons, albeit rare, included submicroscopic genomic rearrangements, monogenic diseases, and polygenic inheritance disorders of the embryo. OBJECTIVE: The aim of the study was to analyze the incidence of chromosomal aberrations in material from the miscarriage. MATERIAL AND METHODS: The study included 47 samples of miscarriage material from 47 women. Fluorescent hybridization in-situ (FISH) was used for genetic examination. RESULTS: Chromosomal abnormalities were diagnosed in 72% of the samples, with trisomy 21 (25.5%), trisomy 16 (17%), and trisomy 18 (12.8%) as the most common. An abnormal number of copies of chromosome 18, 21, 22, indicating the coexistence of trisomy 18, 21, 22, was detected in 1 patient. It was another miscarriage in case of 14 subjects (29.8%). CONCLUSIONS: Chromosomal aberrations were diagnosed in the majority of fetal tissue samples from spontaneous miscarriages. More than one chromosomal aberration in a single embryo is an extremely rare occurrence. Miscarriage due to chromosomal aberrations occurred in the vast majority of women > 35 years of age.

Triorchidism: genetic and imaging evaluation in an adult male.

We report the results of imaging and cytogenetic studies in a case of triorchidism in a 54 years old male without any associated anomaly. A scrotal ultrasonography revealed the presence of two testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. There was no focal abnormal echogenicity suggesting malignancy. Scrotal MRI confirmed two soft-tissue structures in the left hemiscrotum with normal signal intensity at T1w and T2w images. Both testes had a tunica albuginea with low-signal intensity. Cytogenetic analysis resulted in normal male karyotype 46XY. Array-CGH analysis detected the presence of two interstitial rearrangements: a ~120 Kb deletion of chromosome 1 and a ~140 Kb deletion of chromosome 16. Currently there are little details on the functions of both genes.

[Do chromosomal abnormalities reappear in subsequent pregnancies and how often?]. / Czy i jak czesto aberracje chromosomowe zarodków powtarzaja sie w kolejnej ciazy?

OBJECTIVE: Genetic factors are the most common causes of spontaneous abortions. 50% to 80% of first-trimester abortions reveal-chromosome abnormalities. Evidence for the recurrence of the same or another chromosome abnormality in the next pregnancy is scarce. THE AIM: The aim of our study was to estimate recurrence risk of abortus aneuploidy and to find out whether karyotyping of the abortus allows the prognose subsequent pregnancy outcomes. MATERIAL AND METHODS: Paraffin-embedded chorions have undergone cytogenetic examination using FISH with chromosome-specific probes. 57 chorions from 26 women have been assessed, including chorions from two consecutive abortions from 18 women and chorions from three consecutive abortions from 5 women. RESULTS: 38.6% of 57 specimens had chromosome aberrations. The most prevalent anomalies were 16, 21 and 18 trisomies. 23 patients had a subsequent abortion karyotyped; 15 had a normal initial karyotype and 8 had an aberrant initial karyotype. 3 out of the 8 patients had a repeated chromosome anomaly 5 out of the 15 patients who initially miscarried an aneuploid embryo, had a subsequent miscarriage of an aneuploid embryo. Only 3 (13.04%) out of the 23 patients displayed aneuploidy in each abortus. CONCLUSION: (1) Chromosome aberrations can reappear in subsequent pregnancies in the same patient and may be the cause of recurrent miscarriages. (2) The value of embryo/fetal karyotyping is not decisive in prognosis of subsequent pregnancy outcome. (3) Abnormal fetal karyotype can occur regardless of other causes of pregnancy loss.

Genetic alterations in children and adolescents with acute myeloid leukaemia.

Acute Myeloid Leukemia is a clinically and genetically heterogeneous disease, in which cytogenetic aberrations are the most important factors to determine biological behavior and prognosis. More than 20 different chromosomal abnormalities have been identified in a high percentage of children (70-85%) with the novo AML. We reviewed the most frequently found and the impact of these aberrations on prognosis. Differences according to the age of patients and mainly in relation to adult population have been enhanced, although the low incidence of AML in children and the high number of abnormalities make difficult to accurately define the prognosis significance of these aberrations.

Genetic alterations in children and adolescents with acute myeloid leukaemia

Acute Myeloid Leukemia is a clinically and genetically heterogeneous disease, in which cytogenetic aberrations are the most important factors to determine biological behavior and prognosis. More than 20 different chromosomal abnormalities have been identified in a high percentage of children (70-85%) with the novo AML. We reviewed the most frequently found and the impact of these aberrations on prognosis. Differences according to the age of patients and mainly in relation to adult population have been enhanced, although the low incidence of AML in children and the high number of abnormalities make difficult to accurately define the prognosis significance of these aberrations (AU)

[Successful rituximab monotherapy in a patient with mucosa-associated lymphoid tissue lymphoma of the rectum with trisomy 3, 18].

A 62-year-old man was referred to our hospital with enlargement of mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum after the eradication of Helicobacter pylori. The patient was given a diagnosis of stage I MALT. Endoscopic observation revealed an enlarged rectal tumor with 3, 18 double trisomy. Rituximab monotherapy was given and complete remission was achieved. Rituximab monotherapy can be useful for MALT lymphoma of the rectum.

TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases.

INTRODUCTION: Genomewide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other sarcomas. Our objectives in this study were (1) to test whether the differentially expressed gene, Transducin-Like Enhancer of split (TLE1) belonging to the groucho/TLE family, is also distinct on the protein level; (2) to evaluate this biomarker in a series of well-characterised synovial sarcomas on standard, full-sized tissue sections and (3) to correlate the expression of TLE1 with t(X;18) and other established biomarkers. METHODS: Three-hundred and eighty four spindle cell sarcomas from the German consultation and reference centre of soft tissue tumours initially suspected for synovial sarcoma were revisited. Three-hundred and nineteen of these specimens were analysed immunohistochemically using a monoclonal antibody TLE1 and standard, full-sized tissue sections. The nuclear staining was scored semiquantitatively as -, negative; +, weak; ++, moderate and +++, strong positive. Furthermore, 118 specimens among these were further analysed using FISH and/or PCR to detect t(X;18). We correlated the TLE1 expression with the t(X;18) translocation and other established biomarkers (EMA, PanCK, CK7, CD34 and BCL2). RESULTS: TLE1 expression was observed in 96% of the synovial sarcomas (score+, 249/259) and discriminates them from other soft tissue tumours (p<0.001). Multivariate analysis showed that positive TLE1 staining was a statistically independent diagnostic marker. Furthermore molecular analysis showed that t(X;18) was clearly correlated with TLE1 protein expression (p<0.001). CONCLUSIONS: Expression of TLE1 is significantly correlated with t(X;18) and may serve as a new robust diagnostic biomarker in synovial sarcomas and potential therapeutic target.

Prenatal diagnosis of craniomaxillofacial malformations: a characterization of phenotypes in trisomies 13, 18, and 21 by ultrasound and pathology.

OBJECTIVE: To determine the relationship between trisomies 13, 18, and 21 and craniofacial malformations detected by prenatal sonography. DESIGN: During a 29-year period (1976 through 2004), prenatal sonographic findings of 69 fetuses with trisomy 13; 171 fetuses with trisomy 18; 302 fetuses with trisomy 21; and 17 fetuses with other trisomies were evaluated retrospectively, after fetal karyotype identification. Sonographic findings were compared with autopsy results in 209 patients (trisomy 13, n=39; trisomy 18, n=64; and trisomy 21, n=106). RESULTS: For trisomy 13, cleft deformities were detected prenatally in 65.2%, and of the 39 cases with pathological information, 76.9% were found to have a cleft deformity. Ocular and orbital abnormalities were found in 28%. Malformations of the jaws and abnormal profiles were more frequently diagnosed postnatally than prenatally. For trisomy 18, abnormal profiles (41.5%) and ear abnormalities (5.3%) were the most noticeable ultrasound markers, next to abnormalities of the neurocranium (36.8%) and cranial bone configuration (21.6%). Dysmorphisms of the eye, ear, or nose were detected more frequently in autopsy cases. For trisomy 21, ultrasound showed an aberrant shape of the skull in 14.2% of fetuses. In general, the ocular-orbital and nasal abnormalities in fetuses with trisomy 18 or 21 were more evident in pathological examination than in prenatal ultrasound imaging. CONCLUSIONS: Facial anomalies are common in the major trisomies, and their prenatal sonographic identification should be improved. The above-mentioned facial anomalies provide sufficient reason to consider performing cytogenic evaluation.

[Frequency of chromosomal aberrations in material from abortions]. / Czestosc wystepowania aberracji chromosomowych w materiale z poronien.

UNLABELLED: Examination of fetal tissue from spontaneous miscarriages shows that 50-70% of them were caused by abnormal karyotype. The most frequent genetic abnormalities include abnormal number of chromosomes, aberration of chromosomes structure and chromosome mosaic anomalies. OBJECTIVE: The aim of the study was to find out whether there is any difference in the frequency of chromosomal aberrations in patients who miscarried for the first time comparing to patients with recurrent miscarriages. MATERIAL AND METHODS: Examination was performed on 129 miscarriage material samples from 128 women. Fluorescent hybridization in-situ (FISH) was used for genetic examination. RESULTS: We received 120 results in which 45 (37,5%) were abnormal. The most frequent chromosomal aberration was trisomy followed by triploidy and monosomy of chromosome X. Among 59 samples from first miscarriage we found 25 abnormal karyotypes. In the 61 samples from the second, third and the next miscarriages we found 20 chromosomal abnormalities. CONCLUSIONS: Frequency of chromosomal aberrations in the tissue from the first miscarriage is significantly higher than in samples from second or following miscarriages, which means that genetic factors are less likely to induce recurrent miscarriages. Genetic results confirm that most chromosomal abnormalities arise de-novo.

Fine needle aspiration of pleomorphic lipoma of the neck: report of two cases.

Pleomorphic lipoma is a rare lipocytic neoplasm that most commonly occurs in the head and neck region in middle-aged to elderly men. Clinically, it presents as a slow-growing, well-circumscribed subcutaneous mass. Histopathologically and cytogenetically, it has some features overlapping with other benign and malignant tumors, such as benign spindle cell lipoma, atypical lipomatous tumor, liposarcoma, and malignant fibrous histiocytoma. However, cure rates are high when pleomorphic lipoma is treated with complete surgical excision with clear margins. Therefore, an accurate preoperative diagnosis is very important for proper treatment. Due to the rarity of this tumor, few cases diagnosed by cytology have been reported in the English literature. Here, we report two cases of pleomorphic lipoma, the diagnoses of which were suggested on fine needle aspiration biopsies and subsequently confirmed by surgical excisions.

Fetal nasal bone in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.

OBJECTIVE: To investigate the performance of first-trimester screening for aneuploidies by including assessment of the fetal nasal bone in the combined test of maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). METHODS: Screening by the combined test was performed in singleton pregnancies, including 19,614 with euploid fetuses, 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases the fetal nasal bone was assessed and classified as present or absent. We examined the performance of two screening strategies: firstly, assessment of the nasal bone in all patients and secondly, first-stage screening using the combined test in all patients followed by second-stage assessment of the nasal bone only in those with an intermediate risk of 1 in 51 to 1 in 1000 after the first stage. To validate the new risk algorithm we used a second independent dataset of 19 651 fetuses, including 139 with trisomy 21. RESULTS: The nasal bone was absent in 2.6% of the euploid fetuses, 59.8% with trisomy 21, 52.8% with trisomy 18, 45.0% with trisomy 13 and in none of the fetuses with Turner syndrome. Respective figures for an absent nasal bone in the validation population, which contained fewer Black women, were 0.6%, 62.6%, 55.3%, 35.3% and 41.7%. In a screening policy based on maternal age, fetal NT, FHR, serum free beta-hCG and PAPP-A, for a fixed risk cut-off of 1 : 100, the false-positive rate was 3.0%. The standardized detection rates were 91% for trisomy 21 and 100% for trisomy 18, trisomy 13 and Turner syndrome, respectively. Assessment of the nasal bone in all pregnancies reduced the false-positive rate to 2.5% without changing the detection rate. A detection rate of 93% was achieved with the two-stage strategy at a false-positive rate of 2.4% in which it was necessary to assess the nasal bone in only 15% of the total population. In the validation dataset, screening by the combined test and using a risk cut-off of 1 : 100 detected 90% of the cases with trisomy 21 for a false-positive rate of 4%. Inclusion of the nasal bone increased the detection rate to 92% for a false-positive rate of 2.9%. Contingent screening detected 92% of cases for a false-positive rate of 2.9%. CONCLUSIONS: Assessment of the fetal nasal bone improves the performance of first-trimester screening for trisomy 21.

Single-nucleotide polymorphisms near the microsatellite D17S1303 and the development of hypertension in a 6-year longitudinal study.

This study examined the association of tagging single-nucleotide polymorphisms (SNPs) in the 130 kb region surrounding the microsatellite D17S1303 on chromosome 17p12 with the development of hypertension after 6 years in a cohort of 232 Hong Kong Chinese adults. Four SNPs (rs9899362, rs10491093, rs11658572 and rs9913883) were associated with the development of hypertension (P<0.05), but these associations require confirmation in future studies. Nevertheless, our study provides further evidence for the presence of an unidentified gene or a regulatory element predisposing to hypertension in a region approximately 24 kb downstream of D17S1303.

Integrative analysis of genomic aberrations associated with prostate cancer progression.

Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion-negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression.

Cigarette smoking, familial hematopoietic cancer, hair dye use, and risk of t(14;18)-defined subtypes of non-Hodgkin's lymphoma.

Some evidence suggests that smoking, a family history of hematopoietic cancer, and use of hair dyes are associated with t(14;18)-defined subsets of non-Hodgkin's lymphoma (NHL) in men. To further evaluate these associations and to expand them to women, the authors determined t(14;18)(q32;q21) status by fluorescence in situ hybridization in 172 of 175 tumor blocks from a population-based case-control study conducted in Nebraska during 1983-1986. Exposures in 65 t(14;18)-positive cases and 107 t(14;18)-negative cases were compared with those among 1,432 controls. Odds ratios and 95% confidence intervals were calculated using polytomous logistic regression. Among men, smoking was not associated with risk of t(14;18)-positive or -negative NHL. Among women who had ever smoked cigarettes, there was an association with risk of t(14;18)-negative NHL (odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.1, 3.3) but not t(14;18)-positive NHL (p-difference = 0.01). The risks for t(14;18)-negative NHL among women increased with longer duration (>30 years: OR = 2.1, 95% CI: 1.1, 4.1) and early initiation (age

Tumor suppressor gene alterations in respiratory epithelial adenomatoid hamartoma (REAH): comparison to sinonasal adenocarcinoma and inflamed sinonasal mucosa.

Respiratory epithelial adenomatoid hamartoma (REAH) is an unusual benign sinonasal glandular proliferation. REAH is not considered a neoplasm, although, no molecular evidence exists to support or refute this possibility. Microdissection of 10 cases of REAH, 9 cases of sinonasal adenocarcinoma (SNAC) and 10 cases of chronic sinusitis was performed. DNA was extracted and polymerase chain reaction performed using fluorescently labeled primers flanking known tumor suppressor genes on chromosomes 9p (CDKN2/p16), 11p (H-ras), 17p (p53), and 18q (DCC/DPC4). Polymerase chain reaction products were analyzed semiquantitatively by capillary electrophoresis. Allele ratios were calculated using the peak height from the shorter allele divided by the peak height from the longer allele. The loss of heterozygosity (LOH) ratio was calculated as the allele ratio from tumor tissue divided by the allele ratio from normal tissue. The fractional allelic loss (FAL) was calculated as the percentage of loci that harbored LOH divided by the number of loci that were informative. REAH demonstrated an intermediate FAL of 31% compared with SNAC (64%) and chronic sinusitis (2%). REAH and SNAC had the highest LOH for multiple loci located on 9p (p16) and 18q (DCC/DPC4). The molecular profile of REAH shows a mean FAL of 31%, which would be considered unusually high for a non-neoplastic entity. Appreciable allelic loss within REAH suggests the possibility that REAH may be a benign neoplasm rather than a hamartoma.

Monoallelic deletion of the p53 gene through chromosomal translocation in a small cell osteosarcoma.

Small cell osteosarcoma is a rare bone tumor of high-grade malignancy that most often arises in the metaphysis of long bones in the second decade of life. Cytogenetic and molecular genetic findings in small cell osteosarcoma are poorly defined. Conventional cytogenetic analysis of a small cell osteosarcoma arising in the proximal tibia of a 9-year-old male revealed a diploid chromosomal complement with complex structural rearrangements involving chromosomes 6, 16, and 17. Immunohistochemical assessment of p53 protein expression revealed nuclear p53 immunoreactivity in approximately 15% of the neoplastic cells. Subsequent fluorescence in situ hybridization (FISH) analyses confirmed loss of the p53 gene locus on the derivative chromosome 17 homolog and were negative for amplification of the MDM2, CDK4, c-MYC, HER-2/neu, CCND1, and COPS3 gene loci. To the best of our knowledge, this represents the first demonstration of monoallelic deletion of p53 in small cell osteosarcoma, suggesting that p53 alterations may play an important role in the development of small cell osteosarcoma as well as conventional osteosarcoma.

The effects of analytical factors on second trimester risk estimations.

OBJECTIVE: Triple test with measured maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol combination as a routine procedure for fetal Down's syndrome, trisomy 18 and neural tube defect screening has some intrinsic problems, such as precision. The aim of this study was to evaluate the effect of analytical variation of triple test on prenatal risk estimation. METHOD: Five different serum pools were prepared and triple test was performed seven times for within run and five times for between run precision determination. RESULT: Within run and between run, precision values of risk estimations by measuring the same sample for Triple test were calculated to be 7.9-21.4% and 14.1-31.0% for trisomy 21, 13.2-23.7% and 14.2-15.1% for trisomy 18, 47.2 and 42.0 % for neural tube defect, respectively. CONCLUSION: These results demonstrated that analytical variations have great impact on second trimester risk estimation procedures; therefore, triple test analyses should be carried out in laboratories using strict internal and external quality control programs. Moreover, triple test results should always be interpreted by considering analytical and biological variations.

[Molecular biology in clinical cancer research: the example of digestive cancers]. / Apport de la biologie moléculaire dans la recherche clinique en cancérologie: exemple des cancers digestifs.

Cancer is a DNA disease characterized by uncontrolled cell proliferation due to the accumulation of genetic alterations. Recent progress in molecular biology allowed the identification of markers potentially usefull for patients management through the identification of these genetic alterations and a best understanding of chemotherapy molecular targets. Several examples in digestive oncology underline the relevance of molecular biology in clinical research. If almost all colorectal cancers (CRC) correspond to the same histopathological type (adenocarcinoma), molecular biology allowed the identification of two different molecular mechanisms of colorectal carcinogenesis: chromosomal instability characterized by recurrent allelic losses on chromosomes 17, 5, 18, 8 and 22 that contribute to the inactivation of tumor suppressor genes, and genetic instability characterized by the instability of microsatellite loci due to an alteration of DNA mismatch repair leading to the accumulation of mutations in genes involved in the control of cell cycle and apoptosis. These data are potentially interesting for the management of CRC patients. Indeed, microsatellite instability seems not only to be a good prognostic factor but also a molecular factor that can predict response to adjuvant 5-fluorouracil based chemotherapy. Therapeutic clinical trials taking into account these molecular parameters are still going on. DNA microarray-based gene expression profiling technology that allows the simultaneous analysis of thousand of tumor genes represents also an interesting approach in oncology with the recent identification of a "genetic signature" as a risk factor of tumor recurrence in stage II CRC, a setting in which the benefit of adjuvant chemotherapy remains on debate. At last, a best understanding of chemotherapy molecular targets allowed the identification of genetic markers that can predict the response and/or the toxicity of anti-cancer drugs used in gastrointestinal cancers, which could be helpful in the future to propose for each patient a personalized treatment. Mutations that can predict the response of new target therapies such as the inhibitors of the c-KIT tyrosine kinase activity in gastrointestinal stromal tumors have also been found and will allow the selection of patients who can have benefit from these new therapeutic drugs.

Nature of telomere dimers and chromosome looping in human spermatozoa.

Specific and well-organized chromosome architecture in human sperm cells is supported by the prominent interactions between centromeres and between telomeres. The telomere-telomere interactions result in telomere dimers that are positioned at the nuclear periphery. It is unknown whether composition of sperm telomere dimers is random or specific. We now report that telomere dimers result from specific interactions between the two ends of each chromosome. FISH using pairs of subtelomeric DNA probes that correspond to the small and long arms of seven human chromosomes demonstrates that subtelomeres of one chromosome are brought together. Statistical analysis confirmed that telomere associations could not result from the random proximity of DNA sequences. Therefore, chromosomes in human sperm nuclei adopt a looped conformation. This higher-order chromosome structure is most likely required for chromosome withdrawal/decondensation during the early fertilization events leading to zygote formation.