Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors

The structural complexity of chromosome 1p centromeric region has been an obstacle for fine mapping of tumor suppressor genes in this area. Loss of heterozygosity (LOH) on chromosome 1p is associated with the longer survival of oligodendroglioma (OD) patients. To test the clinical relevance of 1p loss in glioblastomas (GBM) patients and identifiy the underlying tumor suppressor locus, we constructed a somatic deletion map on chromosome 1p in 26 OG and 118 GBM. Deletion hotspots at 4 microsatellite markers located at 1p36.3, 1p36.1, 1p22 and 1p11 defined 10 distinct haplotypes that were related to patient survival. We found that loss of 1p centromeric marker D1S2696 within NOTCH2 intron 12 was associated with favorable prognosis in OD (P = 0.0007) as well as in GBM (P = 0.0175), while 19q loss, concomitant with 1p LOH in OD, had no influence on GBM survival (P = 0.918). Assessment of the intra-chromosomal ratio between NOTCH2 and its 1q21 pericentric duplication N2N (N2/N2N-test) allowed delineation of a consistent centromeric breakpoint in OD that also contained a minimally lost area in GBM. OD and GBM showed distinct deletion patterns that converged to the NOTCH2 gene in both glioma subtypes. Moreover, the N2/N2N-test disclosed homozygous deletions of NOTCH2 in primary OD. The N2/N2N test distinguished OD from GBM with a specificity of 100% and a sensitivity of 97%. Combined assessment of NOTCH2 genetic markers D1S2696 and N2/N2N predicted 24-month survival with an accuracy (0.925) that is equivalent to histological classification combined with the D1S2696 status (0.954) and higher than current genetic evaluation by 1p/19q LOH (0.762). Our data propose NOTCH2 as a powerful new molecular test to detect prognostically favorable gliomas.     

The complex translocation (9;14;14) involving IGH and CEBPE genes suggests a new subgroup in B-lineage acute lymphoblastic leukemia

Many subtypes of acute lymphoblastic leukemia (ALL) are associated with specific chromosomal rearrangements. The complex translocation t(9;14;14), a variant of the translocation (14;14)(q11;q32), is a rare but recurrent chromosomal abnormality involving the immunoglobulin heavy-chain (IGH) and CCAAT enhancer-binding protein (CEBPE) genes in B-lineage ALL (B-ALL) and may represent a new B-ALL subgroup. We report here the case of a 5-year-old girl with B-ALL, positive for CD19, CD38 and HLA-DR. A direct technique and G-banding were used for chromosomal analysis and fluorescentin situ hybridization (FISH) with BAC probes was used to investigate a possible rearrangement of the IGH andCEBPE genes. The karyotype exhibit the chromosomal aberration 46,XX,del(9)(p21),t(14;14)(q11;q32). FISH with dual-color break-apartIGH-specific and CEPBE-specific bacterial artificial chromosome (BAC) probes showed a complex t(9;14;14) associated with a deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) and paired box gene 5 (PAX5) at 9p21-13 and duplication of the fusion gene IGH-CEBPE.     

Molecular analysis of a constitutional complex genome rearrangement with 11 breakpoints involving chromosomes 3, 11, 12, and 21 and a ∼0.5-Mb submicroscopic deletion in a patient with mild mental retardation

Complex chromosome rearrangements (CCRs) are extremely rare but often associated with mental retardation, congenital anomalies, or recurrent spontaneous abortions. We report a de novo apparently balanced CCR involving chromosomes 3 and 12 and a two-way translocation between chromosomes 11 and 21 in a woman with mild intellectual disability, obesity, coarse facies, and apparent synophrys without other distinctive dysmorphia or congenital anomalies. Molecular analysis of breakpoints using fluorescence in situ hybridization (FISH) with region-specific BAC clones revealed a more complex character for the CCR. The rearrangement is a result of nine breaks and involves reciprocal translocation of terminal chromosome fragments 3p24.1→pter and 12q23.1→qter, insertion of four fragments of the long arm of chromosome 12: q14.1→q21?, q21?→q22, q22→q23.1, and q23.1→q23.1 and a region 3p22.3→p24.1 into chromosome 3q26.31. In addition, we detected a ～0.5-Mb submicroscopic deletion at 3q26.31. The deletion involves the chromosome region that has been previously associated with Cornelia de Lange syndrome (CdLS) in which a novel gene NAALADL2 has been mapped recently. Other potential genes responsible for intellectual deficiency disrupted as a result of patient’s chromosomal rearrangement map at 12q14.1 (TAFA2), 12q23.1 (METAP2), and 11p14.1 (BDNF).     

Co-deletion of chromosome 1p/19q and IDH1/2 mutation in glioma subsets of brain tumors in Chinese patients

Objective

To characterize co-deletion of chromosome 1p/19q and IDH1/2 mutation in Chinese brain tumor patients and to assess their associations with clinical features.

Methods

In a series of 528 patients with gliomas, pathological and radiological materials were reviewed. Pathological constituents of tumor subsets, incidences of 1p/19q co-deletion and IDH1/2 mutation in gliomas by regions and sides in the brain were analyzed.

Results

Overall, 1p and 19q was detected in 339 patients by FISH method while the sequence of IDH1/2 was determined in 280 patients. Gliomas of frontal, temporal and insular origin had significantly different pathological constituents of tumor subsets (P<0.001). Gliomas of frontal origin had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively) (P<0.001), while gliomas of temporal origin had significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively) (P = 0.013 and P = 0.003, respectively). Subgroup analysis confirmed these findings in oligoastrocytic and oligodendroglial tumors, respectively. Although the difference of 1p/19q co-deletion was not statistically significant in temporal oligodendroglial tumors, the trend was marginally significant (P = 0.082). However, gliomas from different sides of the brain did not show significant different pathological constituents, incidences of 1p/19q co-deletion or IDH1/2 mutation.

Conclusion

Preferential distribution of pathological subsets, 1p/19q co-deletion and IDH1/2 mutation were confirmed in some brain regions in Chinese glioma patients, implying their distinctive tumor genesis and predictive value for prognosis.     

Fc receptor gene translocation in a t(1;19) pre-B ALL cell line

We have recently mapped the human FCGR2 gene to chromosome 1 bands q23-q24. In situ hybridization of FCGR2 cDNA with a cell line containing a t(1;19)(g23;p13) derived from a patient with pre-B ALL has allowed a more accurate localization of this gene to chromosome 1 band q23. Furthermore, this study indicated a splitting of the FCGR2 gene or gene cluster by the t(1;19). However, Southern analysis showed no genetic rearrangement when compared with a karyotypically normal Epstein-Barr virus (EBV)-transformed cell line from the same patient. This suggests that the translocation breakpoint does not occur within the coding region of this gene.     

Partial monosomy 21 (q11.2→q21.3) combined with 3p25.3→pter monosomy due to an unbalanced translocation in a patient presenting dysmorphic features and developmental delay

We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy (q11.2→q21.3) in combination with a chromosome 3p terminal monosomy (p25.3→pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24 +).arr 3p26.3p25.3(35,333-10,888,738)) × 1,21q11.2q21.3(13,354,643-27,357,765) × 1. Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation.     

Cytologically balanced t(2;20) in a two-generation family with alagille syndrome: cytogenetic and molecular studies.

Alagille syndrome is a clinically defined, dominantly inherited disorder affecting the liver, heart, face, eye, and vertebrae. Alagille syndrome has previously been localized to the short arm of chromosome 20, on the basis of reports of a small number of patients with chromosomal deletions of 20p. We undertook a cytogenetic study of patients with Alagille syndrome and identified a family in which a cytologically balanced translocation between chromosomes 2 and 20, 46,XX/XY, t(2;20)(q21.3;p12), is segregating concordantly with the disease. The breakpoint on chromosome 20p in this t(2;20) is consistent with the shortest region of overlap demonstrated in the reported deletion patients. This is the first report of a translocation associated with 20p and Alagille syndrome, and this rearrangement confirms the location of the Alagille disease gene at 20p12. We have established a somatic cell hybrid from a lymphoblastoid cell line from one of the affected individuals that contains the derivative chromosome 20 (20qter-->p12::2q21.3-->qter) but not the derivative chromosome 2, the normal chromosome 2, or the normal chromosome 20. Southern blot and PCR analysis of probes and sequences from 20p have been studied to define the location of the translocation breakpoint. Our results show that the breakpoint lies distal to D20S61 and D20S56 within band 20p12.     

A new case with 10q23 interstitial deletion encompassing both PTEN and BMPR1A narrows the genetic region deleted in juvenile polyposis syndrome

We report on a patient with a contiguous interstitial germline deletion of chromosome 10q23, encompassing BMPR1A and PTEN, with clinical manifestations of juvenile polyposis and minor symptoms of Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRRS). The patient presented dysmorphic features as well as developmental delay at the age of 5 months. Multiple polyps along all parts of the colon were diagnosed at the age of 3 years, following an episode of a severe abdominal pain and intestinal bleeding. The high-resolution comparative genomic hybridisation revealed a 3.7-Mb deletion within the 10q23 chromosomal region: 86,329,859–90,035,024. The genotyping with four polymorphic microsatellite markers confirmed a de novo 10q deletion on the allele with a paternal origin, encompassing both PTEN and BMPR1A genes. The karyotype analysis additionally identified a balanced translocation involving chromosomes 5q and 7q, and an inversion at chromosome 2, i.e. 46,XY,t(5;7)(q13.3-q36), inv(2)(p25q34). Although many genetic defects were detected, it is most likely that the 10q23 deletion is primarily the cause for the serious phenotypic manifestations. The current clinical findings and deletion of BMPR1A indicate a diagnosis of severe juvenile polyposis, but the existing macrocephaly and PTEN deletion also point to either CS or BRRS, which cannot be ruled out at the moment because of their clinical manifestation later in life and the de novo character of the deletion. The deletion detected in our patient narrows the genetic region deleted in all reported cases with juvenile polyposis by 0.04 Mb from the telomeric side, mapping it to the region chr10:88.5–90.03Mb (GRCh37/hg19), with an overall length of 1.53 Mb.     

Acute promyelocytic leukemia with unusual karyotype

Acute myeloid leukemia (AML-M3) is associated with the translocation t(15;17)(q22;q12-21) which disrupts the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the PML gene on chromosome 15. We report a two-year-old patient with AML-M3 without the usual translocation t(15;17). Cytogenetic studies demonstrated normal appearance of chromosome 15 while the abnormal 17 homologue was apparently a derivative 17, der(17)(17qter-cen-q21:), the rearrangement distinctly shows deletion at 17q21 band and the morphology corresponding to an iso chromosome i(17q-). This case report is a rare cytogenetic presentation of acute promyelocytic leukemia (APML).     

A novel translocation,t(9;21)(q13;q22) rearranging the RUNX1 gene in acute myelomonocytic leukemia

A novel translocation t(9;21)(q13;q22) associated with trisomy 4 has been detected in a patient with acute myelomonocytic leukemia (AML,M4) in relapse. The chromosomal translocation results in rearrangement of the RUNX1 gene at 21q22. The DNA sequence rearranged on chromosome 9 remains unidentified. The diversity of the partners involved in translocations implicating RUNX1 suggests that the functional consequences of the abnormality are more due to the truncation of RUNX1 than to the identity of its partner in the rearrangement.     

A novel <Emphasis Type="Italic">PAX5</Emphasis> rearrangement in <Emphasis Type="Italic">TCF3-PBX1</Emphasis> acute lymphoblastic leukemia: a case report

Background

Chromosome translocations are a hallmark of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Additional genomic aberrations are also crucial in both BCP-ALL leukemogenesis and treatment management. Herein, we report the phenotypic and molecular cytogenetic characterization of an extremely rare case of BCP-ALL harboring two concomitant leukemia-associated chromosome translocations: t(1;19)(q23;q13.3) and t(9;17)(p13;q11.2). Of note, we described a new rearrangement between exon 6 of PAX5 and a 17q11.2 region, where intron 3 of SPECC1 is located. This rearrangement seems to disrupt PAX5 similarly to a PAX5 deletion. Furthermore, a distinct karyotype between diagnosis and relapse samples was observed, disclosing a complex clonal evolution during leukemia progression.

Case presentation

A 16-year-old boy was admitted febrile with abdominal and joint pain. At clinical investigation, he presented with anemia, splenomegaly, low white blood cell count and 92% lymphoblast. He was diagnosed with pre-B ALL and treated according to high risk GBTLI-ALL2009. Twelve months after complete remission, he developed a relapse in consequence of a high central nervous system and bone marrow infiltration, and unfortunately died.

Conclusions

To our knowledge, this is the first report of a rearrangement between PAX5 and SPECC1. The presence of TCF3-PBX1 and PAX5-rearrangement at diagnosis and relapse indicates that both might have participated in the malignant transformation disease maintenance and dismal outcome.

     

Partial monosomy of the long arm of chromosome 16: A distinct clinical entity?

Summary A 7-month-old male child with a de novo, seemingly belanced reciprocal 5p/16q translocation and karyotype 46,XY,t(5;16) (p14;q21), resulting from a maternal meiotic error, is described. The clinical findings in this patient are strikingly similar to those in the only patient with partial deletion 16q hitherto described, [del(16)(q21)], indicating that during the 5p/16q rearrangement, 16q material was lost and suggesting that partial or total deletion of the long arm of chromosome 16 distal to band q21 is accompanied by a distinct clinical phenotype.     

Duplication of C7orf58, WNT16 and FAM3C in an Obese Female with a t(7;22)(q32.1;q11.2) Chromosomal Translocation and Clinical Features Resembling Coffin-Siris Syndrome

We characterized the t(7;22)(q32;q11.2) chromosomal translocation in an obese female with coarse features, short stature, developmental delay and a hypoplastic fifth digit. While these clinical features suggest Coffin-Siris Syndrome (CSS), we excluded a CSS diagnosis by exome sequencing based on the absence of deleterious mutations in six chromatin-remodeling genes recently shown to cause CSS. Thus, molecular characterization of her translocation could delineate genes that underlie other syndromes resembling CSS. Comparative genomic hybridization microarrays revealed on chromosome 7 the duplication of a 434,682 bp region that included the tail end of an uncharacterized gene termed C7orf58 (also called CPED1) and spanned the entire WNT16 and FAM3C genes. Because the translocation breakpoint on chromosome 22 did not disrupt any apparent gene, her disorder was deemed to result from the rearrangement on chromosome 7. Mapping of yeast and bacterial artificial chromosome clones by fluorescent in situ hybridization on chromosome spreads from this patient showed that the duplicated region and all three genes within it were located on both derivative chromosomes 7 and 22. Furthermore, DNA sequencing of exons and splice junctional regions from C7orf58, WNT16 and FAM3C revealed the presence of potential splice site and promoter mutations, thereby augmenting the detrimental effect of the duplicated genes. Hence, dysregulation and/or disruptions of C7orf58, WNT16 and FAM3C underlie the phenotype of this patient, serve as candidate genes for other individuals with similar clinical features and could provide insights into the physiological role of the novel gene C7orf58.     

A 5q12.1–5q12.3 microdeletion in a case with a balanced exceptional complex chromosomal rearrangement

Complex chromosomal rearrangements are very rare chromosomal abnormalities. Individuals with a complex chromosomal rearrangement can be phenotypically normal or display a clinical abnormality. It is believed that these abnormalities are due to either microdeletions or microduplications at the translocation breakpoints or as a result of disruption of the genes located in the breakpoints. In this study we describe a 2-year-old child with mental retardation and developmental delay in whom a de novo apparently balanced exceptional complex chromosomal rearrangement was found through conventional cytogenetic analysis. Using both cytogenetic and FISH analysis, the patient's karyotype was found to be: 46,XY,der(5)t(5;7)(p15.1;7q34),t(5;8)(q13.1;8q24.1)dn. A large, clinically significant deletion which encompassed 887.69 kb was detected at the 5q12.1–5q12.3 (chr5:62.886.523–63.774.210) genomic region using array-CGH. This deleted region includes the HTR1A and RNF180 genes. This is the first report of an individual with an apparently balanced complex chromosomal rearrangement in conjunction with a microdeletion at 5q12.1–5q12.3 in which there are both mental-motor retardation and dysmorphia.     

Ring chromosome 8 and translocation t(8;21) in a patient with acute myeloblastic leukemia

Recurrent translocation t(8;21)(q22;q22) acute myeloid leukemia (AML) is often associated with secondary chromosome changes of which the clinical significance is not clear since they do not seem to impair the prognosis. Uncommon chromosome changes may lead to the identification of leukemogenetic factors associated with t(8;21) since the AML1/RUNX1-ETO fusion gene resulting from the translocation is thought to be unable alone to induce leukemia. We here report a patient with AML, t(8;21) and ring chromosome 8 resulting in partial chromosome 8 deletion. Another patient with partial 8q deletion has been previously reported. It is suggested that more attention be paid to the genes located in distal 8q in relation to leukemogenesis.     

Is a gene for microcephaly located on chromosome 1?

Summary A 3-month-old boy with true microcephaly showed the same balanced reciprocal translocation 1q4p as his carrier mother. This reciprocal translocation had been transmitted for at least four generations. Different banding techniques allowed one to describe the rearrangement as: rcp t(1;4)(1pter 1q31::4p161 4pter; 4qter 4p153::1q321 1qter). On the other hand, the proband's father seemed to be a border-line mentally retarded and one of his relatives suffered from mental retardation of unknown origin. Taking into account all these results together with the current literature, it was concluded that the microcephaly appearing in our case could be due to the following two facts: (a) the father was an heterozygote for the gene for microcephaly, and (b) damage or a minute deletion on chromosome 1 between 1q31 and 1q321 bands could occur in the mother's family resulting in a mutation for microcephaly. If this was so, the gene for microcephaly should be located on chromosome 1 at the level of the 1q31–1q321 junction.     

Familial reciprocal translocation t(17;19) (q11.2;q13.2) associated with neurofibromatosis type 1, including one patient with non-Hodgkin lymphoma and an additional t(14;20) in B lymphocytes

The cosegregation of a reciprocal translocation t(17;19) (q11.2;13.2) with neurofibromatosis type 1 in three generations suggested that the breakpoint on chromosome 17 involved the NF1 gene. In order to map the breakpoint, we analysed DNAs of patients using parts of the NF1 gene as probes. Southern analysis revealed that the chromosome 17 breakpoint lies within intron 23 of the NF1 gene. One of the patients of the family developed a non-Hodgkin lymphoma. An additional translocation t(14;20) (q32;13.1) in his B lymphocytes points to a gene on chromosome 20 that is juxtaposed to the IGH locus on 14q32, and that may be of relevance for the development of this tumor type.     

A, 1;6, translocation associated with congenital glaucoma and cleft lip and palate.

A translocation of a part of the long arm of a chromosome No. 1 onto the long arm of a chromosome No. 6 was observed in a 2 1/2-year-old boy with mental retardation, harelip, cleft palate and congenital glaucoma. Different banding methods revealed that the translocation t(1;6)(q23;q27) apparently was balanced. The conncection between the patients' symptoms and the chromosomal rearrangement might be fortuitous or produced by the chromosome aberration.