Central nervous system (CNS) is an increasingly common site of isolated metastasis for patients with Stage 4 neuroblastoma. To explore the microRNA (miRNA) profile of this metastatic process, miRNA sequencing was performed to identify miRNA sequence families with differential expression between tumor pairs (pre‐CNS primary and CNS metastasis) from 13 patients with Stage 4 neuroblastoma. Seven miRNA sequence families had distinct expression in CNS metastases when compared with their corresponding pre‐CNS primaries. MiR‐7 was upregulated (3.75‐fold), and miR‐21, miR‐22, miR‐29a, miR‐143, miR‐199a‐1‐3p, and miR‐199a‐1‐5p were downregulated (3.5‐6.1‐fold), all confirmed by quantitative reverse transcription‐PCR. MiR‐29a, previously shown to be downregulated in a broad spectrum of solid tumors including neuroblastoma, had the most significant decrease in all 13 CNS metastases (P = 0.001). Its known onco‐targets CDC6, CDK6, and DNMT3A, as well as B7‐H3, an inhibitory ligand for T cells, and natural killer cells, were found to have higher differential expression in these 13 CNS metastases when compared with their paired primaries. Additionally, miR‐29a expression in primary tumors was significantly lower among patients who eventually relapsed in the CNS. Irrespective of the amplification status of MYCN, which is known to be associated with metastasis, pre‐CNS primaries, and CNS metastases had significantly lower miR‐29a expression than non‐CNS primary tumors. Among MYCN amplified cell lines, those from CNS relapse also had lower miR‐29a expression than non‐CNS relapse. These findings raised the hypothesis that miR‐29a could be a biomarker for neuroblastoma CNS metastasis, and its downregulation may play a pivotal role in CNS progression. © 2014 Wiley Periodicals, Inc.

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An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression

Yano, Mio; Imamura, Toshihiko; Asai, Daisuke; Moriya‐Saito, Akiko; Suenobu, So‐ichi; Hasegawa, Daiichiro; Deguchi, Takao; Hashii, Yoshiko; Kawasaki, Hirohide; Hori, Hiroki; Kosaka, Yoshiyuki; Kato, Koji; Horibe, Keizo; Yumura‐Yagi, Keiko; Hara, Junichi;

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TET2 mutations in cytogenetically normal acute myeloid leukemia: Clinical implications and evolutionary patterns

Damm, Frederik; Markus, Birgit; Thol, Felicitas; Morgan, Michael; Göhring, Gudrun; Schlegelberger, Brigitte; Krauter, Jürgen; Heuser, Michael; Bernard, Olivier A.; Ganser, Arnold

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22191pmid: 24898826

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Near‐haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations

Corver, Willem E.; Wezel, Tom; Molenaar, Kees; Schrumpf, Melanie; Akker, Brendy; Eijk, Ronald; Ruano Neto, Dina; Oosting, Jan; Morreau, Hans

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22194pmid: 24909752

Mitochondrial‐rich oncocytic thyroid tumors frequently show near‐haploidization and endoreduplication (masked haploidization), which manifests as a near‐homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome‐wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two‐tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype. © 2014 Wiley Periodicals, Inc.

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Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin

Weinreb, Ilan; Zhang, Lei; Tirunagari, Laxmi MS; Sung, Yun‐Shao; Chen, Chun‐Liang; Perez‐Ordonez, Bayardo; Clarke, Blaise A; Skalova, Alena; Chiosea, Simion I; Seethala, Raja R; Waggott, Daryl; Boutros, Paul C; How, Christine; Liu, Fei‐Fei; Irish, Jonathan C;

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Promoter‐specific alterations of APC are a rare cause for mutation‐negative familial adenomatous polyposis

Pavicic, Walter; Nieminen, Taina T.; Gylling, Annette; Pursiheimo, Juha‐Pekka; Laiho, Asta; Gyenesei, Attila; Järvinen, Heikki J.; Peltomäki, Päivi

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22197pmid: 24946964

In familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation‐negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation‐dependent probe amplification (MLPA, P043‐B1). Promoter‐specific events of APC were addressed by targeted resequencing, MLPA (P043‐C1), methylation‐specific MLPA, and Sanger sequencing of promoter regions. A novel 132‐kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele‐specific APC expression. No promoter‐specific point mutations or hypermethylation were present in any family. In conclusion, promoter‐specific alterations are a rare cause for mutation‐negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele‐specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations. © 2014 Wiley Periodicals, Inc.

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Identification of novel ALK rearrangement A2M–ALK in a neonate with fetal lung interstitial tumor

Onoda, Tadashi; Kanno, Miyako; Sato, Hiroko; Takahashi, Noriyuki; Izumino, Hiroko; Ohta, Hiroshi; Emura, Takaki; Katoh, Hirohisa; Ohizumi, Hiroyuki; Ohtake, Hiroya; Asao, Hironobu; Dehner, Louis P.; Hill, Ashley D.; Hayasaka, Kiyoshi; Mitsui, Tetsuo

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Functional characterization of NTRK1 mutations identified in melanoma

Miranda, Claudia; Mazzoni, Mara; Sensi, Marialuisa; Pierotti, Marco A.; Greco, Angela

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22200pmid: 24965840

Cutaneous melanoma is the most aggressive form of skin cancer, with a complex and heterogeneous aetiology. Deregulation of the mitogen activated protein kinase cascade is common in melanoma, due to activating mutations in the BRAF and NRAS genes. Genetic studies and high‐throughput screening technologies have recently identified several somatic mutations affecting different receptor tyrosine kinase (RTK) genes. For the majority of these, however, the contribution to the complexity of melanoma biology has not been assessed. Among these, two novel missense somatic mutations (M379I and R577G) have recently been identified in the gene encoding the neurotrophic RTK NTRK1. The NTRK1 melanoma‐associated point mutations were introduced in a NTRK1 expression plasmid. Functional characterization of mutants was assessed after transient and stable transfection in HeLa and NIH3T3 cells, respectively. We showed that M379I and R577G NTRK1 receptors do not display the kinase as constitutively activated and are functionally indistinguishable from the wild‐type NTRK1 receptor. Our results indicate that a causative role for M379I and R577G NTRK1 mutations in melanoma development is highly unlikely. This supports the issue that, in parallel to systematic large scale cancer genome screening, functional studies are required to distinguish between mutations that play a causative role in tumor development and others that may only be passenger changes. © 2014 Wiley Periodicals, Inc.

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Clinical significance of miR‐126 in colorectal cancer

Cristóbal, Ion; Aguilera, Oscar; García‐Foncillas, Jesús; Zazo, Sandra; Madoz‐Gúrpide, Juan; Rojo, Federico

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22192pmid: 24898922

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Reply to letter by Cristobal et al.

Liu, Yaling; Zhou, Yu; Feng, Xiao; Yang, Pengchun; Yang, Jingfang; An, Ping; Luo, Hesheng

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22193pmid: 24916021

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2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22190pmid: 24935070

For an overall characterization of pediatric B‐cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of 167 patients, the P2RY8‐CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion transcript, CSF2RA‐CRLF2, in a case with CRLF2 OE, suggesting that this fusion is associated with CRLF2 OE. In survival analysis, no significant differences in 5‐year event‐free survival (EFS) and overall survival were observed between patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4 vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in 5‐year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed (44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1 deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P = 0.04).These findings suggest that CRLF2 OE is not an independent prognostic factor in pediatric BCPALL. © 2014 Wiley Periodicals, Inc.

Mutations of the Ten‐Eleven‐Translocation 2 (TET2) gene have been identified in patients with various myeloid neoplasms, but the clinical relevance of these mutations and their timing during disease development in cytogenetically normal acute myeloid leukemia (CN‐AML) remain unclear. The total coding region of TET2 was analyzed by direct sequencing in 215 CN‐AML patients younger than 60 years from multicenter treatment trials AML‐SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295. Associations were analyzed in the context of other molecular markers, such as CEBPA, DNMT3A, NMP1, FLT3, IDH1/2, RAS, and WT1. To investigate the order of appearance of TET2 and concomitant mutations, targeted deep resequencing was performed in six patients. At least one sequence variation with impact on TET2 protein sequence was found in 13 of the 215 CN‐AML patients (6%). Patients with TET2 mutations tended to be older (P = 0.078) and had higher platelet counts (P = 0.041). TET2‐mutated patients were more likely to have concomitant NPM1 (11 of 13; P = 0.047) and DNMT3A (10 of 13; P = 0.001) mutations but were mutually exclusive to partial tandem duplication of the MLL gene (MLL‐PTD) and IDH1/2 mutations. TET2 mutations were identified as subclones in four of the six investigated patients by deep sequencing. Progenitor‐derived colony assays suggest a stepwise acquisition of mutations during disease development, TET2 mutation being later than NPM1 and DNMT3A. The TET2 mutation status did not influence overall or relapse‐free survival. © 2014 Wiley Periodicals, Inc.

Antonescu, Cristina R

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22195pmid: 24942367

Polymorphous low‐grade adenocarcinoma (PLGA) and cribriform adenocarcinoma of minor salivary gland (CAMSG) are low‐grade carcinomas arising most often in oral cavity and oropharynx, respectively. Controversy exists as to whether these tumors represent separate entities or variants of one spectrum, as they appear to have significant overlap, but also clinicopathologic differences. As many salivary carcinomas harbor recurrent translocations, paired‐end RNA sequencing and FusionSeq data analysis was applied for novel fusion discovery on two CAMSGs and two PLGAs. Validated rearrangements were then screened by fluorescence in situ hybridization (FISH) in 60 cases. Histologic classification was performed without knowledge of fusion status and included: 21 CAMSG, 18 classic PLGA, and 21 with “mixed/indeterminate” features. The RNAseq of 2 CAMSGs showed ARID1A‐PRKD1 and DDX3X‐PRKD1 fusions, respectively, while no fusion candidates were identified in two PLGAs. FISH for PRKD1 rearrangements identified 11 additional cases (22%), two more showing ARID1A‐PRKD1 fusions. As PRKD2 and PRKD3 share similar functions with PRKD1 in the diacylglycerol and protein kinase C signal transduction pathway, we expanded the investigation for these genes by FISH. Six additional cases each showed PRKD2 and PRKD3 rearrangements. Of the 26 (43%) fusion‐positive tumors, there were 16 (80%) CAMSGs and 9 (45%) indeterminate cases. A PRKD2 rearrangement was detected in one PLGA (6%). We describe novel and recurrent gene rearrangements in PRKD1–3 primarily in CAMSG, suggesting a possible pathogenetic dichotomy from “classic” PLGA. However, the presence of similar genetic findings in half of the indeterminate cases and a single PLGA suggests a possible shared pathogenesis for these tumor types. © 2014 Wiley Periodicals, Inc.

2014 Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22199pmid: 24965693

Fetal lung interstitial tumor (FLIT) is a recently reported type of congenital lung lesion comprising solid and cystic components. The pathological features include unique interstitial mesenchyme‐based cell proliferation, and differ from other neoplasms represented by pleuropulmonary blastoma or congenital peribronchial myofibroblastic tumor. FLIT is extremely rare and its gene expression profile has not yet been reported. We provide the first report of a novel chromosomal rearrangement resulting in α‐2‐macroglobulin (A2M) and anaplastic lymphoma kinase (ALK) gene fusion in a patient with FLIT. The tumor cells contained a t(2;12)(p23;p13) and were mesenchymal in origin (e.g., inflammatory myofibroblastic tumors), suggesting the involvement of ALK in this case of FLIT. Break apart fluorescence in situ hybridization demonstrated chromosomal rearrangement at ALK 2p23. Using 5′‐rapid amplification of cDNA ends, we further identified a novel transcript fusing exon 22 of A2M to exon 19 of ALK, which was confirmed by reverse‐transcription polymerase chain reaction. The corresponding chimeric gene was subsequently confirmed by sequencing, including the genomic break point between intron 22 and 18 of A2M and ALK, respectively. Discovery of A2M as a novel ALK fusion partner, together with the involvement of ALK, provides new insights into the pathogenesis of FLIT, and suggests the potential for new therapeutic strategies based on ALK inhibitors. © 2014 Wiley Periodicals, Inc.