Das Translokationskarzinom

The MiT family of translocation-associated renal cell carcinomas comprise approximately 40?% of renal cell carcinomas in young patients but only up to 4?% of renal cell carcinomas in adult patients. The Xp11.2 translocation-associated tumors are the most frequent and were included in the 2004 World Health Organization (WHO) classification. They contain a fusion of the TFE3 gene with ASPSCR1, PRCC, NONO, SPFQ or CLTC resulting in an immunohistochemically detectable nuclear overexpression of TFE3. The Xp11.2 translocation-associated renal cell carcinomas are characterized by ample clear cytoplasm, papillary architecture and abundant psammoma bodies. The TFEB translocation-associated renal cell carcinomas are much rarer and show a biphasic architecture. Fluorescence in situ hybridization permits the detection of a translocation by means of a break apart probe for the TFE3 and TFEB genes and is recommended for the diagnosis of renal cell carcinomas in patients under 30 years of age. The TFE3 and TFEB translocation-associated tumors are classified as MiT family translocation carcinomas in the new WHO classification.The rare renal cell carcinomas harboring an ALK rearrangement with fusion to VCL in young patients with sickle cell trait show a characteristic morphology and are listed in the new WHO classification as a provisional entity.     

Nonrandom cell-cycle timing of a somatic chromosomal translocation: The t(X;17) of alveolar soft-part sarcoma occurs in G2

The cell-cycle timing of somatic chromosomal translocations in cancer remains poorly understood but may be relevant to their etiology and the mechanism of their formation. Alveolar soft-part sarcoma (ASPS) is a rare malignant soft-tissue tumor of uncertain lineage that provides an opportunity to address this question. The great majority of ASPSs have relatively simple near-diploid karyotypes characterized by an unbalanced der(17)t(X;17)(p11.2;q25), resulting in nonreciprocal fusion of TFE3 with ASPSCR1 (a.k.a. ASPL), with consequent net gain of Xp11.2-->pter and loss of 17q25-->qter. The presence of a normal X along with the der(17)t(X;17) in ASPSs that occur in men has been well described in previous cytogenetic reports and is most readily explained by a translocation in the G2 phase of the cell cycle. To establish whether formation in G2 is a general feature of the t(X;17), we examined polymorphic loci in Xp11.2-->qter in ASPS from 9 women, including 7 with an unbalanced t(X;17). Our analysis showed that all 7 displayed retention of heterozygosity at all informative markers on Xp11.2-->qter, supporting preferential formation of the t(X;17) in the G2 phase of the cell cycle. Given that the two derivative chromosomes of a translocation in G2 would be expected to segregate together half the time, the predominance of an unbalanced der(17)t(X;17) also raises the possibility of a selective advantage in ASPS cells for gain of Xp11.2-->pter or loss of 17q25.3-->qter or retention of an active copy of TFE3.     

A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the presence of a t(9;22)(q34;q11.2), which leads to the well-known BCR-ABL1 fusion protein. We describe a patient who was diagnosed clinically with a typical CML but on cytogenetic analysis was found to have a t(9;22)(p24;q11.2). Chromosomal fluorescence in situ hybridization showed that the BCR gene locus spanned the breakpoint at band 22q11.2 but that the ABL1 gene was not rearranged. By means of a candidate gene approach, the JAK2 gene, at 9p24, was identified as the fusion partner of BCR in this case. The BCR-JAK2 fusion protein contains the coiled-coil dimerization domain of BCR and the protein tyrosine kinase domain (JH1) of JAK2. The patient's disease did not respond to Imatinib, and this unresponsiveness was most likely a result of the BCR-JAK2 fusion protein.     

Unique patterns of allelic imbalance distinguish type 1 from type 2 sporadic papillary renal cell carcinoma

The molecular genetic correlates of a recently proposed subclassification of papillary renal cell carcinoma (PRCC) that designates tumors as type 1 and type 2 based on histological features have not yet been established. Alterations of known genes in PRCC include missense mutations in the MET oncogene (7q31) and rare translocations fusing TFE3 at Xp11.2 with a variety of other loci. Previous cytogenetic and allelic loss studies of PRCC cases revealed gain of chromosome 3q, 7, 8, 12q, 16, 17, and 20q, and loss of 1p, 6q, 9p, 11p, 13q, 14q, 18, 21q, X, and Y. We analyzed a series of sporadic type 1 and type 2 PRCC cases for MET mutations, TFE3 rearrangements, and allelic imbalance (AI) on 3p, 6, 7q, 9p, 11, 13q, 14q, 17q, 18, 20q, and 21q and compared selected results with a series of conventional renal cell carcinomas. A somatic mutation M1149T was identified in MET exon 17 in 1 of 35 PRCC cases whereas TFE3 rearrangements were not detected in 22 PRCC cases examined. Significant differences in AI frequency between PRCCs and conventional renal cell carcinoma cases were seen on 3p (37.5% versus 77.8%, P = 0.01), 7q (42.9% versus 5.6%, P = 0.01), and 17q (54.5% versus 20.0%, P = 0.03). Significant differences in AI frequency between type 1 and type 2 PRCCs were noted on 17q (78.6% versus 12.5%, P = 0.006) and 9p (0% versus 37.5%, P = 0.02). Additional analyses suggested that the relationship between 17q AI and PRCC type may be independent of histological grade and stage. Our findings identify genetic differences between the recently proposed type 1 and type 2 PRCCs, and support the premise that these subtypes arise from distinct genetic pathways.     

A novel RBMX‐TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX‐TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12‐year‐old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break‐apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX‐TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come‐together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break‐apart might be below the FISH resolution, resulting in a false negative result.