Neoplasia-associated Chromosome Translocations Resulting in Gene Truncation

Cancer Genomics Proteomics

Brunetti

et al. 2023

Self Cite

Background/Aim: Mesotheliomas are tumors similar to, and probably derived from, mesothelial cells. They carry acquired chromosomal rearrangements, deletions affecting CDKN2A, pathogenetic polymorphisms in NF2, and fusion genes which often contain the promiscuous EWSR1, FUS, and ALK as partner genes. Here, we report the cytogenomic results on two peritoneal mesotheliomas. Materials and Methods: Both tumors were examined using G-banding with karyotyping and array comparative genomic hybridization (aCGH). One of them was further investigated with RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization (FISH). Results: In the first mesothelioma, the karyotype was 25~26,X,+5,+7,+20[cp4]/50~52,idemx2[cp7]/46,XX [2]. aCGH detected gains of chromosomes 5, 7, and 20 with retained heterozygosity on these chromosomes. In the second tumor, the karyotype was 46,XX,inv(10)(p11q25) [7]/46,XX [3]. aCGH did not detect any gains or losses and showed heterozygosity for all chromosomes. RNA sequencing, RT-PCR/Sanger sequencing, and FISH showed that the inv(10) fused MAP3K8 from 10p11 with ABLIM1 from 10q25. The MAP3K8::ABLIM1 chimera lacked exon 9 of MAP3K8. Conclusion: Our data, together with information on previously described mesotheliomas, illustrate two pathogenetic mechanisms in peritoneal mesothelioma: One pathway is characterized by hyperhaploidy, but with retained disomies for chromosomes 5, 7, and 20; this may be particularly prevalent in biphasic mesotheliomas. The second pathway is characterized by rearrangements of MAP3K8 from which exon 9 of MAP3K8 is lost. The absence of exon 9 from oncogenetically rearranged MAP3K8 is a common theme in thyroid carcinoma, lung cancer, and spitzoid as well as other melanoma subtypes.Mesotheliomas are rare, mostly malignant tumors similar to, and probably derived from, mesothelial cells, i.e., the cells lining the body's serous cavities (1-3). More than 80% of mesotheliomas are developed in the wall lining of the pleural cavity, 7% in the peritoneum, 1% in the pericardium, and less than 1% in the tunica vaginalis (4, 5). The three histological types, epithelioid, sarcomatoid, and biphasic (the latter subtype has both epithelioid and sarcomatous differentiation), account for 50-60%, 10%, and 30-40% of mesotheliomas, respectively (3), and influence disease prognosis (6, 7). Malignant mesothelioma is strongly associated with exposure to asbestos (8-11). Other etiological factors are genetic predisposition (12-14), radiation exposure, and viral infection that alone or together with asbestos exposure can cause malignant mesotheliomas (15,16).Mesotheliomas carry acquired genetic aberrations (17). Cytogenetic analysis of 131 tumors has shown that most mesotheliomas have complex karyotypes (18). Comparative genomic hybridization, loss of heterozygosity, and fluorescence in situ hybridization (FISH) studies have detected nonrandom gains and losses of chromosomal regions (19-21). Deletions of or from chromosome arms 1p, 3...

Section: Discussionmentioning

confidence: 99%

Genetic Pathways in Peritoneal Mesothelioma Tumorigenesis

Cancer Genomics Proteomics

Brunetti

et al. 2023

Self Cite

“…Thus, HMGA2::GSN chimeric protein would contain the three AT-hook domains of HMGA2 and the entire functional part of GSN without the signal peptide which is found in the first 27 amino acids of native GSN protein (Figure 2B and C) (48,49). Very few HMGA2 fusion genes result in chimeric HMGA2 proteins (17,33). The HMGA2::LPP chimera found in lipomas, chondroid hamartomas, and chondromas codes for a chimeric HMGA2::LPP protein (10, 11, 19, 50-52).…”

Section: Discussionmentioning

confidence: 99%

“…Tumorigenic properties were detected for both the HMGA2::LPP (58-60) and HMGA2::EGFR fusion proteins (53), whereas functional studies have not been performed to test for the effects of HMGA2::YAP1, HMGA2::NCOR2, and the present HMGA2::GSN chimeric protein. Although the 3´-end partners (LPP, EGFR, YAP1, NCOR2, and GSN) in HMGA2 chimeric proteins are involved in different cell functions and have been implicated in tumor development (33), it is worthy of note that all the above-mentioned HMGA2-chimeras contain the three AThook domains of HMGA2 (17,33). In this sense, the pattern is similar to what is seen in other rearrangements of HMGA2 found in lipomas and other tumors, i.e., disruption of the HMGA2 locus leaves intact exons 1-3 of the gene which encode the AT-hook domains and separates them from the 3´terminal part of the gene which contains regulatory elements for the expression of HMGA2 (34,(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

“…3 (10-17). The recombination of 12q14 involves a wide variety of partners (8, 9, [16][17][18]. The by-far most common event is the translocation t(3;12)(q28;q14) which fuses HMGA2 with a gene from 3q28 named LIM domain containing preferred translocation partner in lipoma (LPP) (3)(4)(5)(6)(7)(8)(9)(10)(11)19), but also many other genomic recombinations giving rise to HMGA2 chimeric genes have been reported in lipomas (Table I) (10)(11)(12)(13)(14)(15)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Fusion of the High-mobility Group AT-Hook 2 (HMGA2) and the Gelsolin (GSN) Genes in Lipomas With t(9;12)(q33;q14) Chromosomal Translocation

Brunetti

et al. 2023

In Vivo

Background/Aim: Lipomas are benign tumors composed of mature fat cells. They are common soft tissue tumors that often carry chromosome aberrations involving 12q14 resulting in rearrangements, deregulation, and generation of chimeras of the high-mobility group AT-hook 2 gene (HMGA2) which maps in 12q14.3. In the present study, we report the finding of t(9;12)(q33;q14) translocation in lipomas and describe its molecular consequences. Materials and Methods: Four lipomas from two male and two female adult patients were selected because their neoplastic cells carried a t(9;12)(q33;q14) as the sole karyotypic aberration. The tumors were investigated using RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing techniques. Results: RNA sequencing of a t(9;12)(q33;q14)-lipoma detected an in-frame fusion of HMGA2 with the gelsolin gene (GSN) from 9q33. RT-PCR together with Sanger sequencing confirmed the presence of an HMGA2::GSN chimera in the tumor as well as in two other tumors from which RNA was available. The chimera was predicted to code for an HMGA2::GSN protein which would contain the three AT-hook domains of HMGA2 and the

“…In recent years, utilization of high throughput sequencing technology on T-ALLs has revealed also numerous other fusion genes and gene mutations (6-9). The combined use of high throughput sequencing, mainly transcriptome sequencing, and karyotyping has detected specific fusion genes of unquestionable pathogenetic significance (10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

NovelMYCBP::EHD2andRUNX1::ZNF780AFusion Genes in T-cell Acute Lymphoblastic Leukemia

Cancer Genomics Proteomics

Johannsdottir

et al. 2022

Background/Aim: T-cell acute lymphoblastic leukemia (T-ALL) is a rare malignancy characterized by proliferation of early T-cell precursors that replace normal hematopoietic cells. T-ALL cells carry non-random chromosome aberrations, fusion genes, and gene mutations, often of prognostic significance. We herein report the genetic findings in cells from a T-ALL patient. Materials and Methods:Bone marrow cells from a patient with T-ALL were examined using G-banding, array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization. Results: G-banding revealed del(1)(p34), add(5)(q14), trisomy 8, and monosomy 21 in the leukemic cells. aCGH detected the gross unbalances inferred from the karyotyping results, except that heterozygous loss of chromosome 21 did not include its distal part; 21q22.12-q22.3 was undeleted. In addition, aCGH detected a submicroscopic interstitial 7.56 Mbp deletion in the q arm of chromosome 19 from 19q13.2 to 19q13.33. RNA sequencing detected and RT-PCR/Sanger sequencing confirmed the presence of two novel chimeras, MYCBP::EHD2 and RUNX1::ZNF780A. They were generated from rearrangements involving subbands 1p34.3 (MYCBP), 19q13.2 (ZNF780A), 19q13.33 (EHD2), and 21q22.12 (RUNX1), i.e., at the breakpoints of chromosomal deletions. Conclusion: The leukemic cells showed the heterozygous loss of many genes as well as the generation of MYCBP::EHD2 and RUNX1::ZNF780A chimeras. Because the partner genes in the chimeras were found at the breakpoints of the chromosomal deletions, we believe that both the heterozygous losses and the generation of the two chimeras occurred simultaneously, and that they were pathogenetically important.