Genetic Pathways in Peritoneal Mesothelioma Tumorigenesis

Abstract

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...

Acute Lymphoblastic Leukemia With Near-haploid Karyotype and Philadelphia Chromosome

“…Loss-of-heterozygosity based on the B-allele frequency methodology and single nucleotide polymorphism (SNP) (32) showed that the disomic chromosomes 6, 10, 18, and, 21 retained heterozygosity (Table I). This is consistent with previous observations that in neoplasms with near-haploid karyotypes, the disomic chromosomes are both maternal and paternal (19,(40)(41)(42)(43). aCGH also revealed that the breakpoints in both the ABL1 and BCR genes occurred in their intron 1.…”