A Comprehensive Genome-Based Mutational Analysis by Next Generation Sequencing Technology in Patients With Malignant Pleural and Peritoneal Mesothelioma

Abstract

Mice with miR-21 loss demonstrated delay in spontaneous tumor formation, decreased growth rate, and reduced macroscopic lung metastases compared to MMTV-PyMT mice with intact miR-21. When challenged with orthotopic tumor implantation, miR-21+/and miR-21-/-mice had increased delay in allograft tumor formation compared to wild-type mice, suggesting stromal changes in the mammary microenvironment modulated by miR-21. Conclusion: Modulation of miR-21 expression in a murine tumor model appears to play an important role in breast cancer tumorigenesis and progression. Expression of miR-21 may be linked to treatment resistance and development of an aggressive tumor phenotype. As modulation of miR-21 appears to delay de novo tumorigenesis as well as tumor allograft formation, multiple mechanisms of tumorigenesis may be implicated. Targeted inhibition of the miR-21 pathway may be an attractive therapeutic option to both sensitize tumors to cytotoxic treatment while modulating the peritumoral stroma.

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

“…We found biallelic deletions in three noncontiguous regions in telomeric cluster 1: (i) deletion of SETD2 (exon 1) and its adjacent FLJ39534 gene (exons 1-2); (ii) deletion of KLHL18 (kelch like family member 18) (exons 2-10); and (iii) deletion of SMARCC1 (exons 3-5). Moreover, we found biallelic deletions in the centromeric cluster 2, including BAP1 (exons [11][12][13][14][15][16][17].…”

“…Although we detected CN alterations in SMARCC1, no nucleotide level mutations were found in this gene, confirming previous studies based on NGS (9-12) and underscoring the limitations of this technique when used alone. Together, the combination of high-density aCGH and tNGS detected a much higher percentage of genetic alterations in BAP1, SETD2, PBRM1, and SMARCC1 than reported in the MM literature, which is largely based on NGS sequencing (9)(10)(11)(12). This is because NGS sequencing is a technique that is effective at identifying nucleotide mutations, but is not optimized for the identification of minute or larger chromosomal deletions (8).…”

“…Thus, an important implication of our study is that conventional NGS approaches are insufficient to identify reliably all of the different genetic alterations that occur in MM, and most likely in other cancers. For example, using a NGS approach, Bueno et al (11) and Ugurluer et al (12) reported inactivating nucleotide mutations of BAP1 and SETD2 in 20-30% and 8% of MMs, respectively. Instead, when combining high-density aCGH (to detect minute deletions of <3 kb) and tNGS (to detect nucleotide level mutations), we found that BAP1 and SETD2 were inactivated-either by minute biallelic deletion or LOH combined with point mutations-in 48% and 27% of MMs, respectively.…”

“…Conventional NGS studies revealed that the most commonly mutated genes in MMs are BRCA1-associated protein 1 (BAP1), CDKN2A (cyclindependent kinase inhibitor 2a), and NF2 (neurofibromin 2) (9-12). The reported frequency of BAP1 inactivation, the most commonly mutated gene in MM, using NGS or Sanger sequencing, was between 20% and 30% (9)(10)(11)(12)(13)(14)(15).…”

Malignant peritoneal mesothelioma and Crohn disease

“…Peritoneal MM has developed in several individuals with recurrent peritonitis resulting from familial Mediterranean fever (FMF). There was no history of asbestos exposure in one case, but it is unclear whether exposure to asbestos or asbestos-like minerals found in certain regions of Turkey occurred in any of the other cases seen in individuals with FMF or whether any had predisposing mutations in the BAP1 gene 2 8 10 11. Peritoneal MM has also been described in an individual with no apparent exposure to asbestos who had recurrent peritonitis related to severe diverticulitis 12…”