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Exome Sequencing Studies of Malignant Pleural Mesothelioma


NGS technologies have allowed DNA and RNA to be sequenced at an unprecedented speed, uncovering potential driver genes, and creating new biological applications. In the last decade, NGS has been used to detect driver genetic mutations in cancer and provide new information about tumorigenesis. In the first study to investigate malignant pleural mesothelioma (MPM) with NGS, shotgun pyrosequencing was used to characterize the RNA expression levels and mutations of four patients, and several different mutations were found in four transcriptomes. Additionally, RNA editing gene deletions and gene silencing have been identified. In 2010, the first full genome sequence of an MPM tumor and matching normal tissue was performed using a combination of sequencing by synthesis and pyrosis sequencing methodologies.
Exome Sequencing Studies of Malignant Pleural MesotheliomaThis study shows that aneuploidy and chromosomal rearrangements in this tumor are more than point mutations. A large deletion in the dipeptidyl peptidase-like 10 (DPP10) gene was further investigated in 53 additional MPM tumors by altering the expression of the corresponding transcript. Statistically longer survival DPP10 expression was observed in expressing patients compared with DPP10 deficient patients. In 2016, Bueno and his team conducted a comprehensive analysis of the mutational landscape of MPM. Ninety-nine MPM tumors were examined by complete exome sequencing, while an additional 103 samples were characterized by targeted exome sequencing. Repetitive mutations were found in SF3B1 and TRAF7, in which BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 were significantly mutated.
In 2018, a comprehensive molecular profile of 74 primary MPM samples, including the Cancer Genome Atlas (TCGA) program, exome sequencing, copy number sequences, mRNA sequencing, non-coding RNA profiling, DNA methylation, and reverse phase protein sequences. The genes significantly mutated in this study are BAP1, NF2, TP53, LATS2 and SETD2. In addition, this study identified a new haploid molecular MPM subtype. The TCGA study performed a comparison of significantly mutated genes between Bueno and TCGA cohorts. This analysis identified five genes that were frequently mutated in both studies; The SET domain containing BRCA1-associated protein-1, neurofibromin 2, tumor protein P53, 2, histone lysine methyltransferase, and SET domain bifurcated histone lysine methyltransferase 1.

BAP1

BAP1 is a region frequently erased in MPM, 21.1. It is in position on the short (p) arm of chromosome 3. This gene codes for a deubiquitinase involved in cell cycle regulation, modulation of gene transcription, cellular differentiation, and DNA repair. BAP1 is one of the most commonly mutated genes in MPM. Germline BAP1 mutations have been associated with the development of BAP1 tumor susceptibility syndrome, which includes uveal and cutaneous melanoma, atypical spitz tumors, renal cell carcinoma, and MPM. In all these malignancies except MPM, mutations except BAP1 are associated with a poor prognosis. In contrast, some studies have shown that patients with MPM carrying BAP1 mutations have longer overall survival compared to wild type BAP1 patients.
In one study, BAP1 immunohistochemistry was performed using a tissue microarray containing 229 MPM tumors. The results showed that in patients with nuclear BAP1 staining, loss of BAP1 nuclear staining was associated with a longer median survival of 16,11 months. Baumann et al. Compared survival in 23 patients with MPM who carried germline mutations in 23 patients. From the BAP1 Surveillance, Epidemiology, and End Results (SEER) database, they found a 7-fold increase in long-term survival with a control group of MPM patients and patients with the BAP1 mutation. Given its prevalence in MPM, loss of nuclear BAP1 expression by IHC is widely used as a diagnostic marker in MPM.
Recently, BAP1 status has been associated with drug response. While I in Vitro studies showed MPM cell lines carrying BAP1 mutations, compared to wild type cells, gemcitabine remained significantly less sensitive. Silencing suggests that BAP1 MPM has a significant role in wild-type cells. Kumar et al. Conducted a retrospective study analyzing the presence or absence of nuclear BAP1 by IHC in MPM tumors from 60 patients in the MS01 trial. Nuclear BAP1 expression has been associated with a small but statistically insignificant reduction in survival in patients treated with vinorelbine.

NF2

NF2 is located on the long (q) arm of chromosome 22 at position 12.2, and chromosome 22 loss is a common change in MPM. This gene codes for a protein known as merlin (mosezrin-radixin-like protein) or schwannomine, which regulates key signaling pathways involved in cell growth, adhesion, and microtubule stabilization. Germline mutation or chromosomal deletion is associated with NF2 cranial and peripheral nerve tumors as well as meningioma and ependymoma. Germline mutations in NF2 have also been associated with MPM, but patients with both neurofibromatosis type 2 syndrome and MPM are extremely rare. Recent studies have shown that NF2 mutations occur in 14-19% of MPM. In addition, karyotype or FISH analysis showed that 56% MPMs showed 22q chromosome loss. 22q deletions are more often associated with epithelioid than non-epithelioid MPM.
In a 2009 study proposal, MPM tumors that can be inactivated with NF2 upstream regulators can be detected where NF2 deviations. In a study of 204 MPM patients, it was found that low cytoplasmic merlin expression predicted shorter recurrence interval and shorter overall survival. Lopez-Lago et al. They investigated the relationship between merlin loss and mTORC1 activation in MPM cell lines and found that merlin-negative or merlin-depleted cell lines were more sensitive to the growth inhibitory effect of rapamycin. In 2014, low merlin expression was found to be associated with increased sensitivity of MPM cell lines to the FAK inhibitor VS-471. However, in clinical studies, the FAK inhibitor defactinib did not improve progression-free or overall survival after first-line chemotherapy in patients with MPM.

TP53

TP53, found at 17p31.1, encodes tumor protein p53 (p53), a sequence-specific DNA-binding protein with a tumor suppressor function that regulates transcription and controls cell apoptosis in the presence of DNA damage. Called the guardian of the genome, p53 plays a role in many cellular processes such as checkpoint control, cellular aging, and BCL-2 mediated apoptosis. TP53, in general, is the gene most frequently altered in cancer disease. The frequency of TP53 mutations in MPM in different studies is variable, but is generally much lower than in other solid tumors.
Exome Sequencing Studies of Malignant Pleural MesotheliomaTP53 was significantly more frequently mutated in females, all samples were analyzed (10/40, 25%) compared to males (17/169, 10%) (Fisher p = 0.044), including two large MPM studies. In addition, Bueno and his team reported that MPM patients with TP53 mutations had a shorter overall survival than those with wild-type TP53.

AYAR 2

SETD2 pairs with 3p21.31 and codes for a histone methyltransferase specific for lysine-36 of histone H3, which regulates transcription through epigenetic mechanisms. Inactivating SETD2 mutations have been identified in multiple cancers. In particular, targeted sequencing has revealed the SETD2 bi-allelic inactivation in clear cell renal cell carcinoma tumors, suggesting for the first time that SETD2 may contribute to tumorigenesis. In MPM, single nucleotide mutations and 3p losses in SETD2 are frequently observed. Over the past few years, SETD2 changes have been associated with DNA-damaging chemotherapy resistance mechanisms in a number of cancers.

SETTINGS1

SETDB1 is located at 1q21, another region frequently deleted in MPM and codes for histone-lysine N-methyltransferase SETDB1, which trimethylates Lys-9 of histone H3. As an epigenetic modulator, SETDB1 has a critical role in various biological processes such as embryonic development, adipocyte differentiation and inflammation. It also allows the regulation of various signaling pathways, including the p13K-AKT axis, the p53, STAT1-CCND1 / CDK6 axis, and gene promoter methylation.
Targeted deep sequencing revealed somatic SETDB1 mutations in 10% of patients with MPM. No significant relationship was found between the mutation in SETDB1 and survival. Mutations in SETDB1 were identified in 3% of MPMs in a different cohort. Hmeljak et al. They found that the SETDB1 mutations were coexisting with TP53 and that there was an intense loss of heterozygosity in 3% of MPM. This rare genomic subtype has been found to be associated with the female and younger age at the time of diagnosis.

LATS2

LATS2, found in 13q12.11, codes for a serine / threonine kinase involved in a wide array of programs such as cell cycle regulation, cell motility and differentiation. LATS2 loss through copy number change or mutation has been described in MPM as well as several different types of cancer. In a cohort of 266 MPM samples, mutations in LATS2 were observed in 5% of samples, with a lower frequency in epithelioid compared to non-epithelioid samples. In addition, LATS2 mutations are more common in patients without asbestos exposure than in patients without exposure. Another study in which the new molecular subgroup of MPM was identified is LATS2 and NF2, which are characterized by a co-occurring mutation. The prognosis for MPM patients in this subgroup is generally poor compared to the cohort.
Several studies have linked LATS2 to the transcription regulator located in Hippo pathways. Mizuno et al. They found that the inactivation of LATS2 leads to YAP overexpression, which when degraded inhibits cell motility and in vitro invasion. Another study showed that LATS2 is a key binding partner of AJUBA, which suppresses YAP activity in mesothelioma.

DDX3X

DDX3X is located on Xp11.4 and codes for an ATP-dependent RNA helicase with RNA-independent ATPase activity induced by DNA or RNA. DDX3X has both cytoplasmic and nuclear functions, including translation, regulation of transcription, pre-mRNA splicing, and mRNA delivery. Its functions are complex and diverse: DDX3X has been regarded as both an oncogene and a tumor suppressor, sometimes in the context of a single type of cancer. An analysis of the COSMIC database found that 12% of genetic abnormalities in DDX3 are typical for tumor suppressors, while 81% are more typical for gain-of-function.

Exome Sequencing Studies of Malignant Pleural MesotheliomaRYR2

RYR2 is found at 1q43 and codes for a member of the ryanodine receptor family of calcium channels that are highly expressed in cardiac muscle but also found in smooth muscle and nervous system. The release of calcium from the sarcoplasmic reticulum to the cytoplasm via RyR2 triggers contraction in myocytes, helping with learning and memory related functions in the brain. Although mutations in RyR2 have been reported in other cancers, mutations in RyR2 MPM were identified in only one study.

ULK2

They code for an Atg1 homologue and an Atg1 homologue and serine / threonine kinase that are normally localized on the membrane of autophagosomes and play a key role in autophagy, particularly in nutrient deprivation or mTOR inhibition. ULK2 is associated with the development of astrocytoma and colorectal cancer, and rare ULK2 mutations have been identified in MPM. In spheroid models of MPM, autophagy has been successfully inhibited by the ULK1 / 2 inhibitor MRT 68921.

DDX51

DDX51 is located at 12q24.33 and the 28S rRNA is located at 3 & # 8242; It is a ribosome synthesis factor necessary for the formation of the tip. The abnormal function of DDX51 has been associated with NSCLC, leukemia, and breast cancer, and few DDX51 mutations have been found in MPM.

References:
ncbi.nlm.nih.gov/pmc/articles/PMC4336947/
sciencedirect.com/science/article/pii/S1556086416304956

Writer: Ozlem Guvenc Agaoglu


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