OS02.4.A Molecular characterization of adult cerebellar glioblastomas identifies distinct prognosis subgroups

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii5-ii5
Author(s):  
T Picart ◽  
D Poncet ◽  
M Barritault ◽  
J Pallud ◽  
P Metellus ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Activating Mutations ◽  
Diagnosis And Prognosis ◽  
Induced Tumors ◽  
Radiation Induced

Abstract BACKGROUND Adult cerebellar glioblastomas (cGBM) are very rare and recent studies have shown that they constitute a heterogeneous group of gliomas. The aim of the present study was to characterize the prevalence and prognostic significance of major driver molecular alterations in a large series of cGBM. MATERIAL AND METHODS Adults with histologically proven cGBM diagnosed between 2003 and 2017 were identified from the French brain tumor database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie. Tumors were reviewed and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A, TERTp, IDH1/2, FGFR1, BRAF and EGFR status. RESULTS A total of 83 adult patients (median age 57 years) with cGBM (hemispheric n= 47, vermian n=14 or both n=22) were identified. Median overall survival was 10 months. Main molecular alterations observed were TERT promoter, H3F3A K27M, hotspot FGFR1 (N546 and K656), BRAF mutations, EGFR amplification and ATRX loss of expression in 19.2%, 18.8%, 10.9%, 2.6%, 19.5% and 22.7% of patients, respectively. cGBM could be classified into 6 mutually exclusive subgroups associated with age at diagnosis and prognosis: pTERT and/or EGFR amplified tumors (n=22, 26.5%, median age = 62 years, median OS = 4 months), H3K27M-mutant tumors (n=15, 18.1%, median age = 48 years, median OS =8 months), tumors with MAPK pathway activating mutations (FGFR1, BRAF) or occurring in NF1 patients (n=15, 18.1%, median age = 41 years, median OS = 57 months), radiation-induced tumors (n=5, 6%, median age = 47 years, median OS = 5 months), IDH-mutant tumors (n=1) and unclassified tumors (n=25, 30.1%, median age = 63 years, median OS = 17 months). In multivariate analysis, MAPK activating mutations and ATRX loss of expression were independently associated with a better outcome and pTERT/EGFR alterations with a worse outcome. CONCLUSION About 18% of tumors diagnosed as cGBM harbor actionable MAPK activating genetic alterations. Targeted sequencing enables to classify these tumors into clinically relevant subgroups.

scholarly journals Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1942
Author(s):  
Stefania Pizzimenti ◽  
Simone Ribero ◽  
Marie Angele Cucci ◽  
Margherita Grattarola ◽  
Chiara Monge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Advanced Melanoma ◽  
Braf Mutations ◽  
Downstream Signaling ◽  
Activating Mutations

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

scholarly journals Current Molecular Markers of Melanoma and Treatment Targets

2020 ◽  
Vol 21 (10) ◽  
pp. 3535 ◽  
Author(s):  
Kevin Yang ◽  
Allen S.W. Oak ◽  
Radomir M. Slominski ◽  
Anna A. Brożyna ◽  
Andrzej T. Slominski
Keyword(s):  
Clinical Decision Making ◽  
Clinical Decision ◽  
Genetic Alterations ◽  
Diagnostic Tools ◽  
Genetic Mutations ◽  
Molecular Alterations ◽  
Diagnosis And Prognosis ◽  
Appropriate Treatment ◽  
Histopathologic Diagnosis ◽  
Malignant Lesions

Melanoma is a deadly skin cancer that becomes especially difficult to treat after it metastasizes. Timely identification of melanoma is critical for effective therapy, but histopathologic diagnosis can frequently pose a significant challenge to this goal. Therefore, auxiliary diagnostic tools are imperative to facilitating prompt recognition of malignant lesions. Melanoma develops as result of a number of genetic mutations, with UV radiation often acting as a mutagenic risk factor. Novel methods of genetic testing have improved detection of these molecular alterations, which subsequently revealed important information for diagnosis and prognosis. Rapid detection of genetic alterations is also significant for choosing appropriate treatment and developing targeted therapies for melanoma. This review will delve into the understanding of various mutations and the implications they may pose for clinical decision making.

Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10011-10011 ◽  
Author(s):  
Donald Williams Parsons ◽  
Katherine A. Janeway ◽  
David Patton ◽  
Brent Coffey ◽  
Paul M. Williams ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mapk Pathway ◽  
A Priori ◽  
Current Treatment ◽  
Braf Mutations ◽  
Match Trial ◽  
Molecular Alterations ◽  
Dna And Rna ◽  
Therapy Choice ◽  
Treatment Refractory

10011 Background: The screening protocol for the NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial detects tumor alterations that are used to assign patients with treatment-refractory or recurrent cancers to phase 2 treatment arms of molecularly-targeted therapies. Methods: Patients age 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at U.S. based COG sites are eligible. DNA and RNA extracted from FFPE tumor samples are sequenced using an Oncomine cancer gene panel for detection of mutations, amplifications, and fusions. Loss of SMARCB1, SMARCA4, and PTEN expression is detected by immunohistochemistry. Lists of actionable mutations (aMOIs) based upon available clinical and pre-clinical data are used a priori to determine eligibility for treatment arms. Results: Between 7/24/17 and 12/31/18, 422 patients with a median age of 13 years (range 1-21) were enrolled from 93 COG sites. Solid tumors comprised 71% (n = 300) of diagnoses, CNS tumors 24% (n = 101) and lymphomas/histiocytoses 5% (n = 21). A tumor sample was submitted for 390 patients, sequencing was attempted for 370 (95%), and results were confirmed for 357 (92%). Median turn-around time was 15 days. An aMOI for at least one of the 10 current treatment arms was identified in 112 patients (29%, 95% CI 24%-33%); 95 patients (24%, 95% CI 20%-29%) were assigned to a treatment arm with 39 patients (10%, 95% CI 7%-13%) enrolled to date. The aMOI rate was similar in patients less than 12 years of age (35%) compared to patients 12 years and older (25%). Actionable MAPK pathway alterations were found in 11% of patients (n = 41), most often HRAS/ KRAS/ NRAS mutations (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11). Other genes with recurrent aMOIs included SMARCB1 (n = 14), ALK (n = 8), CDK4 (n = 8), PIK3CA (n = 7), PTEN (n = 7), FGFR1 (n = 5), and BRCA1/BRCA2 (n = 5). Conclusions: Approximately one-quarter of patients with tumor submitted for Pediatric MATCH screening have been assigned to an investigational therapy, facilitating the evaluation of molecularly-targeted agents in biomarker-positive pediatric cohorts through a collaborative nationwide study. Clinical trial information: NCT03155620.

scholarly journals Isoform-Specific Ras Activation and Oncogene Dependence during MYC- and Wnt-Induced Mammary Tumorigenesis

2006 ◽  
Vol 26 (21) ◽  
pp. 8109-8121 ◽  
Author(s):  
Joanne W. Jang ◽  
Robert B. Boxer ◽  
Lewis A. Chodosh
Keyword(s):  
Protein Kinase ◽  
Tumor Growth ◽  
Mapk Pathway ◽  
Mammary Tumorigenesis ◽  
Mitogen Activated Protein Kinase ◽  
Activating Mutations ◽  
Ras Activation ◽  
Pathway Activation ◽  
Induced Tumors ◽  
Mitogen Activated Protein

ABSTRACT We have previously shown that c-MYC-induced mammary tumorigenesis in mice proceeds via a preferred secondary pathway involving spontaneous activating mutations in Kras2 (C. M. D'Cruz, E. J. Gunther, R. B. Boxer, J. L. Hartman, L. Sintasath, S. E. Moody, J. D. Cox, S. I. Ha, G. K. Belka, A. Golant, R. D. Cardiff, and L. A. Chodosh, Nat. Med. 7:235-239, 2001). In contrast, we now demonstrate that Wnt1-induced mammary tumorigenesis proceeds via a pathway that preferentially activates Hras1. In addition, we find that expression of oncogenic forms of Kras2 and Hras1 from their endogenous promoters has markedly different consequences for the progression of tumors to oncogene independence. Spontaneous activating Kras2 mutations occurring in either MYC- or Wnt1-induced tumors were strongly associated with oncogene-independent tumor growth following MYC or Wnt1 downregulation. In contrast, Hras1-mutant Wnt1-induced tumors consistently remained oncogene dependent. Additionally, Kras2-mutant tumors exhibited substantially higher levels of ras-GTP, phospho-Erk1/2, and phospho-Mek1/2 compared to Hras1-mutant tumors, suggesting the involvement of the ras/mitogen-activated protein kinase (MAPK) pathway in the acquisition of oncogene independence. Consistent with this, by use of carcinogen-induced ras mutations as well as knock-in mice harboring a latent activated Kras2 allele, we demonstrate that Kras2 activation strongly synergizes with both c-MYC and Wnt1 in mammary tumorigenesis and promotes the progression of tumors to oncogene independence. Together, our findings support a model for tumorigenesis in which c-MYC and Wnt1 select for the outgrowth of cells harboring mutations in specific ras isoforms and that these secondary mutations, in turn, determine the extent of ras/MAPK pathway activation and the potential for oncogene-independent growth.

Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation

2004 ◽  
Vol 22 (22) ◽  
pp. 4584-4594 ◽  
Author(s):  
Takeshi Nagasaka ◽  
Hiromi Sasamoto ◽  
Kenji Notohara ◽  
Harry M. Cullings ◽  
Masanori Takeda ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Normal Mucosa ◽  
Genetic Alterations ◽  
Dna Hypermethylation ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Activating Mutations ◽  
Multiple Promoters ◽  
High Level

Purpose BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

scholarly journals Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome

2020 ◽  
Vol 4 (9) ◽  
Author(s):  
Patricia Vaduva ◽  
Fideline Bonnet ◽  
Jérôme Bertherat
Keyword(s):  
Cushing Syndrome ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
Adrenal Tumors ◽  
Type I ◽  
Molecular Alterations ◽  
Activating Mutations ◽  
Genome Wide ◽  
Review Reports ◽  
Inactivating Mutations

Abstract This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to PRKAR1A germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of MEN1, APC, and FH and of ARMC5 in isolated forms. PRKACA somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, and seizures and neurological abnormalities syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation.

How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer: Table 1

2009 ◽  
Vol 62 (5) ◽  
pp. 414-421 ◽  
Author(s):  
J Pinto Couto ◽  
H Prazeres ◽  
P Castro ◽  
J Lima ◽  
V Máximo ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Pathology ◽  
Genetic Alterations ◽  
Follicular Cell ◽  
Braf Mutations ◽  
Thyroid Carcinomas ◽  
Ras Mutations ◽  
Molecular Alterations ◽  
Dna Deletions ◽  
Well Differentiated

Well-differentiated thyroid carcinomas comprise two well-defined histological types: papillary and follicular (PTCs and FTCs, respectively). Despite being derived from the same cell (thyroid follicular cell), these two types of tumour accumulate distinct genetic abnormalities during progression. The molecular pathology of thyroid cancer is now better understood because of our ability to identify RET/PTC rearrangements and BRAF mutations in the aetiopathogenesis of the large majority of PTCs and the high prevalence of RAS mutations and PAX8/PPARγ rearrangements in follicular patterned carcinomas (FTCs and follicular variant of PTCs). This review summarises most of the molecular alterations currently used as targets for new biological treatments and looks at some of the changes that are already occurring or may occur in the treatment of patients with thyroid cancer. For simplicity, the review is divided up according to the major genetic alterations identified in well-differentiated thyroid carcinomas (RET/PTC rearrangements, BRAF mutations, RAS mutations and mitochondrial DNA deletions and mutations) and their respective treatments.

scholarly journals Functional and Clinical Significance of ROR1 in Lung Adenocarcinoma

2020 ◽  
Author(s):  
Giovanna Schiavone ◽  
Epistolio Samantha ◽  
Martin Vittoria ◽  
Molinari Francesca ◽  
Barizzi Jessica ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Orphan Receptor ◽  
Entire Cohort ◽  
Molecular Alterations ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Abstract BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is normally detectable in embryonic tissues and absent in adult tissues. ROR1 was shown to inhibit apoptosis, potentiate EGFR signaling and reported to be overexpressed and associated with poor prognosis in several tumor models. This study aimed to assess the expression of ROR1 and verify its prognostic significance in lung adenocarcinoma (AC) patients.METHODS: We analyzed ROR1 expression by quantitative real-time PCR (qRT-PCR) in 56 histologically confirmed lung AC, stage I to IV, in addition we evaluated its association with TTF-1 (thyroid transcription factor-1) expression and the main molecular alterations involved in lung cancerogenesis.RESULTS: ROR1 overexpression was observed in 28.6% of the entire cohort, using a cut-off of 1, or in 51.8% of the cases using the median value as threshold. Among patients without any genetic alteration, ROR1 overexpression was observed in 34.8% considering a cut-off of 1 and 52.2% considering the median value. The distribution of ROR1 was homogeneous among the different molecular categories: we found no association of ROR1 expression and the presence of gene mutations/rearrangements or the expression of TTF-1. Furthermore, ROR1 expression was not correlated with overall survival (OS).CONCLUSIONS: ROR1 overexpression could constitute a potential therapeutic target because altered in a consistent number of lung AC, especially in cases without druggable genetic alterations. ROR1 expression is independent of classical lung cancer molecular alterations and not correlated, in a Caucasian cohort, to TTF-1 expression. Finally, ROR1 expression does not play a prognostic significance.

Genomic profiling of KRAS wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4121-4121
Author(s):  
Deng Wei ◽  
Xiaomo Li ◽  
Xinsheng Zhang ◽  
Tonghui Ma ◽  
Rong Liu
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Mapk Pathway ◽  
Genetic Alterations ◽  
Genomic Profiling ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Dominant Negative Mutation ◽  
Inactivating Mutations

4121 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRASmutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P < 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.

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