Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

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The HGF-MET signaling pathway is enriched in LUAC brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20597 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20597-e20597

Author(s):

Maria A Velez ◽

Zachary A. Yochum ◽

Uma R. Chandran ◽

Anish Chakka ◽

Saveri Bhattacharya ◽

...

Keyword(s):

Brain Metastases ◽

Epithelial Mesenchymal Transition ◽

Metastatic Potential ◽

Mesenchymal Transition ◽

Targeted Next Generation Sequencing ◽

Molecular Alterations ◽

Paired Samples ◽

Met Amplification ◽

Emt Markers

e20597 Background: Brain metastases occur in over 40% of non-small cell lung cancer (NSCLC) patients leading to a poor prognosis. c-Met (MET) is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. We have previously shown that the EMT transcription factor, TWIST1 is required for proliferation in MET driven NSCLC. Therefore, the HGF/MET/TWIST1 pathway may be a significant determinant of metastatic potential to the brain. Methods: We evaluated 125 lung adenocarcinoma (LUAC) brain metastases for MET amplification by FISH as well as other molecular alterations using targeted next generation sequencing in a subset of brain metastases (N = 74) and primary LUAC (N = 171) samples including 13 paired primary and brain sets. MET activation was examined in paired tumors using a HGF-MET proximity binding, dual-antibody assay (VeraTag; Monogram Biosciences). TWIST1 and EMT markers in the paired sets were measured by immunohistochemistry. Results: Compared to primary LUAC, we found that 17 pathogenic variants including TP53, SMAD4, RB1, RET, APC, ALK, FGFR3, EGFR, STK11 and MET alterations were significantly more common in LUAC brain metastases (adj. p values ≤ 0.02). Specifically, MET amplification was significantly enriched in LUAC brain metastases (23/125, 19%) compared to 2-4% in non-brain metastatic and primary sites. Among paired samples, 2/13 brain metastases had MET amplification that was not found in the primary tumor. MET mutations were also present in 16/74 brain cases (22%) compared to 9% (16/171) observed in the lung. VHL mutations were associated with MET altered cases compared to non- MET altered cases. MET expression was increased in the majority of brain metastases compared to the paired LUAC and there were 3 cases with brain specific MET activation. We found that TWIST1 was induced by HGF and determined response to MET TKIs in vitro. Among paired samples, TWIST1 was increased in brain metastases compared to primary LUAC in a subset of cases. Further analyses of TWIST1 and EMT markers is ongoing. Conclusions: Over a third of brain metastases have MET alterations compared to primary LUAC and may be responsive to MET inhibitors.

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Driver Genes of Locally Advanced Well-differentiated Thyroid Cancer: Genetic Landscape Based on the TCGA Database

10.21203/rs.3.rs-582794/v1 ◽

2021 ◽

Author(s):

Ah Ra Jung ◽

Dong Hyuk Jang ◽

Jung Ho Choi ◽

Yoon Se Lee

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Somatic Mutations ◽

Locally Advanced ◽

Prognostic Significance ◽

Genetic Alterations ◽

Driver Genes ◽

Genetic Landscape ◽

Well Differentiated ◽

Genetic Profiles

Abstract Background: Despite the usually favorable prognosis of well-differentiated thyroid cancer (WDTC) following appropriate treatment, advanced T-staged WDTCs are associated with poor prognosis. This study focused on identifying the driver genes of locally advanced WDTC by analyzing the TCGA cohort.Methods: We analyzed data on 501 patients with WDTC from the TCGA cohort. Patients were classified into two subgroups of pathological T4 stage or T1-3 stage (Cluster1 and Cluster2, respectively). The mRNA expression differences between subgroups were compared for several genes in the TCGA cohorts.Results: Cluster1 included 23 patients with pathological T4 classification (Papillary=21/Follicular=2) and Cluster2 included 478 patients (Papillary=371/Follicular=100/Others=7). The Cluster1 subgroup showed worse overall survival than the Cluster2 subgroup (p < 0.05). The two subgroups were analyzed for 34 genes reported in previous studies. Known genetic thyroid cancer alterations, including BRAF, RAS, RET, and ALK, were not different in the two subgroups. In Cluster1, MET, SERPINA1, TIMP1, PROS1, FN1, CDKN2A, and CDKN2B were significantly elevated, while TG, DNAH9, TFF3, CRABP1, TPO, JAK2, KIT, KDR, and NFE2L2 were significantly lower compared with the Cluster2 (all, p < 0.05). A TERT, EIF1AX, and ATM showed significantly frequent somatic mutations in Cluster1 compared to Cluster2. We also identified seven pathways related to the 16 genetic markers.Conclusions: Locally advanced WDTC presented 16 genetic alterations compared to less aggressive thyroid cancers. Somatic mutations associated with local invasion transformation were identified. Genetic profiles associated with locally advanced WDTC have prognostic significance, but these findings must be validated to further understand the pathway.

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PATHOGENIC GENETIC VARIANTS IDENTIFIED BY TARGETED NEXT-GENERATION SEQUENCING IN SOME UNDEFINED PRIMARY IMMUNODEFICIENCY CASES (IZMIR EXPERIENCE)

10.26226/morressier.594a7d45d462b8028d89348d ◽

2017 ◽

Author(s):

Kutukculer Necil

Keyword(s):

Next Generation Sequencing ◽

Primary Immunodeficiency ◽

Genetic Variants ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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Faculty Opinions recommendation of Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718014371.793495250 ◽

2014 ◽

Author(s):

Jean-Pascal Machiels

Keyword(s):

Squamous Cell Carcinoma ◽

Next Generation Sequencing ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Genetic Alterations ◽

Neck Squamous Cell Carcinoma ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Genes ◽

10.3390/genes12050675 ◽

2021 ◽

Vol 12 (5) ◽

pp. 675

Author(s):

Yoon-Jeon Kim ◽

You-Na Kim ◽

Young-Hee Yoon ◽

Eul-Ju Seo ◽

Go-Hun Seo ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Detection Rate ◽

Mutation Detection ◽

Retinal Disease ◽

Mutation Detection Rate ◽

Targeted Next Generation Sequencing ◽

Initial Symptoms ◽

Genetic Landscape ◽

History Of ◽

Genetic Profiles

We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping.

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New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

International Journal of Molecular Sciences ◽

10.3390/ijms22062831 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2831

Author(s):

Ryan Bensen ◽

John Brognard

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cell Fate ◽

Squamous Cell ◽

Copy Number Gain ◽

Genetic Alterations ◽

Distal Portion ◽

Squamous Cell Carcinomas ◽

Cell Fate Decisions ◽

Genetic Landscape

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome’s distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.

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Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab

Scientific Reports ◽

10.1038/s41598-021-86966-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lucía Trilla-Fuertes ◽

Angelo Gámez-Pozo ◽

Joan Maurel ◽

Rocio Garcia-Carbonero ◽

Jaume Capdevila ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Clinical Practice ◽

Cell Carcinoma ◽

Squamous Cell ◽

Genetic Variants ◽

Anal Carcinoma ◽

Genetic Alterations ◽

Daily Clinical Practice ◽

Complete Regression ◽

Anal Squamous Cell Carcinoma

AbstractSquamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80–90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trials.

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A New Role of Vemurafenib as a Neoadjuvant Treatment of Axillary and Brain Melanoma Metastases

Case Reports in Oncological Medicine ◽

10.1155/2013/794239 ◽

2013 ◽

Vol 2013 ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Idit Melnik ◽

Michal Lotem ◽

Boris Yoffe

Keyword(s):

Lymph Node ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Neoadjuvant Therapy ◽

Tumor Necrosis ◽

Neoadjuvant Treatment ◽

Melanoma Metastases ◽

Excisional Surgery ◽

Complete Tumor

Vemurafenib is approved by the FDA for the management of unresectable or metastatic melanoma. However, its role as a neoadjuvant therapy has not been determined. We present the first documented case in which vemurafenib induced complete tumor necrosis of both lymph node and brain metastases within one month or less, an outcome that indicated that the patient was a good candidate for excisional surgery.

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A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial

npj Precision Oncology ◽

10.1038/s41698-021-00191-2 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Istvan Petak ◽

Maud Kamal ◽

Anna Dirner ◽

Ivan Bieche ◽

Robert Doczi ◽

...

Keyword(s):

Clinical Benefit ◽

Progressive Disease ◽

Genetic Alterations ◽

Outcome Data ◽

Computational Method ◽

Molecular Profile ◽

Precision Oncology ◽

Driver Genes ◽

Oncology Clinical Trial ◽

Molecularly Targeted Agents

AbstractPrecision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

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