Abstract 2167: Genomic profiling of pediatric and adolescent ependymomas: Underlying genetic alterations for prognosis and therapeutic orientation

2021 ◽  
Author(s):  
Débora Cabral de Corrêa ◽  
Indhira Dias Oliveira ◽  
Francine Tesser-Gamba ◽  
Maria Teresa de Seixas Alves ◽  
Nasjla Saba-Silva ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Genomic Profiling ◽  
Therapeutic Orientation

Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 59-59
Author(s):  
Woojung Lee ◽  
Scott Spencer ◽  
Josh John Carlson ◽  
Tam Dinh ◽  
Victoria Dayer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Eligibility Criteria ◽  
Comprehensive Genomic Profiling

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

Genomic profiling of esophageal squamous cell carcinoma to reveal actionable genetic alterations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16042-e16042
Author(s):  
Fang Liu ◽  
Xiaomo Li ◽  
Si Liu ◽  
Tonghui Ma ◽  
Boning Cai ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Squamous Cell ◽  
Survival Rates ◽  
Mek Inhibitor ◽  
Genetic Alterations ◽  
Genomic Profiling ◽  
Missense Mutations ◽  
Cancer Genes ◽  
Loss Of Function ◽  
Pik3ca Mutations

e16042 Background: Esophageal cancer is the eighth most common cancer in the world and more than half of global cases occur in China. Studies demonstrated that esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) are two distinct disease entities. Due to the lack of effective therapies, the five-year survival rates of ESCC patients remain dismal. Therefore, there is an urgent need to establish a framework through genomic profiling to facilitate the development of precision therapies for ESCC. Methods: To characterize therapeutic targets in 118 Chinese ESCC patients, deep panel sequencing of 831 cancer genes (OncoPanscan, Genetronhealth) was performed on their tumor tissues and paired genomic DNA samples. Results: The most frequently mutated genes in our ESCC cohort were TP53 (97%), PIK3CA (19%), CDKN2A (18%), NOTCH1 (17%), KMT2D (15%), LRP1B (15%) NOTCH3 (15%) NFE2L2 (13%), and EP300 (12%). Consistent with previous reports, we found significantly elevated mutations in cancer-related genes including NOTCH1 (16.9%), NOTCH2 (3.2%), NOTCH3 (15.3%) and RB1 (9.3%). Importantly, 17.8% (21/118) patients in our cohort harbored the 11q13 amplicon ( CCND1, FGF3, FGF4 and FGF19). The median copy number was 8.19 (range 6.07-42.3). These patients can participate in clinical trials with FGFR inhibitor alone or in combination with CDK4/6 inhibitors. Additionally, we also observed frequent genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NFE2L2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) pathway. 80% (12/15) of missense mutations in NFE2L2 were located at the KEAP1 binding domain of NRF2 protein. These mutations were either around the ETGE motif (D77G, E79Q, G81V/D and E82D) or the DLG motif (D27V, I28T, D29G, L30F, G31E, V32E, R34G). We also identified four missense mutations of KEAP1 and one alternation of CUL3 in splicing site. Taken together, 17% (20/118) of ESCC patients harbored mutations in the NFE2L2/KEAP1/CUL3 pathway, which may be eligible for clinical trials of glutaminase inhibitor telaglenastat. Two patients had high level of ERBB2 amplification which can be targeted with anti-HER2 therapy. Furthermore, 11.9% (14/118) patients carried activating PIK3CA mutations including N345K, E542K, E545K, M1043I and H1047R which may be targeted by PIK3CA inhibitor alpelisib. Lastly, patients with loss-of-function mutation in NF1 (n = 4), STK11 (n = 1) and PTEN (n = 3) can be respectively targeted with MEK inhibitor and mTOR inhibitor. Overall, 43% of patients in our ESCC cohort had actionable genetic mutations with corresponding precision therapy options. Conclusions: Our findings indicated that amplification of the 11q13 amplicon and dysfunction of the KEAP1-NRF2-CUL3 axis are the major driving events of ESCC. The results of genomic profiling can guide physicians to enroll a significant portion of ESCC patients into genomically matched clinical trials.

scholarly journals Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations

2020 ◽  
Vol 33 (12) ◽  
pp. 2397-2406 ◽  
Author(s):  
Erik A. Williams ◽  
Meagan Montesion ◽  
Nikunj Shah ◽  
Radwa Sharaf ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Molecular Subtype ◽  
Genetic Alterations ◽  
Experimental Models ◽  
Genomic Profiling ◽  
Missense Mutations ◽  
Wild Type ◽  
Single Nucleotide Variants ◽  
Sequencing Platform ◽  
Comprehensive Genomic Profiling

AbstractWhile the genomics of BRAF, NRAS, and other key genes influencing MAP kinase (MAPK) activity have been thoroughly characterized in melanoma, mutations in MAP2K1 (MEK1) have received significantly less attention and have consisted almost entirely of missense mutations considered secondary oncogenic drivers of melanoma. Here, we investigated melanomas with in-frame deletions of MAP2K1, alterations characterized as MAPK-activating in recent experimental models. Our case archive of clinical melanoma samples with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform was searched for MAP2K1 genetic alterations. Clinical data, pathology reports, and histopathology were reviewed for each case. From a cohort of 7119 advanced melanomas, 37 unique cases (0.5%) featured small in-frame deletions in MAP2K1. These included E102_I103del (n = 11 cases), P105_A106del (n = 8), Q58_E62del (n = 6), I103_K104del (n = 5), I99_K104del (n = 3), L98_I103del (n = 3), and E41_F53del (n = 1). All 37 were wild type for BRAF, NRAS, and NF1 genomic alterations (“triple wild-type”), representing 2.0% of triple wild-type melanomas overall (37/1882). Median age was 66 years and 49% were male. The majority arose from primary cutaneous sites (35/37; 95%) and demonstrated a UV signature when available (21/25; 84%). Tumor mutational burden was typical for cutaneous melanoma (median = 9.6 mut/Mb, range 0–35.7), and frequently mutated genes included TERTp (63%), CDKN2A (46%), TP53 (11%), PTEN (8%), APC (8%), and CTNNB1 (5%). Histopathology revealed a spectrum of appearances typical of melanoma. For comparison, we evaluated 221 cases with pathogenic missense single nucleotide variants in MAP2K1. The vast majority of melanomas with missense SNVs in MAP2K1 showed co-mutations in BRAF (58%), NF1 (23%), or NRAS (18%). In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.

scholarly journals Genomic Heterogeneity Contributed to the Different Prognosis of Adult and Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Yanxin Chen ◽  
Yongzhi Zheng ◽  
Yan Huang ◽  
Jiazheng Li ◽  
Jingjing Wen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Ras Signaling ◽  
Gene Rearrangements ◽  
Genomic Profiling ◽  
Pediatric All ◽  
Two Populations ◽  
Biological Differences

Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior than children. Hence, ALL is still a challenging disease to be cured in adults population. Aberrant genetic alterations has been observed previously in acute lymphoblastic leukemia (ALL), while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the correlation between the genomic heterogeneity and prognosis. We collected the survival informations and surveyed the gene mutations profile using whole-exome sequencing (WES) in samples from 39 adults and 54 children of de novo ALL in our institution.The sequencing revealed 663 high-confidence somatic single-nucleotide variants (SNVs), 25 stopgain and 17 frameshift insertion in 690 genes in the 39 adult ALL samples. While in the 54 pediatric ALL samples, 232 SNVs, 12 stopgain and 10 frameshift insertion in 284 genes were identified. The results showed the similar common mutation types in adult and pediatric ALL. However, the median number of detected gene mutations was 19 (range: 1-53) per sample in adult ALL and 4.5(range: 1-19) in pediatric ALL(P<0.001), indicating the reduced prevalence of genetic alterations in pediatric ALL. A significant correlation between the increased of number of gene mutations and age was found (R2 = 0.3096, P<0.001,FigureC). The most frequently mutated genes were NOTCH1 in 6 samples (15.38%), TTN in 5 samples(12.8%), IKZF1 in 4 samples(10.2%) and NRAS in 4 samples(10.2%) in adult ALL. In pediatric ALL, the most frequently mutated genes were KRAS in 15 samples(27.7%), NOTCH1 in 13 samples (24.1%), NRAS in 9 samples(16.7%) and CREBBP in 6 samples(11.1%). The SETD2 and TTN mutations were significantly enriched in adult ALL. While the KRAS, ARID1A and CREBBP mutations were significantly enriched in pediatric ALL. (P<0.05,FigureA, B). Moreover, TP53 mutation was found in 1(0.03%) adult and 2(0.03%) pediatric ALL samples. 67 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. Analysis of transcriptome sequencing data identified transcripts derived from 41 gene rearrangements in 25 (60.9%) adult ALL samples and 20 gene rearrangements in 15 (27.7%) pediatric ALL samples. The most frequent gene rearrangements were BCR/ABL1 fusions (13 samples), fusions of PAX5/ZCCH7 (4 samples) in adult ALL. The most common gene rearrangements in pediatric ALL were MLL fusions(7 samples), TEL-AML1 fusions (6 samples). Using integrated genomic analysis, we identified 3 functional pathways recurrently mutated in adult ALL: transcriptional regulation, NOTCH1 signaling, Ras signaling, and 5 in pediatric ALL: PI3K-AKT-mTOR signaling, JAK-STAT signaling, NOTCH1 signaling, Ras signaling, microRNA processing. The incidence of relapse was 33.3% and 7.7% in the adult and pediatric ALL, respectively(P=0.003). The overall survival(OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL(P=0.003, P<0.001, respectively,FigureD, E), indicating an unfavorable prognosis. Moreover, the number of gene mutations seems to be related with the decreased of times to relapse(R2 = 0.0571, P=0.39). Patients with different genetic subtypes were assigned to the different subgroups. The signatures may related to the inferior outcome of adults compared to children were identified. Adult ALL patients had more enrichment for alterations of amino acid degradation and transcription misregulation, which may explain in part the disparity in the different responses to treatment of the two populations. The study in genomic profiling across the age spectrum elucidated the genomic heterogeneity between adult and pediatric ALL, including the different in the counts of gene mutation, the frequently mutated genes and the fusion genes, which may be the contributing factors that influence prognosis. This genomic landscape enhanced the understanding of the biological differences of disease between the two populations and provided a clue for novel therapeutic approaches. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genomic Profiling by Array Comparative Genomic Hybridization Reveals Novel DNA Copy Number Changes in Breast Phyllodes Tumours

2009 ◽  
Vol 31 (1) ◽  
pp. 31-39
Author(s):  
Arno Kuijper ◽  
Antoine M. Snijders ◽  
Els M. J. J. Berns ◽  
Vibeke Kuenen-Boumeester ◽  
Elsken van der Wall ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Comparative Genomic Hybridization ◽  
Copy Number Change ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Genomic Profiling ◽  
Genomic Hybridization ◽  
Dna Copy Number ◽  
Copy Number Changes

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0–16) per case. A mean of 2.0 gains (range 0–10) and 3.0 losses (range 0–9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 558-558
Author(s):  
Xin Huang ◽  
Huanwen M. Wu ◽  
Changbin Zhu ◽  
Di Shao ◽  
Dan Guo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Genetic Data ◽  
Genetic Alterations ◽  
Clinicopathological Parameters ◽  
Genomic Profiling ◽  
Cyclin E1 ◽  
Comprehensive Genomic Profiling

558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]

scholarly journals Molecular and Genomic Profiling of Lung Cancer in the Era of Precision Medicine: A Position Paper from the Italian Association of Thoracic Oncology (AIOT)

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1627
Author(s):  
Nicola Normanno ◽  
Massimo Barberis ◽  
Filippo De Marinis ◽  
Cesare Gridelli ◽  
Keyword(s):  
Lung Cancer ◽  
Clinical Practice ◽  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Genetic Alterations ◽  
Position Paper ◽  
Genomic Profiling ◽  
Next Generation ◽  
Italian Association ◽  
Generation Sequencing

The identification of the optimal cancer treatment has become progressively more intricate for non-small-cell lung cancer (NSCLC) patients due to the multitude of options available. The testing of biomarkers to predict clinical responses to therapies is pivotal to stratify the patients based on the molecular features of their tumors. The number of actionable genetic alterations to be tested is increasing together with the comprehension of the molecular mechanisms underlying tumor growth and development. The possibility of using next generation sequencing-based approaches enhanced the acquisition of genetic data with potential clinical usefulness, and favored the integration of precision medicine in clinical practice. The availability of targeted sequencing panels that cover genetic alterations in hundreds of genes allows the performance of a comprehensive genomic profiling (CGP) of lung tumors. However, different issues still need to be solved, from the tissue needed for next generation sequencing analysis, to the choice of the test and its interpretation in the clinical context. This position paper from the Italian Association of Thoracic Oncology (AIOT) summarizes the results of a discussion from a Precision Medicine Panel meeting on the challenges to bringing CGP and, therefore, precision medicine into the daily clinical practice.

scholarly journals Advanced Lung Adenocarcinoma Patient with ERBB2 Amplification Identified by Comprehensive Genomic Profiling Benefits from Trastuzumab

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Chi-Wei Tao ◽  
Mei-Yin Chen ◽  
Ching-Min Tseng ◽  
Nina Lapke ◽  
Shu-Jen Chen ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Lung Lesion ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Lung Adenocarcinoma Patient ◽  
Nsclc Patients ◽  
Next Generation Sequencing Ngs ◽  
Erbb2 Amplification

For non-small-cell lung cancer (NSCLC) patients without established actionable alterations in genes such as EGFR or ALK, options for targeted therapy remain limited in clinical practice. About 5% of lung adenocarcinoma patients have tumors with ERBB2 genetic alterations, with even fewer patients harboring ERBB2 amplification. Currently, clinical trials mainly use IHC, FISH, or mutation testing to identify potential responders to ERBB2-targeting agents. The use of next-generation sequencing (NGS) to detect ERBB2 alterations, including copy number variants, is rare. In this study, we present an EGFR- and ALK-negative advanced NSCLC case for which we conducted comprehensive tumor genomic profiling to identify potentially actionable alterations. The tumor harbored an ERBB2 amplification, and trastuzumab-based therapy resulted in an excellent response, with a necrotic regression of the patient’s lung lesion. Although he developed brain metastasis four months after trastuzumab initiation, he survived for an additional period of eight months without local recurrence or other systemic metastasis. This case report shows that the use of comprehensive genetic testing enables the identification of rare actionable alterations in NSCLC patients without other options for targeted treatment.

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