ERBB2 Pathway in Biliary Tract Carcinoma: Clinical Implications of a Targetable Pathway

2020 ◽  
pp. 1-8
Author(s):  
Oded Jacobi ◽  
Jeffrey S. Ross ◽  
Tal Goshen-Lago ◽  
Riad Haddad ◽  
Assaf Moore ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Tissue Samples ◽  
Genomic Landscape ◽  
High Prevalence ◽  
Before And After ◽  
Disease Stabilization ◽  
Poor Outcomes ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Copy Number Amplification

<b><i>Background/Aims:</i></b> Current chemotherapy regimens for cholangiocarcinoma (CCA) yield poor outcomes, with a median overall survival of &#x3c;12 months. Recent data on the genomic landscape of CCAs have created opportunities for targeted therapy. Yet, data regarding its efficacy are scarce. We aimed to describe the genomic landscape of a CCA patient cohort using next-generation sequencing (NGS), focusing on the ERBB/EFGR pathway and assessing response to anti-HER2 agents. <b><i>Methods:</i></b> Tissue samples of intrahepatic CCA (IHCC) and extrahepatic CCA (EHCC) underwent NGS for somatic aberrations. The clinical outcomes for patients treated with anti-HER2 agents were evaluated. <b><i>Results:</i></b> A total of 1,863 CCA cases (1,615 IHCCs and 248 EHCCs) underwent NGS, and they revealed a high prevalence of ERBB alterations (IHCC, 4.2%; EHCC, 9.7%). Among these, 23.8% of the IHCCs and 53.6% of the EHCCs had a point mutation in ERBB2, and 66.6% of the IHCCs and 41.2% of the EHCCs had ERBB copy number amplification. Three EHCC patients were diagnosed at our institute with ERBB/EGFR aberrations; 2 patients were treated with neratinib and 1 patient with a chemotherapy-trastuzumab combination. All 3 achieved disease stabilization and a clinical benefit. One patient underwent a liquid biopsy before and after 3 months of treatment, demonstrating disappearance of the ERBB2 clone and emergence of a Myc-mutated clone after treatment. <b><i>Conclusions:</i></b> The genomic landscape of CCAs may harbor targetable alterations, especially in the ERBB/EGFR pathway. These alterations may have clinical significance in everyday practice.

scholarly journals Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas

2021 ◽  
Vol 11 (4) ◽  
pp. 268
Author(s):  
Antonio Juan Ribelles ◽  
Pablo Gargallo ◽  
Pablo Berlanga ◽  
Vanessa Segura ◽  
Yania Yáñez ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Clinical Benefit ◽  
Soft Tissue Sarcomas ◽  
Histopathological Analysis ◽  
Next Generation ◽  
Reference Centre ◽  
Genomic Landscape ◽  
Biological Studies ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1–18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas’ therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting.

scholarly journals Episomal HPV16 responsible for aggressive and deadly metastatic anal squamous cell carcinoma evidenced in peripheral blood

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Péré ◽  
Raphael Vernet ◽  
Simon Pernot ◽  
Juliette Pavie ◽  
Nicolas Robillard ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Tissue Samples ◽  
Anal Squamous Cell Carcinoma ◽  
Hpv Dna ◽  
Hpv Status ◽  
Episomal Hpv16 ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

AbstractArchival tissue samples collected longitudinally from a patient who died from HPV16-induced high-grade anal intraepithelial squamous cell carcinoma with vertebral HPV16–positive metastasis were retrospectively analyzed by the Capture-HPV method (Capt-HPV) followed by Next-Generation Sequencing (NGS). Full length nucleotide sequences of the same HPV16 were identified from the initial and second anal biopsy samples, from plasma sample and from vertebral metastasis biopsy. Remarkably, HPV was episomal in each sample. The HPV genome sequence was closest to the HPV16 Qv18158E variant subtype (A1 lineage) exhibiting base substitutions and deletions in 7 and 2 HPV loci, respectively. In conclusion, the powerful Capt-HPV followed by NGS allows evidencing the detailed cartography of tumoral and circulating HPV DNA, giving rise to a unique and unexpected episomal virus molecular status in a context of aggressive carcinoma, underlying the importance of HPV status and its association with clinical features for further prospective studies.

scholarly journals Novel RB1 and MET Gene Mutations in a Case with Bilateral Retinoblastoma Followed by Multiple Metastatic Osteosarcoma

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 28
Author(s):  
Attila Mokánszki ◽  
Yi-Che Chang Chien ◽  
János András Mótyán ◽  
Péter Juhász ◽  
Emese Sarolta Bádon ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Genetic Alterations ◽  
Causative Role ◽  
Rb1 Gene ◽  
Tissue Samples ◽  
Metastatic Osteosarcoma ◽  
Bilateral Retinoblastoma ◽  
Chondroblastic Osteosarcoma ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Retinoblastoma (Rb) is a malignant tumor of the developing retina that affects children before the age of five years in association with inherited or early germline mutations of the RB1 gene. The genetic predisposition is also a driver for other primary malignancies, which have become the leading cause of death in retinoblastoma survivors. Other malignancies can occur as a consequence of radiotherapy. We describe a patient with retinoblastoma in which we detected a novel RB1 c.2548C > T, p.(Gln850Ter) and a synchronous MET c.3029C > T, p.(Thr1010Ile) mutation as well. After presenting with bilateral retinoblastoma, the patient developed at least four different manifestations of two independent osteosarcomas. Our goal was to identify all germline and somatic genetic alterations in available tissue samples from different time periods and to reconstruct their clonal relations using next generation sequencing (NGS). We also used structural and functional prediction of the mutant RB and MET proteins to find interactions between the defected proteins with potential causative role in the development of this unique form of retinoblastoma. Both histopathology and NGS findings supported the independent nature of a chondroblastic osteosarcoma of the irradiated facial bone followed by an osteoblastic sarcoma of the leg (tibia).

scholarly journals Effect of matcha consumption on gut microbiota in healthy Japanese individuals: study protocol for a double-blind crossover interventional study

2021 ◽  
Author(s):  
Maya Takegami ◽  
Yoshitaka Hashimoto ◽  
Tomoki Miyoshi ◽  
Chihiro Munekawa ◽  
Takashi Yoshimura ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Medical Information ◽  
Intestinal Flora ◽  
University Hospital ◽  
Double Blind ◽  
Before And After ◽  
Next Generation Sequencing Ngs ◽  
Sequence Similarities ◽  
Generation Sequencing

Abstract Background: This study compares and clarifies the changes in intestinal flora resulting from the continuous consumption of two types of matcha.Methods: Healthy adults will consume two types of matcha tea for four weeks, and differences in the intestinal microflora before and after drinking will be compared. Gut microbiota will be identified using next-generation sequencing (NGS). Phylogenetic classification of the enterobacteria will be performed based on sequence similarities. The relative proportions of the classified enterobacteria to the total nucleotide sequences will be compared between the samples obtained from the two groups consuming different matcha.Discussion: The continuous consumption of matcha may improve dysbiosis and prevent atherosclerosis. The effects may vary according to the type of matcha used.Trial registration:The study was registered with university hospital medical information network (UMIN) (UMIN000040303), and all participants gave their written informed consent. Registered 1 November 2020, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000045982.

scholarly journals Less frequently mutated genes in colorectal cancer: evidences from next-generation sequencing of 653 routine cases

2016 ◽  
Vol 69 (9) ◽  
pp. 767-771 ◽  
Author(s):  
Umberto Malapelle ◽  
Pasquale Pisapia ◽  
Roberta Sgariglia ◽  
Elena Vigliar ◽  
Maria Biglietto ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Somatic Mutations ◽  
Gene Mutations ◽  
Next Generation ◽  
Genomic Landscape ◽  
Next Generation Sequencing Ngs ◽  
Pcr Targeting ◽  
Diagnostic Setting ◽  
Generation Sequencing

AimsThe incidence of RAS/RAF/PI3KA and TP53 gene mutations in colorectal cancer (CRC) is well established. Less information, however, is available on other components of the CRC genomic landscape, which are potential CRC prognostic/predictive markers.MethodsFollowing a previous validation study, ion-semiconductor next-generation sequencing (NGS) was employed to process 653 routine CRC samples by a multiplex PCR targeting 91 hotspot regions in 22 CRC significant genes.ResultsA total of 796 somatic mutations in 499 (76.4%) tumours were detected. Besides RAS/RAF/PI3KA and TP53, other 12 genes showed at least one mutation including FBXW7 (6%), PTEN (2.8%), SMAD4 (2.1%), EGFR (1.2%), CTNNB1 (1.1%), AKT1 (0.9%), STK11 (0.8%), ERBB2 (0.6%), ERBB4 (0.6%), ALK (0.2%), MAP2K1 (0.2%) and NOTCH1 (0.2%).ConclusionsIn a routine diagnostic setting, NGS had the potential to generate robust and comprehensive genetic information also including less frequently mutated genes potentially relevant for prognostic assessments or for actionable treatments.

Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14500-e14500 ◽  
Author(s):  
Maher Albitar ◽  
Sucha Sudarsanam ◽  
Wanlong Ma ◽  
Shiping Jiang ◽  
Wayne Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Tp53 Mutation ◽  
Continuous Variable ◽  
Colorectal Cancers ◽  
Wild Type ◽  
Tissue Samples ◽  
Mutation Status ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e14500 Background: PD-L1 expression as detected by immunohistochemistry (IHC) is significantly lower in colorectal cancers (CRC) when compared with lung cancer or other types of cancer. We explored if mutations in the RAS/RAF gene family, TP53 or PIK3CA can define a subgroup of CRC that express PD-L1. Methods: Tissue samples collected from 107 patients with CRC were studied for the expression of PD-L1 using clone SP142. The same samples were also tested for mutations in NRAS, KRAS, HRAS, BRAF, TP53, and PIK3CA using Next Generation Sequencing (NGS). Results: Of the 107 CRC samples only 15 (14%) showed PD-L1 positive tumor cells (≥1%) and 8 of the 15 (7.5% of total) had PD-L1 in ≤5% of tumor cells. Detected mutations in these samples were as follows: TP53 65%, KRAS 49.5%, PI3KCA 22.5%, NRAS 5%, HRAS 1%, and BRAF 17%. There was no correlation between PD-L1 expression and mutation status in any of the RAS/RAF genes. There was also no correlation between TP53 mutation and PD-L1 expression. This was true irrespective if PD-L1 expression is considered as a continuous variable or when cut-off points of 5%, 20%, or 50% were used. However, patients without any mutation in RAS or TP53 had significantly (P = 0.005) more expression of PD-L1 when cut-off point of 5% is used. This remained true if PD-L1 expression is considered as a continuous variable (P = 0.04). There was no correlation between PIK3CA and PD-L1 expression. Conclusions: PD-L1 expression is significantly more common in CRC that lack mutations in RAS or TP53. PD-L1 expression is detected in 31% of patients with wild-type RAS/TP53 as compared with 12% in patients with RAS/TP53 mutations (P = 0.04). If a cut-off point of 5% is used, 31% of RAS/TP53-wild-type CRC were positive for PD-L1, while only 6% of RAS/TP53- mutant CRC were positive for PD-L1 (P = 0.005). This suggests that in CRC without RAS/TP53 mutation, the PD-L1 may play a more important role in oncogenesis. Exploring immunotherapy in this group of CRC patients might be justified.

Molecular comparison of primary colorectal cancer (pCRC) with peritoneal metastases (PM).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 498-498 ◽  
Author(s):  
Matthew K Stein ◽  
Forrest W Williard ◽  
Miriam Tsao ◽  
Benjamin Deschner ◽  
Paxton Vandiver Dickson ◽  
...  
Keyword(s):  
Copy Number Variants ◽  
Peritoneal Metastases ◽  
Primary Colorectal Cancer ◽  
Not Otherwise Specified ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Molecular Comparison ◽  
Poor Outcomes ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

498 Background: PM from CRC are associated with poor outcomes; however, molecular differences are not defined. Methods: We compared tumor profiles of pCRC and PM patients (pts) from Caris Life Sciences. Testing included next-generation sequencing (NGS) of 592 genes, immunohistochemistry (IHC), copy number variants (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were termed pathogenic (PATH) or variants of undetermined significance (VUS). TMB in mutations/Mb (MMB) was compared. Results: 617 pCRC and 348 PM pts had similar gender (55% male) and age (median 59). 232 pCRC were left-sided (LS), 189 right-sided (RS), 147 rectum (R) and 49 not otherwise specified (NOS); PM were 45 RS, 29 LS, 22 R and 252 NOS. For pts with IHC testing, expression was increased in PM in TOPO1 (62% v. 52%, p < 0.01), ERCC1 (27% v. 18%, p < 0.01) and MLH1 (96% v. 92%, p < 0.05) and decreased in PD-1 (36% v. 65%, p < 0.01), TOP2A (76% v. 100%, p < 0.01) and PTEN (64% v. 72%, p < 0.05). By sidedness, LS PM were more frequently TOP01 and PD-L1 and less commonly MGMT positive compared to pCRC. PTEN IHC was higher in R pCRC than PM. 7 CNVs were increased in PM ( ADGR2A2, CCND1, ELL, FGF3, FGF4, JAK3 and PDGFRB) and FLT3 CNVs were decreased. MYC CNVs were more common in RS PM compared to pCRC. No difference was seen in PM and pCRC PATHs in KRAS, BRAF, SMAD2, SMAD4, PTEN. PM had more PATHs in GNAS (8% v. 1%, p < 0.01) while pCRC PATHs were increased in APC (76% v. 48%, p < 0.01), TP53 (72% v. 53%, p < 0.01), ARID1A (29% v. 12%, p < 0.05), PIK3CA (22% v. 15%, p < 0.05) and FBXW7 (13% v. 7%, p < 0.01). LS PM had increased FLCN PATHs (12% v. 2%, p < 0.01); R PM had more PATHs in KMT2D (20% v. 1%, p < 0.01) and RNF43 (13% vs. 3%, p < 0.05). VUS were increased in 39/592 (7%) genes for PM compared to pCRC. No MSI or fusion difference was seen. 53% pCRC (median = 8) pts had TMB ≥8 MMB compared to 43% PMs (median = 7; p = 0.03); no TMB difference was seen for LS, RS or R subgroups. Conclusions: Compared to pCRC, PM had more PATHs in GNAS and less in classic CRC markers APC and TP53. While TMB was generally lower in PM, differences in IHC expression, CNV and VUSs may serve as biomarkers for PM requiring further study.

scholarly journals Next-Generation Sequencing in 305 Consecutive Patients: Clinical Outcomes and Management Changes

2019 ◽  
Vol 15 (12) ◽  
pp. e1028-e1034 ◽  
Author(s):  
William Davis ◽  
Gabriel Makar ◽  
Pallav Mehta ◽  
Gord G. Zhu ◽  
Robert Somer ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Poor Response ◽  
Oncologic Outcomes ◽  
Next Generation ◽  
Duration Of Treatment ◽  
Tissue Samples ◽  
Off Label ◽  
Oncology Treatment ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

PURPOSE: Next-generation sequencing (NGS) is increasingly used to identify actionable mutations for oncology treatment. We examined the results and use of NGS assays at our institution. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 305 consecutive patients who had NGS testing of tumor samples from March 2014 to April 2017. NGS was performed by FoundationOne. RESULTS: Of the 305 tissue samples sent to FoundationOne, 189 reports were potentially usable. Of these reports, 76 (40.21%) demonstrated an aberration targetable by on-label therapies and 126 (66.67%) by off-label therapies, and 170 (89.94%) revealed actionable aberrations via all potential avenues, including clinical trials; 21 of these 189 potentially usable reports (11.1%) yielded a change in management, including use of on-label therapies (n = 7), use of off-label therapies (n = 6), enrollment in a clinical trial (n = 6), and discontinuation of a medication with a predicted poor response (n = 3; one report was used twice). For the six patients with off-label use, median duration of treatment was 46 days and discontinued after death (n = 3) or progression (n = 3). CONCLUSION: Only a minority of NGS assay results (6.9% percent of all tests ordered and 11.1% of useable tests) resulted in a management change. A small minority of patients started off-label therapy on the basis of NSG assay results and overall had poor responses to off-label treatment. Although in theory NGS assays may improve oncologic outcomes, the results of our initial 305 patients showed low clinical utility.

scholarly journals A novel NGS library preparation method to characterize native termini of fragmented DNA

2020 ◽  
Vol 48 (8) ◽  
pp. e47-e47 ◽  
Author(s):  
Kelly M Harkins ◽  
Nathan K Schaefer ◽  
Christopher J Troll ◽  
Varsha Rao ◽  
Joshua Kapp ◽  
...  
Keyword(s):  
Library Preparation ◽  
Single Nucleotide ◽  
Preparation Methods ◽  
Fragmented Dna ◽  
Genomic Landscape ◽  
Dna Fragment ◽  
Nucleotide Resolution ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Biological and chemical DNA fragmentation generates DNA molecules with a variety of termini, including blunt ends and single-stranded overhangs. We have developed a Next Generation Sequencing (NGS) assay, XACTLY, to interrogate the termini of fragmented DNA, information traditionally lost in standard NGS library preparation methods. Here we describe the XACTLY method, showcase its sensitivity and specificity, and demonstrate its utility in in vitro experiments. The XACTLY assay is able to report relative abundances of all lengths and types (5′ and 3′) of single-stranded overhangs, if present, on each DNA fragment with an overall accuracy between 80–90%. In addition, XACTLY retains the sequence of each native DNA molecule after fragmentation and can capture the genomic landscape of cleavage events at single nucleotide resolution. The XACTLY assay can be applied as a novel research and discovery tool for fragmentation analyses and in cell-free DNA.

scholarly journals OR15-03 High Prevalence of Gene Variants in Boys of Prepubertal Age with Clinical Suspicion of Central Hypogonadism and Low AMH

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Franco Brunello ◽  
E Gabriela Sansó ◽  
Paula Scaglia ◽  
María Esnaola Azcoiti ◽  
Ariel Berenstein ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Clinical Suspicion ◽  
Gene Variants ◽  
High Prevalence ◽  
History Of ◽  
Potential Pathogenicity ◽  
Next Generation Sequencing Ngs ◽  
Prepubertal Age ◽  
Generation Sequencing ◽  
Low Serum

Abstract Introduction: In boys of prepubertal age, the diagnosis of central hypogonadism may be difficult to ascertain since gonadotropins and testosterone are normally low. Sertoli cell markers, like AMH and inhibin B, may be useful. In recent years, with the development of next generation sequencing (NGS) technology, the number of genes associated with central hypogonadism has had an exponential increase. However, even with these advanced techniques, the gene variants with potential pathogenicity can be found at present in only 30-50% of the patients. Hypothesis of the study: Low serum AMH is an appropriate screening biomarker to select patients for NGS, in order to make a genetic diagnosis in boys of prepubertal age with suspected central hypogonadism. Patients and methods: All patients aged 1-10 yr referred between 2001 and 2018 with clinical suspicion of central hypogonadism (micropenis and cryptorchidism and/or microorchidism), with low serum AMH (&lt;10th centile) were included. Serum AMH was determined by ELISA (Beckman-Coulter), and LH, FSH and testosterone (T) by ECLIA (Roche). NGS was performed with the TruSight™ One Sequencing Panel in a NextSeq® 500 sequencer (Illumina). Results are expressed as medians (range). Results: 13 patients were included. Age at first visit was 4.4 (0.1-9.2) yr. Cryptorchidism was present in all of them, micropenis in 10 and microorchidism in 11. Orchiopexy was required in 11 boys and the other 2 responded to hCG treatment. 4 patients had olfactory disturbances, 1 had sensory deafness and 1 had piebaldism. 2 patients had a family history of olfactory disturbances and/or central hypogonadism. 7 patients could be followed up to pubertal age, and the diagnosis of central hypogonadism was clinically confirmed. At age 6.1 yr (1.2-10), AMH was 159 pmol/L (65-363), LH was &lt;0.1 IU/L in all, FSH was 0.61 IU/L (&lt;0.1-1.9). 17 variants in 9 genes associated with central hypogonadism were found in 10 of 13 patients. 5 boys had 1 gene variant, while 4 had 2 gene variants and 1 had 3 gene variants indicating probable oligogenicity, in the following genes: FGFR1 (n:4), CHD7 (n:3), PROKR2 (n:2), SOX10 (n:2), AXL (n:2), HS6ST1 (n:1), AMHR2 (n:1), NSMF (n:1), DCC (n:1). Conclusion: A high prevalence of gene variants was found in boys of prepubertal age with a suspicion of central hypogonadism based on micropenis and cryptorchidism and/or microorchidism with low serum AMH.

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