scholarly journals The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

2021 ◽  
Vol 22 (8) ◽  
pp. 3826
Author(s):  
Lisa Elefanti ◽  
Carolina Zamuner ◽  
Paolo Del Fiore ◽  
Camilla Stagni ◽  
Stefania Pellegrini ◽  
...  
Keyword(s):  
Early Stage ◽  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Prognostic Features ◽  
Mutation Burden ◽  
Number Variation ◽  
Molecular Landscape ◽  
Gains And Losses

Acral melanoma (AM) is a rare and aggressive subtype of melanoma affecting the palms, soles, and nail apparatus with similar incidence among different ethnicities. AM is unrelated to ultraviolet radiation and has a low mutation burden but frequent chromosomal rearrangements and gene amplifications. Next generation sequencing of 33 genes and somatic copy number variation (CNV) analysis with genome-wide single nucleotide polymorphism arrays were performed in order to molecularly characterize 48 primary AMs of Italian patients in association with clinicopathological and prognostic features. BRAF was the most commonly mutated gene, followed by NRAS and TP53, whereas TERT promoter, KIT, and ARID1A were less frequently mutated. Gains and losses were recurrently found in the 1q, 6p, 7, 8q, 20 and 22 chromosomes involving PREX2, RAC1, KMT2C, BRAF, CCND1, TERT, and AKT3 genes, and in the 6q, 9, 10, 11q and 16q chromosomes including CDKN2A, PTEN, and ADAMTS18 genes, respectively. This study confirmed the variety of gene mutations and the high load of CNV in primary AM. Some genomic alterations were associated with histologic prognostic features. BRAF mutations, found with a higher rate than previously reported, correlated with a low Breslow thickness, low mitotic count, low CNV of the AMs, and with early-stage of disease.

scholarly journals Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 546 ◽  
Author(s):  
Philipp Jansen ◽  
Ioana Cosgarea ◽  
Rajmohan Murali ◽  
Inga Möller ◽  
Antje Sucker ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Gene Mutations ◽  
Diagnostic Value ◽  
Clinicopathological Parameters ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Targeted Next Generation Sequencing ◽  
Melanocytic Tumors ◽  
Frequent Mutations ◽  
Melanoma Subtypes

Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.

1068: TP53 Gene Mutations as a Prognostic Marker for PSA Progression in Early Stage Prostate Cancer

2004 ◽  
Vol 171 (4S) ◽  
pp. 282-282
Author(s):  
Markus D. Sachs ◽  
Horst Schlechte ◽  
Katrin Schiemenz ◽  
Severin V. Lenk ◽  
Dietmar Schnorr ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Marker ◽  
Early Stage ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Psa Progression ◽  
Tp53 Gene Mutations

scholarly journals DeepRePath: Identifying the Prognostic Features of Early-Stage Lung Adenocarcinoma Using Multi-Scale Pathology Images and Deep Convolutional Neural Networks

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3308
Author(s):  
Won Sang Shim ◽  
Kwangil Yim ◽  
Tae-Jung Kim ◽  
Yeoun Eun Sung ◽  
Gyeongyun Lee ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Early Stage ◽  
External Validation ◽  
Area Under The Curve ◽  
The Cancer Genome Atlas ◽  
Deep Convolutional Neural Networks ◽  
Prognostic Features ◽  
Multi Scale ◽  
Model Based ◽  
Number Of Patients

The prognosis of patients with lung adenocarcinoma (LUAD), especially early-stage LUAD, is dependent on clinicopathological features. However, its predictive utility is limited. In this study, we developed and trained a DeepRePath model based on a deep convolutional neural network (CNN) using multi-scale pathology images to predict the prognosis of patients with early-stage LUAD. DeepRePath was pre-trained with 1067 hematoxylin and eosin-stained whole-slide images of LUAD from the Cancer Genome Atlas. DeepRePath was further trained and validated using two separate CNNs and multi-scale pathology images of 393 resected lung cancer specimens from patients with stage I and II LUAD. Of the 393 patients, 95 patients developed recurrence after surgical resection. The DeepRePath model showed average area under the curve (AUC) scores of 0.77 and 0.76 in cohort I and cohort II (external validation set), respectively. Owing to low performance, DeepRePath cannot be used as an automated tool in a clinical setting. When gradient-weighted class activation mapping was used, DeepRePath indicated the association between atypical nuclei, discohesive tumor cells, and tumor necrosis in pathology images showing recurrence. Despite the limitations associated with a relatively small number of patients, the DeepRePath model based on CNNs with transfer learning could predict recurrence after the curative resection of early-stage LUAD using multi-scale pathology images.

scholarly journals The Role of RNA in DNA Breaks, Repair and Chromosomal Rearrangements

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 550
Author(s):  
Matvey Mikhailovich Murashko ◽  
Ekaterina Mikhailovna Stasevich ◽  
Anton Markovich Schwartz ◽  
Dmitriy Vladimirovich Kuprash ◽  
Aksinya Nicolaevna Uvarova ◽  
...  
Keyword(s):  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
Nonhomologous End Joining ◽  
Published Data ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
End Joining ◽  
Homology Directed Repair ◽  
Chromosome Aberration Frequency

Incorrect reparation of DNA double-strand breaks (DSB) leading to chromosomal rearrangements is one of oncogenesis’s primary causes. Recently published data elucidate the key role of various types of RNA in DSB formation, recognition and repair. With growing interest in RNA biology, increasing RNAs are classified as crucial at the different stages of the main pathways of DSB repair in eukaryotic cells: nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Gene mutations or variation in expression levels of such RNAs can lead to local DNA repair defects, increasing the chromosome aberration frequency. Moreover, it was demonstrated that some RNAs could stimulate long-range chromosomal rearrangements. In this review, we discuss recent evidence demonstrating the role of various RNAs in DSB formation and repair. We also consider how RNA may mediate certain chromosomal rearrangements in a sequence-specific manner.

KIT Gene Mutations and Patterns of Protein Expression in Mucosal and Acral Melanoma

2012 ◽  
Vol 16 (2) ◽  
pp. 135-142 ◽  
Author(s):  
Suzan Abu-Abed ◽  
Nancy Pennell ◽  
Teresa Petrella ◽  
Frances Wright ◽  
Arun Seth ◽  
...  
Keyword(s):  
Protein Expression ◽  
Kinase Inhibitors ◽  
Case Series ◽  
Gene Mutations ◽  
Mucosal Melanoma ◽  
Acral Melanoma ◽  
Formalin Fixed Paraffin ◽  
Kit Gene ◽  
Formalin Fixed Paraffin Embedded ◽  
Optimized Conditions

Background: Recently characterized KIT (CD117) gene mutations have revealed new pathways involved in melanoma pathogenesis. In particular, certain subtypes harbor mutations similar to those observed in gastrointestinal stromal tumors, which are sensitive to treatment with tyrosine kinase inhibitors. Objective: The purpose of this study was to characterize KIT gene mutations and patterns of protein expression in mucosal and acral melanoma. Methods: Formalin-fixed, paraffin-embedded tissues were retrieved from our archives. Histologic assessment included routine hematoxylin-eosin stains and immunohistochemical staining for KIT. Genomic DNA was used for polymerase chain reaction-based amplification of exons 11 and 13. Results: We identified 59 acral and mucosal melanoma cases, of which 78% showed variable levels of KIT expression. Sequencing of exons 11 and 13 was completed on all cases, and 4 (6.8%) mutant cases were isolated. Conclusion: We successfully optimized conditions for the detection of KIT mutations and showed that 8.6% of mucosal and 4.2% of acral melanoma cases at our institution harbor KIT mutations; all mutant cases showed strong, diffuse KIT protein expression. Our case series represents the first Canadian study to characterize KIT gene mutations and patterns of protein expression in acral and mucosal melanoma.

scholarly journals Evaluation of EGFR, KRAS and BRAF gene mutations in renal cell carcinoma

2014 ◽  
Vol 1 (4) ◽  
pp. 40-45 ◽  
Author(s):  
Omer Bayrak ◽  
Haluk Sen ◽  
Ersan Bulut ◽  
Beyhan Cengiz ◽  
Metin Karakok ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Melting Curve ◽  
Gene Mutations ◽  
Poor Response ◽  
Renal Tumors ◽  
Sequencing Analysis ◽  
Braf Mutations ◽  
Dna Sequencing Analysis

A subset of renal cell carcinoma (RCC) patients has been shown to respond to anti-EGFR therapy. As KRAS and BRAF mutations are associated with poor response to anti-EGFR therapy in some cancers, it has been suggested that screening for KRAS and BRAF mutations in RCC may be a promising strategy to identify patients who might respond to EGFR-targeted therapy. The aim of this study was to investigate the mutation status of EGFR, KRAS and BRAF in RCC patients. Renal tumors and normal renal samples from forty-eight patients who underwent radical or partial nephrectomy for kidney cancer were used in this study. Histological classification of the tumors was performed according to International Union against Cancer (UICC) / American Joint Committee on Cancer (AJCC) classification. Seventeen patients (48%) had clear-cell RCC, 7 (20%) had chromophobe RCC, and 11 patients (32%) had papillary RCC. DNA isolated from the samples was subjected to melting curve mutation analysis for EGFR, BRAF and KRAS using ABI-3130 DNA sequencer. DNA sequencing analysis of RCC samples, when compared with morphologically normal matched regions, did not show any exon mutations. Our results do not support the notion that EGFR, KRAS and BRAF might be mutated in RCC.

scholarly journals The Genetic Control of Stoichiometry Underlying Autism

2020 ◽  
Vol 43 (1) ◽  
pp. 509-533 ◽  
Author(s):  
Robert B. Darnell
Keyword(s):  
Large Scale ◽  
Biochemical Analysis ◽  
Critical Role ◽  
Gene Mutations ◽  
Loss Of Function ◽  
Case Control Studies ◽  
Neurologic Disorder ◽  
Regulatory Variants ◽  
Whole Exome ◽  
Number Variation

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes—stoichiometry—plays a critical role in defining the clinical features of autism.

scholarly journals Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

2020 ◽  
Vol 22 (6) ◽  
Author(s):  
Ludovica Marando ◽  
Brian J. P. Huntly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Influence Strategies ◽  
Prognostic Information ◽  
Therapeutic Implications ◽  
Genomic Landscape ◽  
Genetic Landscape ◽  
Molecular Landscape ◽  
Acute Myeloid

Abstract Purpose of Review The field of acute myeloid leukemia (AML) has been revolutionized in recent years by the advent of high-throughput techniques, such as next-generation sequencing. In this review, we will discuss some of the recently identified mutations that have defined a new molecular landscape in this disease, as well as their prognostic, predictive, and therapeutic implications. Recent Findings Recent studies have shown how many cases of AML evolve from a premalignant period of latency characterized by the accumulation of several mutations and the emergence of one or multiple dominant clones. The pattern of co-occurring mutations and cytogenetic abnormalities at diagnosis defines risk and can determine therapeutic approaches to induce remission. Besides the genetic landscape at diagnosis, the continued presence of particular gene mutations during or after treatment carries prognostic information that should further influence strategies to maintain remission in the long term. Summary The recent progress made in AML research is a seminal example of how basic science can translate into improving clinical practice. Our ability to characterize the genomic landscape of individual patients has not only improved our ability to diagnose and prognosticate but is also bringing the promise of precision medicine to fruition in the field.

scholarly journals Genomic based analyses reveal unique mutational profiling and identify prognostic biomarker for overall survival in Chinese small-cell lung cancer

2019 ◽  
Vol 49 (12) ◽  
pp. 1143-1150 ◽  
Author(s):  
Yu Wang ◽  
Xiao Han ◽  
Xingwen Wang ◽  
Wei Sheng ◽  
Zheng Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Gene Mutations ◽  
Small Cell ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
Mutational Profiling ◽  
Mutation Burden ◽  
Clonal Mutation

Abstract Objective As an aggressive subtype of lung cancer, small-cell lung cancer (SCLC) presents a poor prognosis. Although molecular and clinical characteristics have been established for SCLC, limited investigation has been performed for predicting survival of SCLC patients. Methods Genomic alterations were profiled in Chinese SCLC patients (N = 37) using targeted sequencing. Clonal mutation burden (CMB) integrated the number of mutations with the clonal structure of the tumor. Specific pathways involving DNA damage repair (DDR) and cell cycle as well as CMB were studied as potential biomarkers for prognosis of SCLC. Results TP53 and RB1 gene mutations were the most common alterations (91.9% and 83.8%, respectively), followed by LRP1B, FAM135B, SPTA1, KMT2D, FAT1, and NOTCH3. Survival analysis revealed that mutation status of the DDR pathway was associated with worse OS in our cohort. Importantly, patients with higher CMB exhibited worse OS in our cohort and this observation was successfully validated in the cBioportal cohort. Moreover, multivariate analysis demonstrated CMB as a promising independent prognostic factor for OS in Chinese SCLC patients. Interestingly, patients with loss of function of RB1, validated by immunohistochemistry staining, appeared to have worse OS. Conclusions The mutational profiling of Chinese SCLC patients signified an ethnicity dependent component. CMB was firstly found to be associated with OS of Chinese SCLC patients and could be regarded as a prognostic marker for SCLC.

scholarly journals ctDNA monitoring using patient-specific sequencing and integration of variant reads

2020 ◽  
Vol 12 (548) ◽  
pp. eaaz8084 ◽  
Author(s):  
Jonathan C. M. Wan ◽  
Katrin Heider ◽  
Davina Gale ◽  
Suzanne Murphy ◽  
Eyal Fisher ◽  
...  
Keyword(s):  
Residual Disease ◽  
Early Stage ◽  
Area Under The Curve ◽  
Patient Specific ◽  
Sequencing Data ◽  
Liquid Biopsies ◽  
Whole Exome ◽  
Mutation Burden ◽  
Median Area ◽  
Personalized Cancer

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

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