scholarly journals Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiwei Bai ◽  
Jianxin Shi ◽  
Chuzhong Li ◽  
Shuai Wang ◽  
Tongwu Zhang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Skull Base ◽  
Genome Sequencing ◽  
Unknown Etiology ◽  
High Recurrence Rate ◽  
Driver Gene ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Skull Base Chordomas ◽  
Skull Base Chordoma

AbstractChordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10−6). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

Review of 200 consecutive patients with mutation profiling in a lung cancer individualized medicine clinic.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19013-e19013
Author(s):  
Michael Asiedu ◽  
Julian R. Molina ◽  
Jin Jen ◽  
Jin Sung Jang ◽  
Anja Roden ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Individualized Medicine ◽  
Treatment Decisions ◽  
Mutation Testing ◽  
Egfr Mutations ◽  
Driver Gene ◽  
Whole Genome ◽  
Number Of Patients ◽  
Mutation Profiling

e19013 Background: Mutation profiling to assess for potentially druggable mutations in NSCLC is being offered at an increasing number of cancer centers throughout North America and internationally. Although data continue to accumulate for the potential value of mutation testing in designing chemotherapeutic regimens, the treatment impact of obtaining information beyond assessment of EGFR and ALK status remains unclear. How best to obtain and clinically utilize these data, including information from exome and whole genome sequencing, also remains unclear. Methods: Patients were reviewed electronically in a multidisciplinary conference regarding indications for testing and results of mutation profiling from various methods, including the mass-spec based LungCarta test, targeted NexGen sequencing, exome, and whole genome sequencing. Outcomes of the multidisciplinary review were communicated back to treating physicians. Results: Mutation testing was performed on 200 patients using a variety of approaches. The majority (>150) were surgically resected stage I and II tumors. Mutations in at least 1 major cancer driver gene, including EGFR, KRAS, MET, BRAF and PIK3CA, were found in 47% of all patients tested. EGFR mutations were present in 14.8% of patients tested, KRAS 21.3%, BRAF 2.6%, PIK3CA 3.2%, and MET 4.5%. A total of 8 patients underwent either exome or whole genome sequencing. A limited number of patients (<10) had mutation results that impacted treatment decisions from this cohort. Conclusions: Mutation profiling can influence treatment decisions in NSCLC, but at a low frequency. The role of exome and or whole genome sequencing for patients with NSCLC is evolving and remains undefined.

scholarly journals Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Ho Jang ◽  
Youngmi Hur ◽  
Hyunju Lee
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Snp Array ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Driver Genes

Abstract DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes.

scholarly journals Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pauline A. J. Mendelaar ◽  
Marcel Smid ◽  
Job van Riet ◽  
Lindsay Angus ◽  
Mariette Labots ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Fragile Sites ◽  
Response To Treatment ◽  
Whole Genome Sequencing Data ◽  
Driver Gene ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genomic Landscape

AbstractIn contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.

scholarly journals Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaotong Li ◽  
Sushant Kumar ◽  
Arif Harmanci ◽  
Shantao Li ◽  
Robert R. Kitchen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Cancer Genome ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Genomic Features ◽  
Clonal Architecture

Abstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Results Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Conclusions Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.

scholarly journals Deep whole genome sequencing identifies recurrent genomic alterations in commonly-used breast cancer cell lines and patient derived xenograft models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Andrei Goga ◽  
Alex Swarbrick
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Pdx Models

Abstract BackgroundBreast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions. ResultsHere we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1 , previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. ConclusionsOur WGS data provides a comprehensive genome sequencing resource of these models.

Whole-genome sequencing of cholangiocarcinoma to reveal distinct profiles of patients with underlying cirrhosis or inflammatory disorders.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 340-340
Author(s):  
Nicholas Timothy Holzapfel ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Bernard Lam ◽  
Julie Wilson ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Braf V600e ◽  
Biological Information ◽  
Base Substitution ◽  
Unknown Etiology ◽  
Whole Genome ◽  
Mutational Signatures ◽  
Tp53 Mutations ◽  
Inflammatory Disorders

340 Background: Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options. Molecular profiling of these tumours has revealed a number of actionable mutations and four clusters have been defined through integrative genomic analysis. We sought to explore whole genome sequencing (WGS) data in 20 patients enriched for CCA arising in the setting of cirrhosis or inflammatory disorders. Methods: A previously established Biliary Tract Cancer (BTC) database at the Princess Margaret Cancer Centre (PMCC)/University Health Network (UHN) was used to identify patients of clinical interest including long-term survivors, those with germ-line mutations, and those with chronic inflammatory disorders. WGS and bioinformatic analyses were performed at the Ontario Institute for Cancer Research. Results: The 20 resected samples included 12 patients (pts) with intrahepatic CCA, 7 perihilar CCA, and 1 distal CCA. 8 pts were alive > 8 years post resection and one patient harboured a germline MLH1 pathogenic variant (MLH1 G67R). 3 pts had documented cirrhosis (hepatitis B n = 2, haemochromatosis n = 1); other inflammatory disorders (n = 4) included ulcerative colitis (UC) without documented PSC (n = 1), PSC alone (n = 1), UC with PSC (n = 1), and ankylosing spondylitis (n = 1). The remaining cases were randomly selected. The predominant COSMIC single base substitution (SBS) mutational signatures were 1, 8 and 5, and the median TMB was 1.75 mutations per MB (0.73-33.23). The pt with an MLH1 mutation exhibited a TMB of 33.23 with predominance of SBS26. Actionable variants were enriched in the 8 pts who are alive and disease free including 2 predicted FGFR fusions and mutations in IDH1 (n = 1), BRAF V600E (n = 1), and BAP1 (n = 1). TP53 mutations (n = 7) were present exclusively in patients with cirrhosis or inflammatory disorders and the median survival in the group was 12 months (3 -21 months). Although SBS signatures were similar in this group, in the two cases of UC, SBS17 (unknown etiology) was evident. SBS17 was also dominant in one case where the TMB was 13 mutations per MB and the patient died within 3 months of diagnosis. A somatic case of homologous recombination deficiency, with no causative genetic alteration identified, was evident in a further patient receiving maintenance rituximab for a coexisting stage 4 mantle cell lymphoma. Conclusions: WGS may provide additional biological information in CCA particularly in patients with underlying inflammatory disorders, where TP53 mutations are prevalent and mutational signatures are distinct.

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