scholarly journals Methylation profiling reveals novel molecular classes of rhabdomyosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael R. Clay ◽  
Anand Patel ◽  
Quynh Tran ◽  
Dale J. Hedges ◽  
Ti-Cheng Chang ◽  
...  
Keyword(s):  
Copy Number ◽  
Soft Tissue Sarcomas ◽  
Genomic Analysis ◽  
Adult Type ◽  
Histologic Subtype ◽  
Sequencing Studies ◽  
Poor Outcomes ◽  
Aggressive Clinical Course ◽  
Age Range ◽  
Methylation Profiling

AbstractRhabdomyosarcomas (RMS) represent a family of aggressive soft tissue sarcomas that present in both children and adults. Pathologic risk stratification for RMS has been based on histologic subtype, with poor outcomes observed in alveolar rhabdomyosarcoma (ARMS) and the adult-type pleomorphic rhabdomyosarcoma (PRMS) compared to embryonal rhabdomyosarcoma (ERMS). Genomic sequencing studies have expanded the spectrum of RMS, with several new molecularly defined entities, including fusion-driven spindle cell/sclerosing rhabdomyosarcoma (SC/SRMS) and MYOD1-mutant SC/SRMS. Comprehensive genomic analysis has previously defined the mutational and copy number spectrum for the more common ERMS and ARMS and revealed corresponding methylation signatures. Comparatively, less is known about epigenetic correlates for the rare SC/SRMS or PRMS histologic subtypes. Herein, we present exome and RNA sequencing, copy number analysis, and methylation profiling of the largest cohort of molecularly characterized RMS samples to date. In addition to ARMS and ERMS, we identify two novel methylation subtypes, one having SC/SRMS histology and defined by MYOD1 p. L122R mutations and the other matching adult-type PRMS. Selected tumors from adolescent patients grouped with the PRMS methylation class, expanding the age range of these rare tumors. Limited follow-up data suggest that pediatric tumors with MYOD1-mutations are associated with an aggressive clinical course.

scholarly journals Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3394
Author(s):  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Stella Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

scholarly journals Integrated Genomic Analysis of Sézary Syndrome

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Mao ◽  
Tracy Chaplin ◽  
Bryan D. Young
Keyword(s):  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Snp Microarray ◽  
The Impact ◽  
Chromosome Regions

Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results. In addition, we tested the impact of SNP loss of heterozygosity (LOH) identified in SS cases on the gene expression profiles of SS cases detected with Affymetrix GeneChip U133A. The results showed: (1) frequent SNP copy number change and LOH involving 1, 2p, 3, 4q, 5q, 6, 7p, 8, 9, 10, 11, 12q, 13, 14, 16q, 17, and 20, (2) reduced SNP copy number at FAT gene (4q35) in 75% of SS cases, and (3) the separation of all SS cases from normal control samples by SNP LOH gene clusters at chromosome regions of 9q31q34, 10p11q26, and 13q11q12. These findings provide some intriguing information for our current understanding of the molecular pathogenesis of this tumour and suggest the possibility of presence of functional SNP LOH in SS tumour cells.

The impact of multimodality therapies in marginally inoperable soft tissue sarcomas (STS): The Toronto Sarcoma Program (TSP) experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11548-11548
Author(s):  
Olga Vornicova ◽  
Jay Wunder ◽  
Peter W. M. Chung ◽  
Abha A. Gupta ◽  
Rebecca Anne Gladdy ◽  
...  
Keyword(s):  
Cox Regression ◽  
Soft Tissue Sarcomas ◽  
Tumor Board ◽  
Disease Characteristics ◽  
Kaplan Meier ◽  
Progression Of Disease ◽  
Modality Approach ◽  
Poor Outcomes ◽  
The Impact

11548 Background: The mainstay therapy of operable STS remains surgery, which may include (neo)adjuvant therapies. Within the TSP, marginally inoperable STS are often treated with sequential chemo (CTX) and radiation (RT) therapy, followed by surgery (SX). Herein we present our experience of multi-modality therapies for marginally inoperable STS patients (pts). Methods: This was a dual-center, single program, retrospective review. Pts were included if deemed to have marginally inoperable primary or recurrent STS, as determined at the TSP tumor board. Pts included must have had CTX with the intent of having RT and SX after. Pts demographics, treatment details and clinical outcomes data were collected. Relapse free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Multivariate analysis of the influence of disease characteristics and treatment on outcomes was assessed using Cox regression. Results: From June 2005 to May 2019, 75 pts were identified. Median age was 52 years (range 16-72). Pts were predominantly male (55%). Histological subtypes included dedifferentiated liposarcoma (29%), leiomyosarcoma (27%), synovial sarcoma (19%) and others (25%). Primary tumor was located in the retroperitoneum (48%), extremity (23%), pelvis (12%), thorax (9%), and other sites (8%). All pts had doxorubicin and ifosfamide CTX (median 4 cycles; range 1-6), while RT dose delivered was 50.4Gy/28 fractions in 58 (77%) of cases. Twenty three pts (31%) achieved partial response, 40 pts (53%) had stable disease and 12 pts (16%) had progression of disease (PD) on CTX, of which half (8%) did not undergo further treatment. Nine pts (12%) underwent CTX followed by SX due to significant response, 9 pts (12%) underwent CTX and RT without SX due to persistent tumor unresectability or PD. The final 50 pts (67%) completed multi-modality treatment (CTX, RT & SX). Overall, 59 pts (79%) had SX; negative margins were achieved in 53 (71%). 19 pts (25%) had postoperative complications, causing death in 2 pts (2.7%). With a median follow-up of 72 months, median RFS and OS were 26.9 months (95% CI: 0-86.0), and 65 months (95% CI: 13.5-116.4). Extremity location was associated with superior RFS (median not reached [NR], HR 0.28 95% CI 0.09-0.83, p = 0.022), and OS (median NR, HR 0.29 95% CI 0.09-0.90, p = 0.032). Receipt of RT was associated with superior RFS (median NR, HR 0.23 95% CI 0.10-0.52, p < 0.001); and OS (median NR, HR 0.21 95% CI 0.09-0.50, p < 0.001). Pts who had PD after CTX were associated with poor outcomes - RFS (median 4.7 months, HR 2.03 95% CI 0.61-6.76, p = 0.24); and OS (median 21.9 months, HR 2.48 95% CI 0.73-8.47, P = 0.144). Conclusions: Multi-modality approach resulted in successful resection for most pts with marginally inoperable STS. Extremity location and RT administration were associated with better RFS and OS, while progression on CTX confers worse survival outcomes.

Childhood Nonrhabdomyosarcoma Soft Tissue Sarcomas Are Not Adult-Type Tumors

2006 ◽  
Vol 24 (12) ◽  
pp. 1958-1959 ◽  
Author(s):  
Sheri L. Spunt ◽  
Alberto S. Pappo
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcomas ◽  
Adult Type

scholarly journals Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease

Blood ◽  
2018 ◽  
Vol 132 (9) ◽  
pp. 948-961 ◽  
Author(s):  
Susan Branford ◽  
Paul Wang ◽  
David T. Yeung ◽  
Daniel Thomson ◽  
Adrian Purins ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
High Risk ◽  
Genomic Analysis ◽  
Kinase Domain ◽  
Cancer Genes ◽  
High Risk Disease ◽  
Key Points ◽  
Kinase Domain Mutations ◽  
Poor Outcomes ◽  
Generation Sequencing

Key Points Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.

scholarly journals DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations

2020 ◽  
Vol 21 (5) ◽  
pp. 1818 ◽  
Author(s):  
Evelina Miele ◽  
Rita De Vito ◽  
Andrea Ciolfi ◽  
Lucia Pedace ◽  
Ida Russo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Soft Tissue ◽  
Abdominal Wall ◽  
Current Knowledge ◽  
Soft Tissue Sarcomas ◽  
Molecular Techniques ◽  
Round Cell ◽  
Undifferentiated Sarcoma ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor (CIC) rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with CIC alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of CIC rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors.

scholarly journals A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 665 ◽  
Author(s):  
Marguerite Tyran ◽  
Nadine Carbuccia ◽  
Séverine Garnier ◽  
Arnaud Guille ◽  
José Adelaïde ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Copy Number ◽  
Genomic Analysis ◽  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Tyrosine Kinase Receptor ◽  
Cdk Inhibitors ◽  
Breast Cancers

Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC–BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.

Genomic Characterization of Primary Invasive Lobular Breast Cancer

2016 ◽  
Vol 34 (16) ◽  
pp. 1872-1881 ◽  
Author(s):  
Christine Desmedt ◽  
Gabriele Zoppoli ◽  
Gunes Gundem ◽  
Giancarlo Pruneri ◽  
Denis Larsimont ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Clinical Investigation ◽  
Endocrine Treatment ◽  
Cancer Genes ◽  
Lobular Breast Cancer ◽  
Primary Tumors ◽  
Histologic Subtype ◽  
Increased Risk ◽  
Invasive Lobular Breast Cancer

Purpose Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. Methods From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. Results Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. Conclusion This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment.

scholarly journals Dedifferentiated Solitary Fibrous Tumor: A Concise Review

2018 ◽  
Vol 142 (6) ◽  
pp. 761-766 ◽  
Author(s):  
Nicholas J. Olson ◽  
Konstantinos Linos
Keyword(s):  
Solitary Fibrous Tumor ◽  
Correct Diagnosis ◽  
The Body ◽  
Molecular Alterations ◽  
Concise Review ◽  
Mesenchymal Neoplasm ◽  
Fibrous Tumor ◽  
Aggressive Clinical Course ◽  
Age Range ◽  
Ancillary Studies

Solitary fibrous tumor (SFT) is a unique mesenchymal neoplasm that was originally believed to be of submesothelial origin. Eventually, SFT expanded to include what was previously called hemangiopericytoma in other regions of the body that had similar immunohistochemical and morphologic features. Although most are benign, many studies have tried to identify histologic features that predict which tumors will behave in an aggressive manner. Recently, dedifferentiation has been described in rare cases of SFT and does appear to correlate with a more aggressive clinical course. Dedifferentiated SFT occurs in a similar age range and location as conventional SFT and can resemble multiple different malignant entities. Utilization of ancillary studies and thorough tissue sampling is important to reach the correct diagnosis. The morphologic features, immunohistochemistry, molecular alterations, and prognosis will be discussed.

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