scholarly journals Distinct Genomic Features Across Cytolytic Subgroups in Skin Melanoma

2020 ◽  
Author(s):  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares ◽  
Apostolos Zaravinos
Keyword(s):  
Copy Number ◽  
Cytotoxic T Cells ◽  
Acquired Resistance ◽  
Cytolytic Activity ◽  
Cancer Genes ◽  
Checkpoint Inhibition ◽  
Skin Melanoma ◽  
Primary Tumors ◽  
Genomic Features ◽  
Copy Number Aberrations

Abstract Background: Skin melanoma is a highly immunogenic cancer with extensive genetic and transcriptional diversity. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibition, a subgroup of them later relapse and develop acquired resistance. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T cells and NK cells to eliminate cancer cells, and is associated with improved patient survival. Here, we questioned whether CYT associates with different genomic profiles in skin melanoma. Methods: We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen.garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Results: Metastatic skin melanomas had significantly higher CYT compared to primary tumors. We also assessed enrichment for immune-related gene sets within CYT-high tumors; whereas, CYT-low tumors were enriched for non-immune related genes sets. In addition, distinct mutational and neoantigenic loads, primarily composed of C>T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where non-telomeric chromosomal regions harboring chromothripsis, contained a higher number of cancer genes. CYT-high patients had markedly higher immunophenoscore and should consequently, display an expected clinical benefit compared to CYT-low patients who either received or not, checkpoint inhibition. Conclusions: Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma.

scholarly journals 867 Distinct genomic features across cytolytic subgroups in skin melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A919-A919
Author(s):  
Apostolos Zaravinos ◽  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares
Keyword(s):  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Acquired Resistance ◽  
Cytolytic Activity ◽  
Skin Melanoma ◽  
Mutational Signatures ◽  
Genomic Features ◽  
Copy Number Aberrations ◽  
Melanoma Patients

BackgroundSkin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T cells and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors (ICI), a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles in skin melanoma.MethodsWe explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. We calculated the tumor immune contexture, somatic mutations, recurrent copy number aberrations, chromothripsis, cancer neoepitopes, immunophenoscore, mutational signatures, kataegis and strand asymmetry in each cytolytic subgroup.ResultsCYT was higher in enriched in immune-related gene sets metastatic tumors. Distinct mutational and neoantigen loads, primarily composed of C>T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. More chromothripsis events were found across CYT-low tumors SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures in both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b were mutually exclusive with SBS5 and SBS1 in both CYT subgroups. Mutational strand asymmetries related to the processes of DNA transcription and replication differed between CYT-high and CYT-low tumors. CYT-high patients had markedly higher immunophenoscore and should consequently, display an expected clinical benefit compared to CYT-low patients who either received or not, ICI.ConclusionsOur data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma patients, which could affect their relapse rate or resistance to ICI.

scholarly journals Distinct genomic features across cytolytic subgroups in skin melanoma

2021 ◽  
Author(s):  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares ◽  
Apostolos Zaravinos
Keyword(s):  
Immune Checkpoint ◽  
Cytolytic Activity ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Skin Melanoma ◽  
Related Gene ◽  
Mutational Signatures ◽  
Genomic Features ◽  
Immune Related Gene ◽  
Gene Sets

Abstract Background Skin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma. Methods We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC. Results Metastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients. Conclusions Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition 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.

A Gynecologic Oncology Group study of frequent copy number aberrations in African American versus Caucasian women with stage I versus stage IIIC/IV endometrioid endometrial cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16501-e16501
Author(s):  
C. Morrison ◽  
D. Gaile ◽  
K. Darcy ◽  
S. Liu ◽  
L. Shepherd ◽  
...  
Keyword(s):  
African American ◽  
Endometrial Cancer ◽  
Copy Number ◽  
Stage I ◽  
Gynecologic Oncology Group ◽  
Stage Iiic ◽  
Primary Tumors ◽  
Copy Number Aberrations ◽  
Caucasian Women ◽  
Versus Stage

e16501 Background: An array-based comparative genomic hybridization (aCGH) analysis was performed to determine if frequent (>40%) copy number aberrations (CNAs) exist in African American (AA) versus Caucasian (C) women with stage I versus stage IIIC/IV endometrioid endometrial cancers (EEC). Methods: Tumor DNA was isolated from 80 frozen primary tumors from the GOG-210 protocol. RPCI 19K BAC arrays were hybridized (GeneTAC HybStation) and scanned (Gene Pix 4200AL Laser Scanner). Spot fluorescence values were quantified using ImaGene, vetted for quality and loess corrected with adjustments for chip-specific spatial effects. The genome was segmented to identify regions with common copy number means (DNAcopy software). Posterior aberration probabilities for the regions were obtained using CGHcall and data was visualized and annotated using iGenomicViewer in R. Validation will be performed by fluorescence in situ hybridization using select BAC probes and endometrial cancer tissue microarrays (TMAs) with either 400 cases linked with clinical, treatment and outcome data or 180 AA versus 120 C women from GOG-136. Results: Recurrent CNAs were identified in all stage and race groups. Distinct genomic losses and gains were observed that appear to segregate Caucasian women with stage I disease from African American women with stage I disease and African American or Caucasian women with stage IIIC/IV disease. Conclusions: The GOG-210 bank yielded high quality DNA for detecting and mapping CNAs in frozen primary tumors with high resolution. Our results would imply that racial disparity for AA EEC has a genetic basis regardless of stage. Validation studies are currently underway in two endometrial cancer TMAs. [Table: see text] No significant financial relationships to disclose.

scholarly journals MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii389-iii389
Author(s):  
Rahul Kumar ◽  
Maximilian Deng ◽  
Kyle Smith ◽  
Anthony Liu ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Copy Number ◽  
Driver Mutations ◽  
P Value ◽  
Next Generation ◽  
Driver Genes ◽  
Methylation Array ◽  
Primary Tumors ◽  
Group 4 ◽  
Group 3

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.

scholarly journals Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma

Hepatology ◽  
2011 ◽  
Vol 54 (4) ◽  
pp. 1227-1236 ◽  
Author(s):  
Deshui Jia ◽  
Lin Wei ◽  
Weijie Guo ◽  
Ruopeng Zha ◽  
Meiyan Bao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Cancer Genes ◽  
Genome Wide

scholarly journals Listeria monocytogenes-reactive T lymphocyte clones with cytolytic activity against infected target cells.

1986 ◽  
Vol 164 (1) ◽  
pp. 363-368 ◽  
Author(s):  
S H Kaufmann ◽  
E Hug ◽  
G De Libero
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Cytolytic Activity ◽  
Target Cells ◽  
Intracellular Bacteria ◽  
Spleen Cells ◽  
Ifn Gamma ◽  
Cell Clones

Lyt-2+ T cell clones were established from Listeria monocytogenes-infected mice. The clones secreted IFN-gamma after stimulation with spleen cells from L. monocytogenes-infected mice plus IL-2. Spleen cells from normal mice were not stimulatory. Furthermore, cloned T cells lysed L. monocytogenes-infected macrophages. Cytolysis was antigen-specific and H-2K-restricted. These findings suggest a role for specific cytotoxic T cells in the immune response to intracellular bacteria.

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