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Increased PI3K pathway activity is associated with recurrent breast cancer in patients with low and intermediate 21-gene recurrence score

Lin, Lawrence Hsu; Wesseling-Rozendaal, Yvonne; Vasudevaraja, Varshini; Shen, Guomiao; Black, Margaret; van Strijp, Dianne; Neerken, Sigi; van de Wiel, Paul A; Jour, George; Cotzia, Paolo; Darvishian, Farbod; Snuderl, Matija
AIMS/OBJECTIVE:We investigated key signalling pathways' activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence. METHODS:This is a retrospective case-control study of 18 patients with recurrent breast carcinoma with low and intermediate 21-gene RS (<25) and control group of 15 non-recurrent breast cancer patients. DNA and mRNA were extracted from tumour tissue. mRNA expression of genes involved in oestrogen receptor (ER), androgen receptor (AR), PI3K and MAPK signalling pathways was measured by real-time quantitative reverse transcription-qPCR (OncoSIGNal G4 test, InnoSIGN). Tumour mutational landscape was assessed by targeted DNA sequencing (Oncomine Precision Assay). RESULTS:mutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.
PMID: 38383139
ISSN: 1472-4146
CID: 5634392

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features

Lin, Lawrence Hsu; Tran, Ivy; Yang, Yiying; Shen, Guomiao; Miah, Pabel; Cotzia, Paolo; Roses, Daniel; Schnabel, Freya; Darvishian, Farbod; Snuderl, Matija
Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.
PMID: 37595637
ISSN: 1530-0285
CID: 5607792

Automated and robust extraction of genomic DNA from various leftover blood samples

You, Jianlan; Osea, Jan; Mendoza, Sandra; Shiomi, Tomoe; Gallego, Estefania; Pham, Bernice; Kim, Angie; Sinay-Smith, Abraham; Zayas, Zasha; Neto, Antonio G; Boytard, Ludovic; Chiriboga, Luis; Cotzia, Paolo; Moreira, Andre L
With the development of genomic technologies, the isolation of genomic DNA (gDNA) from clinical samples is increasingly required for clinical diagnostics and research studies. In this study, we explored the potential of utilizing various leftover blood samples obtained from routine clinical tests as a viable source of gDNA. Using an automated method with optimized pre-treatments, we obtained gDNA from seven types of clinical leftover blood, with average yields of gDNA ranging from 3.11 ± 0.45 to 22.45 ± 4.83 μg. Additionally, we investigated the impact of storage conditions on gDNA recovery, resulting in yields of 8.62-68.08 μg when extracting gDNA from EDTA leftover blood samples stored at 4 °C for up to 13 weeks or -80 °C for up to 78 weeks. Furthermore, we successfully obtained sequenceable gDNA from both Serum Separator Tube and EDTA Tube using a 96-well format extraction, with yields ranging from 0.61 to 71.29 μg and 3.94-215.98 μg, respectively. Our findings demonstrate the feasibility of using automated high-throughput platforms for gDNA extraction from various clinical leftover blood samples with the proper pre-treatments.
PMID: 37543277
ISSN: 1096-0309
CID: 5597832

Integrated analysis of ovarian juvenile granulosa cell tumors reveals distinct epigenetic signatures and recurrent TERT rearrangements

Vougiouklakis, Theodore; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Linn, Rebecca L; Feng, Xiaojun; Chiang, Sarah; Barroeta, Julieta E; Thomas, Kristen M; Schwartz, Lauren E; Shukla, Pratibha S; Malpica, Anais; Oliva, Esther; Cotzia, Paolo; DeLair, Deborah F; Snuderl, Matija; Jour, George
PURPOSE/OBJECTIVE:-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. EXPERIMENTAL DESIGN/METHODS:Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS)-panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. RESULTS:non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level further supporting its diagnostic utility in distinguishing among these tumors. CONCLUSIONS:rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
PMID: 35031544
ISSN: 1557-3265
CID: 5119182

Tubulopapillary Carcinoma of the Breast: A Distinct Morphologic Entity with Molecular and Immunohistochemical Analysis [Meeting Abstract]

Salama, Abeer; Schwartz, Christopher; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Jour, George; Park, Kyung; Snuderl, Matija; Cotzia, Paolo; Darvishian, Farbod
ISI:000770360200172
ISSN: 0023-6837
CID: 5243152

Comparison of Fresh Cell Pellets and Cell Blocks for Genomic Profiling of Advanced Cancers in Pleural Effusion Specimens: Promising Preliminary Results from a Validation Study [Meeting Abstract]

Chen, Fei; Kim, Christine; Shen, Guomiao; Feng, Xiaojun; Jour, George; Cotzia, Paolo; Brandler, Tamar; Sun, Wei; Snuderl, Matija; Simsir, Aylin; Park, Kyung
ISI:000770360200230
ISSN: 0023-6837
CID: 5243162

Tubulopapillary Carcinoma of the Breast: A Distinct Morphologic Entity with Molecular and Immunohistochemical Analysis [Meeting Abstract]

Salama, Abeer; Schwartz, Christopher; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Jour, George; Park, Kyung; Snuderl, Matija; Cotzia, Paolo; Darvishian, Farbod
ISI:000770361800173
ISSN: 0893-3952
CID: 5243282

Comparison of Fresh Cell Pellets and Cell Blocks for Genomic Profiling of Advanced Cancers in Pleural Effusion Specimens: Promising Preliminary Results from a Validation Study [Meeting Abstract]

Chen, Fei; Kim, Christine; Shen, Guomiao; Feng, Xiaojun; Jour, George; Cotzia, Paolo; Brandler, Tamar; Sun, Wei; Snuderl, Matija; Simsir, Aylin; Park, Kyung
ISI:000770361800231
ISSN: 0893-3952
CID: 5243292

Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas

Lin, Lawrence Hsu; Allison, Douglas H R; Feng, Yang; Jour, George; Park, Kyung; Zhou, Fang; Moreira, Andre L; Shen, Guomiao; Feng, Xiaojun; Sabari, Joshua; Velcheti, Vamsidhar; Snuderl, Matija; Cotzia, Paolo
Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (p < 0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.
PMID: 34362997
ISSN: 1530-0285
CID: 4979862

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19

Gomes, Claudia; Zuniga, Marisol; Crotty, Kelly A; Qian, Kun; Tovar, Nubia Catalina; Lin, Lawrence Hsu; Argyropoulos, Kimon V; Clancy, Robert; Izmirly, Peter; Buyon, Jill; Lee, David C; Yasnot-Acosta, Maria Fernanda; Li, Huilin; Cotzia, Paolo; Rodriguez, Ana
High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations.
PMCID:8441539
PMID: 34504035
ISSN: 2575-1077
CID: 5061302