18 results on '"Yelensky, Roman"'
Search Results
2. Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies.
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Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, Bose R, Vergilio JA, Suh J, Yelensky R, Lipson D, Chmielecki J, Waintraub S, Leyland-Jones B, Miller VA, and Stephens PJ
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast secondary, Carcinoma, Lobular drug therapy, Carcinoma, Lobular genetics, Carcinoma, Lobular secondary, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic drug effects, High-Throughput Nucleotide Sequencing methods, Humans, In Situ Hybridization, Fluorescence, Lymphatic Metastasis, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prognosis, Receptor, ErbB-2 antagonists & inhibitors, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Genomics methods, Molecular Targeted Therapy, Mutation genetics, Neoplasm Recurrence, Local genetics, Receptor, ErbB-2 genetics
- Abstract
Background: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified., Methods: DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements., Results: Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein., Conclusions: Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2654-2662. © 2016 American Cancer Society., (© 2016 American Cancer Society.)
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- 2016
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3. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting.
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He J, Abdel-Wahab O, Nahas MK, Wang K, Rampal RK, Intlekofer AM, Patel J, Krivstov A, Frampton GM, Young LE, Zhong S, Bailey M, White JR, Roels S, Deffenbaugh J, Fichtenholtz A, Brennan T, Rosenzweig M, Pelak K, Knapp KM, Brennan KW, Donahue AL, Young G, Garcia L, Beckstrom ST, Zhao M, White E, Banning V, Buell J, Iwanik K, Ross JS, Morosini D, Younes A, Hanash AM, Paietta E, Roberts K, Mullighan C, Dogan A, Armstrong SA, Mughal T, Vergilio JA, Labrecque E, Erlich R, Vietz C, Yelensky R, Stephens PJ, Miller VA, van den Brink MR, Otto GA, Lipson D, and Levine RL
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- Chromosome Aberrations, Clinical Laboratory Techniques methods, DNA Mutational Analysis methods, DNA, Neoplasm analysis, Gene Expression Regulation, Neoplastic, Hematologic Neoplasms pathology, High-Throughput Nucleotide Sequencing, Humans, Mutation, Polymorphism, Genetic, RNA, Neoplasm analysis, Sensitivity and Specificity, Systems Integration, DNA Fingerprinting methods, Gene Expression Profiling methods, Genomics methods, Hematologic Neoplasms genetics, Hematologic Neoplasms metabolism
- Abstract
The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments-certified College of American Pathologists-accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs, and gene fusions, with similar accuracy to lower-throughput assays that focus on specific genes and types of genomic alterations. Profiling of 3696 samples identified recurrent somatic alterations that impact diagnosis, prognosis, and therapy selection. This comprehensive genomic profiling approach has proved effective in detecting all types of genomic alterations, including fusion transcripts, which increases the ability to identify clinically relevant genomic alterations with therapeutic relevance., (© 2016 by The American Society of Hematology.)
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- 2016
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4. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options.
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Ross JS, Badve S, Wang K, Sheehan CE, Boguniewicz AB, Otto GA, Yelensky R, Lipson D, Ali S, Morosini D, Chliemlecki J, Elvin JA, Miller VA, and Stephens PJ
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- Adult, Aged, Aged, 80 and over, Base Sequence, Breast Neoplasms pathology, Breast Neoplasms therapy, Carcinoma pathology, Carcinoma therapy, Exons genetics, Female, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Introns genetics, Middle Aged, Molecular Targeted Therapy, Mutation, Neoplasm Grading, Precision Medicine, Sequence Analysis, DNA methods, Breast Neoplasms genetics, Carcinoma genetics, Genomics
- Abstract
Context: Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy., Objective: To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC., Design: Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage., Results: The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment., Conclusions: Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.
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- 2015
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5. Concordance of genomic alterations between primary and recurrent breast cancer.
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Meric-Bernstam F, Frampton GM, Ferrer-Lozano J, Yelensky R, Pérez-Fidalgo JA, Wang Y, Palmer GA, Ross JS, Miller VA, Su X, Eroles P, Barrera JA, Burgues O, Lluch AM, Zheng X, Sahin A, Stephens PJ, Mills GB, Cronin MT, and Gonzalez-Angulo AM
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms therapy, Cluster Analysis, Female, Gene Expression Profiling, Humans, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Recurrence, Local, Neoplasm Staging, Breast Neoplasms genetics, Breast Neoplasms pathology, Gene Expression Regulation, Neoplastic, Genomics
- Abstract
There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.
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- 2014
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6. Unique molecular signatures as a hallmark of patients with metastatic breast cancer: Implications for current treatment paradigms
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Wheler, Jennifer J, Parker, Barbara A, Lee, Jack J, Atkins, Johnique T, Janku, Filip, Tsimberidou, Apostolia M, Zinner, Ralph, Subbiah, Vivek, Fu, Siqing, Schwab, Richard, Moulder, Stacy, Valero, Vicente, Schwaederle, Maria, Yelensky, Roman, Miller, Vincent A, Stephens, M Philip J, Meric-Bernstam, Funda, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Genetics ,Good Health and Well Being ,Antineoplastic Agents ,Breast Neoplasms ,Female ,Genes ,Neoplasm ,High-Throughput Nucleotide Sequencing ,Humans ,Molecular Targeted Therapy ,Neoplasm Proteins ,Genomics ,PI3K ,Clinical Trials ,Oncology and carcinogenesis - Abstract
Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.
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- 2014
7. Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.
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Hirshfield, Kim M., Tolkunov, Denis, Zhong, Hua, Ali, Siraj M., Stein, Mark N., Murphy, Susan, Vig, Hetal, Vazquez, Alexei, Glod, John, Moss, Rebecca A., Belyi, Vladimir, Chan, Chang S., Chen, Suzie, Goodell, Lauri, Foran, David, Yelensky, Roman, Palma, Norma A., Sun, James X., Miller, Vincent A., and Stephens, Philip J.
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TUMOR classification ,TUMOR prevention ,RARE diseases ,CANCER treatment ,LONGITUDINAL method ,GENETIC mutation ,RESEARCH funding ,GENOMICS ,SPECIALTY hospitals ,DATA analysis software ,GENE expression profiling ,DESCRIPTIVE statistics ,PREVENTION - Abstract
Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least onegenomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol- 4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy wereclinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. [ABSTRACT FROM AUTHOR]
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- 2016
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8. Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.
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Heilmann, andreas M., Subbiah, Vivek, Wang, Kai, Sun, James X., Elvin, Julia a., Chmielecki, Juliann, Sherman, Steven I., Murthy, Ravi, Busaidy, Naifa L., Subbiah, Ishwaria, Yelensky, Roman, Nangia, Chaitali, Vergilio, Jo-anne, Khan, Saad a., Erlich, Rachel L., Lipson, Doron, Ross, Jeffrey S., Miller, Vincent a., Shah, Manisha H., and ali, Siraj M.
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ANTINEOPLASTIC agents ,CANCER chemotherapy ,COMPUTED tomography ,MEDICAL protocols ,ONCOLOGY ,RESEARCH funding ,GENOMICS ,THYROID gland tumors ,DISEASE progression ,EVEROLIMUS ,DIAGNOSIS - Abstract
Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients. [ABSTRACT FROM AUTHOR]
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- 2016
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9. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets.
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Hwajeong Lee, Kai Wang, Johnson, Adrienne, Jones, David M., Ali, Siraj M., Elvin, Julia A., Yelensky, Roman, Lipson, Doron, Miller, Vincent A., Stephens, Philip J., Javle, Milind, and Ross, Jeffrey S.
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CHOLANGIOCARCINOMA ,GENOMICS ,GENETIC mutation ,CARCINOMA ,PANCREATIC cancer - Abstract
Aim We queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy. Methods Comprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma. Results There were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0-13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified. Conclusions Comprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies. [ABSTRACT FROM AUTHOR]
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- 2016
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10. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations.
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Ross, Jeffrey S., Wang, Kai, Khaira, Depinder, Ali, Siraj M., Fisher, Huge A.G., Mian, Badar, Nazeer, Tipu, Elvin, Julia A., Palma, Norma, Yelensky, Roman, Lipson, Doron, Miller, Vincent A., Stephens, Philip J., Subbiah, Vivek, and Pal, Sumanta K.
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TRANSITIONAL cell carcinoma ,BLADDER ,GENOMICS ,NUCLEIC acid hybridization ,FIBROBLAST growth factor receptors ,CLINICAL trials ,BLADDER tumors ,CANCER relapse ,CELL receptors ,DATABASES ,GENE amplification ,GENES ,GENETICS ,METASTASIS ,GENETIC mutation ,ONCOGENES ,PHOSPHOTRANSFERASES - Abstract
Background: In the current study, the authors present a comprehensive genomic profile (CGP)-based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs).Methods: DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism-driven clinical trials.Results: All 295 patients assessed were classified with high-grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin-dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001).Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702-711. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2016
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11. Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies.
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Al‐Rohil, Rami N., Tarasen, Ashley J., Carlson, J. Andrew, Wang, Kai, Johnson, Adrienne, Yelensky, Roman, Lipson, Doron, Elvin, Julia A., Vergilio, Jo‐Anne, Ali, Siraj M., Suh, James, Miller, Vincent A., Stephens, Philip J., Ganesan, Prasanth, Janku, Filip, Karp, Daniel D., Subbiah, Vivek, Mihm, Martin C., and Ross, Jeffrey S.
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SQUAMOUS cell carcinoma ,TARGETED drug delivery ,GENOMICS ,NEUROFIBROMATOSIS ,PROTEIN-tyrosine kinases ,ATAXIA telangiectasia mutated protein ,PHOSPHOINOSITIDES ,EPIDERMAL growth factor receptors ,CANCER treatment ,CANCER invasiveness ,DRUG therapy ,COMPARATIVE studies ,GENES ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RISK assessment ,TUMOR classification ,SKIN tumors ,EVALUATION research ,TREATMENT effectiveness ,RETROSPECTIVE studies ,GENE expression profiling ,TUMOR treatment - Abstract
Background: The authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic-derived drug targets of therapy for patients with conventional therapy-resistant disease.Methods: Comprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials.Results: There were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%).Conclusions: In the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249-257. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2016
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12. Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations.
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Ali, Siraj M., Pal, Sumanta K., Wang, Kai, Palma, Norma A., Sanford, Eric, Bailey, Mark, He, Jie, Elvin, Julia A., Chmielecki, Juliann, Squillace, Rachel, Dow, Edward, Morosini, Deborah, Buell, Jamie, Yelensky, Roman, Lipson, Doron, Frampton, Garrett M., Howley, Peter, Ross, Jeffrey S., Stephens, Philip J., and Miller, Vincent A.
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CANCER genetics ,DNA analysis ,PENILE tumors ,GENETIC mutation ,TUMOR classification ,GENOMICS ,GENE expression profiling ,DESCRIPTIVE statistics ,GENETICS - Abstract
Background. Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs). Materials and Methods. DNA was extracted from 40 mm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 6923 for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials. Results. Twenty male patients with a median age of 60 years (range, 46-87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%). Conclusion. CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients. [ABSTRACT FROM AUTHOR]
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- 2016
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13. Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine.
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Levin, Maren K., Wang, Kai, Yelensky, Roman, Cao, Ying, Ramos, Corinne, Hoke, Nicholas, Pippen, John, Blum, Joanne L., Brooks, Barry, Palmer, Gary, Palma, Norma, Balasubramanian, Sohail, Ross, Jeffrey S., and O'Shaughnessy, Joyce
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METASTATIC breast cancer ,DNA repair ,CHROMATIN ,GENOMICS ,ESTROGEN receptors - Abstract
We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor ( ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients' primary ( n = 4) or metastatic ( n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single-agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54-86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients' cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients' cancers had variants of unknown significance in these pathways. Mutations in PIK3 CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients' tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients' cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER-positive, endocrine therapy-pretreated, HER2-negative metastases, are supported by preclinical data showing that sensitivity to 5-fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER-positive, HER2-negative breast cancers may predict for highly durable responses to capecitabine. [ABSTRACT FROM AUTHOR]
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- 2015
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14. OncogenicAlterations in ERBB2/HER2Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin.
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Chmielecki, Juliann, Ross, Jeffrey S., Wang, Kai, Frampton, Garrett M., Palmer, Gary A., Ali, Siraj M., Palma, Norma, Morosini, Deborah, Miller, Vincent A., Yelensky, Roman, Lipson, Doron, and Stephens, Philip J.
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TUMOR classification ,TUMOR genetics ,TUMOR treatment ,DNA analysis ,GENE amplification ,GENETIC mutation ,ONCOGENES ,GENOMICS ,DESCRIPTIVE statistics ,SEQUENCE analysis - Abstract
Background. TargetedERBB2/HER2inhibitors areapproved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents.Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications. Materials and Methods.We explored the spectrum of activating ERBB2 alterations across a collection of ∼7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes. Results. Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%).Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases. Conclusion. Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor typesmay identify∼3.5 times the number of patients who may benefit from ERBB2-targeted therapy. [ABSTRACT FROM AUTHOR]
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- 2015
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15. A Targeted Next-Generation Sequencing Assay Detects a High Frequency of Therapeutically Targetable Alterations in Primary and Metastatic Breast Cancers: Implications for Clinical Practice.
- Author
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Vasan, Neil, Yelensky, Roman, Wang, Kai, Moulder, Stacy, Dzimitrowicz, Hannah, Avritscher, Rony, Wang, Baliang, Wu, Yun, Cronin, Maureen T., Palmer, Gary, Symmans, W. Fraser, Miller, Vincent A., Stephens, Philip, and Pusztai, Lajos
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BREAST tumors ,BREAST tumor treatment ,METASTASIS ,CANCER treatment ,DNA analysis ,BIOLOGICAL assay ,BIOPHYSICS ,BIOPSY ,MAMMALS ,RESEARCH methodology ,TISSUE culture ,GENOMICS ,DESCRIPTIVE statistics ,SEQUENCE analysis ,IN vitro studies ,GENETICS - Abstract
The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencing-based genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,154×. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = .24). The most common actionable alterations were in PIK3CA (n = 9, phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor receptor inhibitors). Our sequencing assay also correctly identified all six cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when tumor content was adequate. In addition, two known activating HER2 mutations were identified, both in unamplified cases. Conclusion. Overall, 84% of cancers harbored at least one genomic alteration linked to potential treatment options. Systematic evaluation of the predictive value of these genomic alterations is critically important for further progress in this field. [ABSTRACT FROM AUTHOR]
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- 2014
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16. Evaluating and improving power in whole-genome association studies using fixed marker sets.
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Pe'er, Itsik, de Bakker, Paul I. W., Maller, Julian, Yelensky, Roman, Altshuler, David, and Daly, Mark J.
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GENOMES ,GENETIC research ,BAYESIAN analysis ,GENETIC polymorphisms ,GENOMICS - Abstract
Emerging technologies make it possible for the first time to genotype hundreds of thousands of SNPs simultaneously, enabling whole-genome association studies. Using empirical genotype data from the International HapMap Project, we evaluate the extent to which the sets of SNPs contained on three whole-genome genotyping arrays capture common SNPs across the genome, and we find that the majority of common SNPs are well captured by these products either directly or through linkage disequilibrium. We explore analytical strategies that use HapMap data to improve power of association studies conducted with these fixed sets of markers and show that limited inclusion of specific haplotype tests in association analysis can increase the fraction of common variants captured by 25–100%. Finally, we introduce a Bayesian approach to association analysis by weighting the likelihood of each statistical test to reflect the number of putative causal alleles to which it is correlated. [ABSTRACT FROM AUTHOR]
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- 2006
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17. Efficiency and power in genetic association studies.
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de Bakker, Paul I. W., Yelensky, Roman, Pe'er, Itsik, Gabriel, Stacey B., Daly, Mark J., and Altshuler, David
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GENETIC polymorphisms , *GENOMES , *GENETIC research , *CHROMOSOME polymorphism , *GENETICS , *GENOMICS - Abstract
We investigated selection and analysis of tag SNPs for genome-wide association studies by specifically examining the relationship between investment in genotyping and statistical power. Do pairwise or multimarker methods maximize efficiency and power? To what extent is power compromised when tags are selected from an incomplete resource such as HapMap? We addressed these questions using genotype data from the HapMap ENCODE project, association studies simulated under a realistic disease model, and empirical correction for multiple hypothesis testing. We demonstrate a haplotype-based tagging method that uniformly outperforms single-marker tests and methods for prioritization that markedly increase tagging efficiency. Examining all observed haplotypes for association, rather than just those that are proxies for known SNPs, increases power to detect rare causal alleles, at the cost of reduced power to detect common causal alleles. Power is robust to the completeness of the reference panel from which tags are selected. These findings have implications for prioritizing tag SNPs and interpreting association studies. [ABSTRACT FROM AUTHOR]
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- 2005
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18. Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes.
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Giulino-Roth, Lisa, Kai Wang, MacDonald, Theresa Y., Mathew, Susan, Tam, Yifang, Cronin, Maureen T., Palmer, Gary, Lucena-Silva, Norma, Pedrosa, Francisco, Pedrosa, Marcia, Teruya-Feldstein, Julie, Bhagat, Govind, Alobeid, Bachir, Leoncini, Lorenzo, BeIIan, Cristiana, Rogena, Emily, Pinkney, Kerice A., Rubin, Mark A., Ribeiro, Raul C., and Yelensky, Roman
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LYMPHOMAS , *PEDIATRIC research , *NUCLEOPROTEINS , *GENOMICS , *TUMOR growth , *CHROMATIN , *GENETICS - Abstract
To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL), we performed clinical-grade next-generation sequencing of 182 cancer-related genes on 29 formalinfixed, paraffin embedded primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (P < .0001). Alterations in tumor-related genes not previously described in BL were identified. Truncating mutations in ARID1A, a member of the SWI/SNF nucleosome remodeling complex, were seen in 17% of cases. MCL1 pathway alterations were found in 22% of cases and confirmed in an expanded panel. Other clinically relevant genomic alterations were found in 20% of cases. Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that comprehensive genomic profiling may Identify additional treatment options in refractory disease. [ABSTRACT FROM AUTHOR]
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- 2012
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