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Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas

Girard, Nicolas; Shen, Ronglai; Guo, Tianhua; Zakowski, Maureen F; Heguy, Adriana; Riely, Gregory J; Huang, James; Lau, Christopher; Lash, Alex E; Ladanyi, Marc; Viale, Agnes; Antonescu, Cristina R; Travis, William D; Rusch, Valerie W; Kris, Mark G; Pao, William
PURPOSE: Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown. EXPERIMENTAL DESIGN: All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays. RESULTS: We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge. CONCLUSIONS: Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies.
PMCID:2783876
PMID: 19861435
ISSN: 1078-0432
CID: 306942

The protein tyrosine phosphatase receptor D, a broadly inactivated tumor suppressor regulating STAT function [Editorial]

Chan, Timothy A; Heguy, Adriana
PMID: 19755842
ISSN: 1551-4005
CID: 306952

PIK3CA mutation associates with improved outcome in breast cancer

Kalinsky, Kevin; Jacks, Lindsay M; Heguy, Adriana; Patil, Sujata; Drobnjak, Marija; Bhanot, Umeshkumar K; Hedvat, Cyrus V; Traina, Tiffany A; Solit, David; Gerald, William; Moynahan, Mary Ellen
PURPOSE: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. EXPERIMENTAL DESIGN: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology. RESULTS: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). CONCLUSION: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.
PMID: 19671852
ISSN: 1078-0432
CID: 306962

Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies

Abdel-Wahab, Omar; Mullally, Ann; Hedvat, Cyrus; Garcia-Manero, Guillermo; Patel, Jay; Wadleigh, Martha; Malinge, Sebastien; Yao, JinJuan; Kilpivaara, Outi; Bhat, Rukhmi; Huberman, Kety; Thomas, Sabrena; Dolgalev, Igor; Heguy, Adriana; Paietta, Elisabeth; Le Beau, Michelle M; Beran, Miloslav; Tallman, Martin S; Ebert, Benjamin L; Kantarjian, Hagop M; Stone, Richard M; Gilliland, D Gary; Crispino, John D; Levine, Ross L
Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis.
PMCID:2710942
PMID: 19420352
ISSN: 0006-4971
CID: 306992

The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers

Veeriah, Selvaraju; Brennan, Cameron; Meng, Shasha; Singh, Bhuvanesh; Fagin, James A; Solit, David B; Paty, Philip B; Rohle, Dan; Vivanco, Igor; Chmielecki, Juliann; Pao, William; Ladanyi, Marc; Gerald, William L; Liau, Linda; Cloughesy, Timothy C; Mischel, Paul S; Sander, Chris; Taylor, Barry; Schultz, Nikolaus; Major, John; Heguy, Adriana; Fang, Fang; Mellinghoff, Ingo K; Chan, Timothy A
Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.
PMCID:2687998
PMID: 19478061
ISSN: 0027-8424
CID: 306982

Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1

Ricarte-Filho, Julio C; Ryder, Mabel; Chitale, Dhananjay A; Rivera, Michael; Heguy, Adriana; Ladanyi, Marc; Janakiraman, Manickam; Solit, David; Knauf, Jeffrey A; Tuttle, R Michael; Ghossein, Ronald A; Fagin, James A
Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
PMCID:2690720
PMID: 19487299
ISSN: 0008-5472
CID: 306972

A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms

Kilpivaara, Outi; Mukherjee, Semanti; Schram, Alison M; Wadleigh, Martha; Mullally, Ann; Ebert, Benjamin L; Bass, Adam; Marubayashi, Sachie; Heguy, Adriana; Garcia-Manero, Guillermo; Kantarjian, Hagop; Offit, Kenneth; Stone, Richard M; Gilliland, D Gary; Klein, Robert J; Levine, Ross L
Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
PMCID:3676425
PMID: 19287384
ISSN: 1061-4036
CID: 307002

Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease

Tilley, Ann E; Harvey, Ben-Gary; Heguy, Adriana; Hackett, Neil R; Wang, Rui; O'Connor, Timothy P; Crystal, Ronald G
RATIONALE: The airway epithelium of smokers is subject to a variety of mechanisms of injury with consequent modulation of epithelial regeneration and disordered differentiation. Several signaling pathways, including the Notch pathway, control epithelial differentiation in lung morphogenesis, but little is known about the role of these pathways in adults. OBJECTIVES: We tested the hypotheses that Notch-related genes are expressed in the normal nonsmoker small airway epithelium of human adults, and that Notch-related gene expression is down-regulated in healthy smokers and smokers with chronic obstructive pulmonary disease (COPD). METHODS: We used microarray technology to evaluate the expression of 55 Notch-related genes in the small airway epithelium of nonsmokers. We used TaqMan quantitative polymerase chain reaction (PCR) to confirm the expression of key genes and we used immunohistochemistry to assess the expression of Notch-related proteins in the airway epithelium. Changes in expression of Notch genes in healthy smokers and smokers with COPD compared with nonsmokers were evaluated by PCR. MEASUREMENTS AND MAIN RESULTS: Microarray analysis demonstrated that 45 of 55 Notch-related genes are expressed in the small airway epithelium of adults. TaqMan PCR confirmed the expression of key genes with highest expression of the ligand DLL1, the receptor NOTCH2, and the downstream effector HES1. Immunohistochemistry demonstrated the expression of Jag1, Notch2, Hes1, and Hes5 in airway epithelium. Several Notch ligands, receptors, and downstream effector genes were down-regulated in smokers, with more genes down-regulated in smokers with COPD than in healthy smokers. Conclusions: These observations are consistent with the hypothesis that the Notch pathway likely plays a role in the human adult airway epithelium, with down-regulation of Notch pathway gene expression in association with smoking and COPD.
PMCID:2654975
PMID: 19106307
ISSN: 1073-449x
CID: 307012

Genomic complexity and BRAF/MEK-dependence in V600E BRAF mutant melanoma [Meeting Abstract]

Xing, Feng; Persaud, Yogindra; Pratilas, Christine; Janakiraman, Manickam; She, Qing-Bai; Liu, Cailian; Dolgalev, Igor; Heguy, Adriana; Wolchok, Jedd; Cobrinik, David; Houghton, Alan; Taylor, Barry; Rosen, Neal; Solit, David
ISI:000216412800341
ISSN: 1535-7163
CID: 5236552

Responses of the human airway epithelium transcriptome to in vivo injury

Heguy, Adriana; Harvey, Ben-Gary; Leopold, Philip L; Dolgalev, Igor; Raman, Tina; Crystal, Ronald G
To identify genes participating in human airway epithelial repair, we used bronchoscopy and brushing to denude the airway epithelium of healthy individuals, sequentially sampled the same region 7 and 14 days later, and assessed gene expression by Affymetrix microarrays with TaqMan RT-PCR confirmation. Histologically, the injured area was completely covered by a partially redifferentiated epithelial layer after 7 days; by 14 days the airway epithelium was very similar to the uninjured state. At day 7 compared with resting epithelium, there were substantial differences in gene expression pattern, with a distinctive airway epithelial "repair transcriptome" of actively proliferating cells in the process of redifferentiation. The repair transcriptome at 7 days was dominated by cell cycle, signal transduction, metabolism and transport, and transcription genes. Interestingly, the majority of differentially expressed cell cycle genes belonged to the G2 and M phases, suggesting that the proliferating cells were relatively synchronized 1 wk following injury. At 14 days postinjury, the expression profile was similar to that of resting airway epithelium. These observations provide a baseline of the functional gene categories participating in the process of normal human airway epithelial repair that can be used in future studies of injury and repair in airway epithelial diseases.
PMID: 17164391
ISSN: 1094-8341
CID: 307032