RESUMEN
Ocular adnexal mucosa associated lymphoid tissue lymphomas (OAMALTL) are the most common lymphomas of the eye. The potential roles for specific antigens in these lymphomas are still controversial. Previously we examined IGHV usage and mutations in Chlamydophila (C) psittaci-negative OAMALTL, demonstrating biased use of the IGHV4 family and IGHV4-34 gene and evidence for antigen selection. Herein, we examined the IGKV/IGLV gene usage and mutations in 34 C. psittaci-negative OAMALTL originating from the orbit (15), conjunctivae (14), and lacrimal gland (5). Clonal potentially functional IGKV/IGLV gene sequences were identified in 30 tumors (18 kappa and 12 lambda). An overrepresentation of the IGKV4 family (P < 0.01) was observed. The IGKV3-20*01 allele was used at a greater frequency than in normal peripheral blood B-lymphocytes (P = 0.02) and commonly paired with the IGHV4-34 allele. Twenty-seven of the 30 unique light chain sequences displayed mutations from germline and evidence for antigen selection. Overall our findings demonstrate that in C. psittaci-negative OAMALTL there is a biased usage of IGKV families and genes, which harbor somatic mutations. These findings and the specific paring between the IGKV3-20*01 and IGHV4-34 alleles suggest that specific antigens could play an important role in the pathogenesis of these lymphomas.
Asunto(s)
Neoplasias del Ojo/genética , Región Variable de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Cadenas lambda de Inmunoglobulina/genética , Linfoma/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Células Clonales/metabolismo , Estudios de Cohortes , Neoplasias de la Conjuntiva/genética , Neoplasias de la Conjuntiva/metabolismo , Neoplasias de la Conjuntiva/patología , Neoplasias del Ojo/metabolismo , Neoplasias del Ojo/patología , Femenino , Estudios de Asociación Genética , Humanos , Región Variable de Inmunoglobulina/metabolismo , Cadenas kappa de Inmunoglobulina/metabolismo , Cadenas lambda de Inmunoglobulina/metabolismo , Enfermedades del Aparato Lagrimal/genética , Enfermedades del Aparato Lagrimal/metabolismo , Enfermedades del Aparato Lagrimal/patología , Tejido Linfoide/metabolismo , Linfoma/metabolismo , Linfoma/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/metabolismo , Neoplasias Orbitales/genética , Neoplasias Orbitales/metabolismo , Neoplasias Orbitales/patologíaRESUMEN
The etiology and pathogenesis of ocular adnexal extranodal marginal zone lymphoma (OAEMZL) are still unknown and the association with Chlamydophila psittaci (C. psittaci) has been shown in only some geographic regions. Herein, we comprehensively examined the frequency of chromosomal translocations as well as CARD11, MYD88 (L265P), and A20 mutations/deletions in 45 C. psittaci negative OAEMZLs. t(14;18)(q32;q21) IGH-MALT1 and t(11;18)(q21;q21) API2-MALT1 were not detected in any of the analyzed tumors while three tumors harbored IGH translocations to an unidentified partner. CARD11 mutations were not found in all analyzed tumors, while the MYD88 L265P mutation was detected in three (6.7%) tumors. A20 mutations and deletions were each detected in seven (15.6%) and six (13.3%) tumors, respectively. Therefore, the observed genetic aberrations could account for the activation of the nuclear factor (NF)-kB signaling pathway in only a minority of the cases. Further studies are needed to identify the molecular mechanisms underlying the pathogenesis of OAEMZL.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al ADN/genética , Neoplasias del Ojo/genética , Guanilato Ciclasa/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Linfoma de Células B de la Zona Marginal/genética , Mutación , Factor 88 de Diferenciación Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Proteínas Adaptadoras de Señalización CARD/metabolismo , Chlamydophila psittaci , Conjuntiva/metabolismo , Conjuntiva/patología , Proteínas de Unión al ADN/metabolismo , Neoplasias del Ojo/metabolismo , Neoplasias del Ojo/patología , Femenino , Guanilato Ciclasa/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Linfoma de Células B de la Zona Marginal/metabolismo , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Órbita/metabolismo , Órbita/patología , Translocación Genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change.
Asunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/clasificación , Carcinoma de Células Renales/metabolismo , Carcinosarcoma/patología , Desdiferenciación Celular , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Neoplasias Renales/clasificación , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neprilisina/análisis , Pronóstico , Proteínas Proto-Oncogénicas c-kit/análisis , Tumor Rabdoide/patologíaRESUMEN
Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.
Asunto(s)
ADN Helicasas/genética , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Hepáticas/genética , Linfoma de Células T/genética , Neoplasias del Bazo/genética , Proteína p53 Supresora de Tumor/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adolescente , Adulto , Anciano , Secuencia de Bases , Niño , Preescolar , Proteínas de Unión al ADN , Proteína Potenciadora del Homólogo Zeste 2 , Exoma/genética , Femenino , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Linfoma de Células T/complicaciones , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias del Bazo/complicaciones , Neoplasias del Bazo/patología , Factores de Transcripción , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Previous studies have suggested that CD30 may be expressed in diffuse large B-cell lymphomas (DLBCLs). However, the prevalence of CD30 + DLBCLs and extent of CD30 expression within an individual tumor have not been fully evaluated. The aim of this study was to determine the frequency and extent of CD30 expression in DLBCLs, and explore possible relationships between CD30 expression and clinical and biologic variables. We retrospectively identified and analyzed 167 cases of CD30 + DLBCLs from our pathology archive. Twenty-one percent (95% confidence interval [CI]: 14.8-27.1%) of these cases expressed CD30, and in 52% of them CD30 was positive in > 80% of tumor cells. CD30 expression was more frequent in DLBCLs with non-germinal center origin phenotype, BCL2 + DLBCLs and in patients ≤ 47 years old. There was significant interaction of BCL2 expression with age and subtype of DLBCL. A multivariate analysis performed in BCL2 + DLBCLs showed a higher frequency of CD30 + cases in non-germinal center DLBCLs (odds ratio [OR]: 6.5, 95% CI: 1.1-36.5) and in patients ≤ 47 years old (OR: 6.9, 95% CI: 1.5-29.5). These associations could suggest a common biologic pathogenesis. The effectiveness of anti-CD30 drugs in other lymphomas opens the possibility for their use in patients with CD30 + DLBCLs.
Asunto(s)
Antígeno Ki-1/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Adulto , Anciano , Factores Biológicos/metabolismo , Estudios Transversales , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/virología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Estudios RetrospectivosRESUMEN
Extranodal marginal zone lymphomas (EMZL) are the most common lymphomas in the ocular adnexa. The etiology and potential role for antigenic stimulation in these lymphomas are still controversial. We have examined IGHV gene usage and mutations in 67 Chlamydophila psittaci-negative ocular adnexal EMZL. Clonal IGHV gene sequences were identified in 43 tumors originating from the orbit (19), conjunctivae (18) and lacrimal gland (6). Forty four potentially functional clonal IGHV gene sequences were detected with overrepresentation of the IGHV4 family and IGHV4-34 gene. All but 3 sequences were mutated with the average percent homology to the germ line of 93.5±6.1. Multinomial model and Focused binomial test demonstrated evidence for positive and/or negative antigen selection in 59% of the potentially functional IGHV genes. Intraclonal variation was detected in 8 of 11 tumor specimens. Overall our findings demonstrate that C. psittaci-negative ocular adnexal EMZL exhibit biased usage of IGHV families and genes with evidence for intraclonal heterogeneity and antigen selection in multiple tumors, implicating B-cell receptor-mediated antigen stimulation in the pathogenesis of these lymphomas.