RESUMEN
BACKGROUND: Human immunodeficiency virus-infected individuals (HIVIIs) have a higher incidence of head and neck squamous cell carcinoma (HNSCC), and clinical and histopathological differences have been observed in their tumors in comparison with those of HNSCC patients without a human immunodeficiency virus (HIV) infection. The reasons for these differences are not clear, and molecular differences between HIV-related HNSCC and non-HIV-related HNSCC may exist. This study compared the mutational patterns of HIV-related HNSCC and non-HIV-related HNSCC. METHODS: The DNA of 20 samples of HIV-related HNSCCs and 32 samples of non-HIV-related HNSCCs was sequenced. DNA libraries covering exons of 18 genes frequently mutated in HNSCC (AJUBA, CASP8, CCND1, CDKN2A, EGFR, FAT1, FBXW7, HLA-A, HRAS, KEAP1, NFE2L2, NOTCH1, NOTCH2, NSD1, PIK3CA, TGFBR2, TP53, and TP63) were prepared and sequenced on an Ion Personal Genome Machine sequencer. DNA sequencing data were analyzed with Ion Reporter software. The human papillomavirus (HPV) status of the tumor samples was assessed with in situ hybridization, the MassARRAY HPV multiplex polymerase chain reaction assay, and p16 immunostaining. Mutation calls were compared among the studied groups. RESULTS: HIV-related HNSCC revealed a distinct pattern of mutations in comparison with non-HIV-related HNSCC. TP53 mutation frequencies were significantly lower in HIV-related HNSCC. Mutations in HIV+ patients tended to be TpC>T nucleotide changes for all mutated genes but especially for TP53. CONCLUSIONS: HNSCC in HIVIIs presents a distinct pattern of genetic mutations, particularly in the TP53 gene. HIV-related HNSCC may have a distinct biology, and an effect of the HIV virus on the pathogenesis of these tumors should not be ruled out. Cancer 2018;124:84-94. © 2017 American Cancer Society.
Asunto(s)
Carcinoma de Células Escamosas/genética , Infecciones por VIH/complicaciones , Neoplasias de Cabeza y Cuello/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Cadherinas/genética , Carcinoma de Células Escamosas/complicaciones , Estudios de Casos y Controles , Caspasa 8/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Ciclina D1/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Receptores ErbB/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Antígenos HLA-A/genética , Neoplasias de Cabeza y Cuello/complicaciones , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación in Situ , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteínas con Dominio LIM/genética , Masculino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/genética , Proteínas Nucleares/genética , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor Notch1/genética , Receptor Notch2/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3Δ/Δ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.
Asunto(s)
Células Epiteliales/metabolismo , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Factor de Transcripción STAT3/metabolismo , Caracteres Sexuales , Transducción de Señal , Animales , Femenino , Eliminación de Gen , Interleucina-6/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Ratones , Modelos Biológicos , Neutrófilos/metabolismo , Receptores de Estrógenos/metabolismo , Microambiente TumoralRESUMEN
The activity of many oncogenic proteins depends on the molecular chaperone Hsp90. Recent studies indicate that tumorigenesis is associated with increased expression of chaperones, such as Hsp90. However, little is known about the isoform dependence and cochaperone contribution on tumor formation. Here we report the first systematic expression profiling for Hsp90alpha and Hsp90beta, the cochaperones Aha1, Cdc37, p23, Tpr2, and the Hsp90 dependent transcription factor HSF1 in a set of different tumor tissue samples. We find that in 10 out of 17 human tumors the expression level of at least one Hsp90 or Hsp90 cochaperone protein is significantly elevated. However, individual tumors show unique patterns of expression. Furthermore, Hsp90alpha and Hsp90beta expression levels are not related. Our results suggest that expression profiling of Hsp90alpha and Hsp90beta and its cochaperone proteins may be useful for cancer diagnosis and prognosis as well as for tailoring of drugs that interfere with the Hsp90 system in a tumor specific manner.