RESUMEN
Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Australia , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patologíaRESUMEN
Phaeochromocytomas (PCs) are tumours of the adrenal medulla chromaffin cells. Paragangliomas (PGLs) arise in sympathetic ganglia (previously called extra-adrenal PCs) or in non-chromaffin parasympathetic ganglia cells that are usually non-secretory. Parenchymal cells from these tumours have a common embryological origin from neural crest ectoderm. Several case series of canine PCs and PGLs have been published and a link between the increased incidence of chemoreceptor neoplasia in brachycephalic dog breeds and chronic hypoxia has been postulated. A similar link to hypoxia in man led to the identification of germline heterozygous mutations in the gene encoding succinate dehydrogenase subunit D (SDHD) and subsequently SDHA, SDHB and SDHC in similar tumours. We investigated canine PCs (n = 6) and PGLs (n = 2) for SDHD and SDHB mutations and in one PGL found a somatic SDHD mutation c.365A>G (p.Lys122Arg) in exon 4, which was not present in normal tissue from this brachycephalic dog. Two PCs were heterozygous for both c.365A>G (p.Lys122Arg) mutation and an exon 3 silent variant c.291G>A. We also identified the heterozygous SDHB exon 2 mutation c.113G>A (p.Arg38Gln) in a PC. These results illustrate that genetic mutations may underlie tumourigenesis in canine PCs and PGLs. The spontaneous nature of these canine diseases and possible association of PGLs with hypoxia in brachycephalic breeds may make them an attractive model for studying the corresponding human tumours.
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Neoplasias de las Glándulas Suprarrenales/veterinaria , Enfermedades de los Perros/genética , Feocromocitoma/veterinaria , Succinato Deshidrogenasa/genética , Neoplasias de las Glándulas Suprarrenales/genética , Animales , Análisis Mutacional de ADN , Perros , Paraganglioma Extraadrenal/genética , Paraganglioma Extraadrenal/veterinaria , Feocromocitoma/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.
Asunto(s)
Hiperparatiroidismo Primario/genética , Hiperparatiroidismo Primario/cirugía , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/prevención & control , Paratiroidectomía , Análisis Mutacional de ADN , Pruebas Genéticas , Humanos , Glándulas Paratiroides/patología , Medición de Riesgo , SíndromeRESUMEN
This study reports, for the first time, the carrier frequency of Canavan disease in the Ashkenazi Jewish population in Australia, and the identification of a novel mutation in the ASPA gene.
Asunto(s)
Enfermedad de Canavan/diagnóstico , Enfermedad de Canavan/genética , Pruebas Genéticas , Australia , Tamización de Portadores Genéticos , Humanos , Judíos/genética , Mutación PuntualRESUMEN
BACKGROUND: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis. METHODS: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. RESULTS: HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. CONCLUSIONS: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
Asunto(s)
Neoplasias de las Paratiroides/genética , Proteínas/genética , Adulto , Anciano , Distribución de Chi-Cuadrado , Cromosomas Humanos Par 1/genética , Análisis Mutacional de ADN , ADN Complementario/química , ADN Complementario/genética , ADN de Neoplasias/química , ADN de Neoplasias/genética , Salud de la Familia , Femenino , Humanos , Hiperparatiroidismo/genética , Pérdida de Heterocigocidad , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Mutación , Neoplasias de las Paratiroides/patología , Polimorfismo Genético , Síndrome , Proteínas Supresoras de TumorRESUMEN
OBJECTIVES: To determine the frequency of heterozygous carriers of the Tay-Sachs disease gene in an asymptomatic Ashkenazi Jewish population and to compare the acceptability of different community testing strategies. DESIGN: Pilot survey of carrier rates and community attitudes. SETTING: Sydney, February 1993 to November 1994. PARTICIPANTS: 147 self- or medically referred people of Ashkenazi Jewish origin were tested. Jewish religious, medical and community organisations and leaders were consulted. OUTCOMES: Prevalence of HEXA mutations, client and community preference for different testing and reporting strategies. RESULTS: Frequency of heterozygous carriers was 1 in 18, with a relative frequency of the three major allelic variants similar to that in overseas studies. Most subjects were medically referred and preferred individual reporting of their carrier status. Community representatives had serious reservations about this strategy and few orthodox Jews participated in the study. An alternative strategy was developed for future testing. CONCLUSIONS: Frequency of heterozygous carriers of the Tay-Sachs disease gene was higher than found among Ashkenazi Jews in other countries, possibly because of ascertainment bias. A testing strategy with medical referral and individual reporting of carrier status may not be appropriate for all the community at risk and a modified strategy is necessary.