RESUMEN
Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma/genética , Genómica , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Australia , Biomarcadores de Tumor/análisis , Canadá , Carcinoma/química , Carcinoma/patología , Carcinoma/terapia , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Mutación , Clasificación del Tumor , Neoplasias Quísticas, Mucinosas y Serosas/química , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Quísticas, Mucinosas y Serosas/terapia , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Fenotipo , Resultado del Tratamiento , Ubiquitina Tiolesterasa/genética , Secuenciación del ExomaRESUMEN
Introducción: Las pérdidas auditivas son heredables en un 50-60% de los casos. Dentro de estas, las sorderas no sindrómicas predominan y se han descrito más de 40 genes asociados. Uno de los más frecuentemente implicados es el gen de Otoferlina(OTO F). Objetivo: Determinar la frecuencia de la mutación p.Q829X en el gen OTO F en 649 individuos colombianos con sordera no sindrómica. Materiales y métodos: Se seleccionó una población de 649 individuos para realizar la búsqueda de la mutación p.Q829X por medio de la técnica PCR-RFLP. Resultados: Se identificaron 12 individuos con la mutación p.Q829X (12/649), quecorresponden a una frecuencia del 1,8%. Conclusiones: La mutación p.Q829X es la más frecuente en el gen OTO F, y la tercera luego de las mutaciones S199F y 35delG en el gen GJB2, causantes de sordera en la población analizada. Se observó variabilidad en el grado de pérdida auditiva en los individuos homocigotos para la mutación y presencia deneuropatía auditiva en el 62,5% de estos casos...
Introduction: Hearing loss is 50-60 % heritable. Among this, non-syndromic hearing loss is predominant and more than 40 genes have been reported. One of the most frequently involved is OTO F gene. Objective: To identify the frequency of mutation p.Q829X in OTO F gene, in 649 Colombian individuals with non-syndromic deafness. Materials and Methods: A total of 649 individuals were selected and screened for p.Q829X mutation using PCR-RFLP analysis. Results: p.Q829X mutation was identified in 12 deaf individuals (12/649) corresponding to a frequencyof 1,8%. Conclusions: p.Q829X mutation is the most common in OTO F gene, and the third cause after S199F and 35delG mutations in GJB2 gene, ofdeafness in the analyzed population. Variability is observed in the degree of hearing loss in individuals homozygous for the mutation and auditoryneuropathy is present in 62,5% of these cases...
