5 research outputs found
Clinical and genetic characterization of 145 spanish patients diagnosed with PTEN hamartoma tumor syndrome
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 20-01-2020Esta tesis tiene embargado el acceso al texto completo hasta el 20-07-2021The PTEN hamartoma tumor syndrome (PHTS) is a rare disease characterized by a large phenotypic variability of benign lesions together with a high predisposition to develop several cancer types (breast, thyroid, endometrial, renal, colorectal and melanoma). This hereditary syndrome is associated to germline mutations in the PTEN gene, although a considerable proportion of patients are not explained by this gene. Altogether, this results in the lack of awareness on the PHTS, underdiagnosis and poor management of these patients.
The first general objective is to characterize the disease in Spanish patients, both at a genetic level and at a clinical level, together with the comparison of our results with that obtained in other studied populations and the evaluation of the usefulness of the diagnostic criteria. The second objective is to look for other genetic factors that can be involved in the phenotype of the PHTS patients who do not harbor PTEN mutations.
To accomplish these objectives, we have gathered a series of 145 Spanish patients diagnosed with PHTS with their respective clinical information and biological samples. The use of a specific checklist allowed us to review the clinical features of interest, and the use of conventional genetic techniques (Sanger, MLPA, aCGH), together with high-throughput procedures (NGS and WES) enabled the molecular characterization, focusing not only in PTEN but also searching for other genes. Moreover, the functional studies gave insights into the implications in pathogenicity of different variants of unknown significance in PTEN.
The results of this work were used to state several recommendations for the diagnosis: the application of the most useful clinical features to drive genetic testing and the performance of this through multigene panels to detect other possibly altered genes that might confer additional clinical risks. Regarding the follow-up, it is relevant to do obesity check-ups and to anticipate the cancer screenings. Moreover, several findings of this study set the basis for future research.
Overall, this work contributes to accelerate and improve the diagnosis and patient care of the PHTS patients.El síndrome de PTEN-tumores hamartomatosos (PHTS) es una enfermedad rara que se caracteriza por una gran variabilidad fenotípica que incluye lesiones benignas, pero también una alta predisposición a desarrollar varios tipos de cáncer (cáncer de mama, tiroides, endometrio, renal, colorrectal y melanoma). Este síndrome hereditario se asocia a mutaciones germinales en el gen PTEN, aunque una proporción considerable de pacientes no pueden explicarse por este gen. Todo ello resulta en el desconocimiento de esta enfermedad, la falta de diagnóstico y el mal manejo de estos pacientes.
Los objetivos generales de este proyecto son, en primer lugar, caracterizar la enfermedad en pacientes españoles, tanto a nivel genético como clínico, comparar nuestros hallazgos con los obtenido en otras poblaciones y evaluar la utilidad de los criterios diagnóstico; y en segundo lugar, la búsqueda de otros factores que puedan estar implicados en el fenotipo PHTS de los pacientes que no portan mutaciones en PTEN.
Para llevar a cabo estos objetivos, hemos reunido una serie de 145 pacientes españoles diagnosticados con PHTS, con su respectiva información clínica y muestras biológicas. El uso de un cuestionario específico nos permitió revisar las manifestaciones clínicas de interés, y el empleo de técnicas genéticas convencionales (Sanger, MLPA, aCGH), junto con técnicas de mayor rendimiento (NGS y WES) ha permitido la caracterización molecular, centrada no sólo en PTEN sino también en la búsqueda de otros genes. Además, los estudios funcionales han arrojado luz acerca de las implicaciones deletéreas de diferentes variantes de significado incierto en PTEN.
Los resultados de este trabajo se han empleado para proponer varias recomendaciones para el diagnóstico: el empleo de las manifestaciones clínicas más útiles para derivar al paciente para estudio genético, y realizar este mediante paneles de genes que permitan detectar otros posibles genes alterados que confieran riesgos clínicos añadidos. De cara al seguimiento de los pacientes, es relevante el control del peso y anticipar las revisiones para la detección precoz de cáncer. Por otra parte, varios hallazgos de nuestro trabajo sientan las bases para continuar investigando en esta enfermedad.
En resumen, este trabajo contribuye a acelerar y mejorar el diagnóstico y la atención de los pacientes con PHTS.This doctoral thesis has been elaborated in the Familial Cancer Clinical Unit at the Spanish National Cancer Research Centre (CNIO) in Madrid under the supervision of Dr. Miguel Urioste Azcorra.
The following grants and fellowships supported this work:
- Fondo de Investigaciones Sanitarias (FIS) project PI14/00459, funded by the Spanish Ministerio de Economía y Competitividad (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER).
- Short contract funded by donation through Federación Española de Enfermedades Raras (FEDER).
- Severo Ochoa Excellence Programme PhD fellowship (BES-2015-071383) 2015-2019, funded by MINECO and the European Social Fund (ESF)
Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers
We thank the Tumor Registry of the Pathology Department of the 12 de Octubre University Hospital for
providing the paraffin-embedded tissues, and Ron Hartong for his help with the English revision of this
manuscript. This work was funded by Projects PI10/00683 and PI16/01650 to J.P, and PI16/01920 to R.G.S, from
the Spanish Ministry of Health and Consumer Affairs and FEDER, and by Project 2012-0036 from the Mutua Madrileña Foundation. This work was supported by R01 (CA72851, CA181572, CA184792, CA202797) and U01 (CA187956, CA214254) grants from the National Cancer Institute, NIH; RP140784 from the CancerPrevention Research Institute of Texas; grants from the Baylor Foundation and Baylor Scott & White Research Institute, Dallas, TX, USA to AG.Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.S
Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome clinical and genetic study in a series of Spanish patients
Background
The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease.
Results
We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research.
Conclusions
This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines
Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome: clinical and genetic study in a series of Spanish patients.
The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease. We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research. This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines
Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome : clinical and genetic study in a series of Spanish patients
Altres ajuts: European Regional Development Fund; Federación Española de Enfermedades Raras (FEDER); European Social Fund (ESF).Background: The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease. Results: We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research. Conclusions: This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines