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Identifying Genomic Biomarkers for Cancer Treatment

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Identifying Genomic Biomarkers for Cancer Treatment UNIVERSIDAD AUTÓNOMA DE MADRID Departamento de Bioquímica Doctoral Thesis Identifying genomic biomarkers for cancer treatment Sara Ruiz Pinto Madrid, 2017 Departamento de Bioquímica Facultad de Medicina Universidad Autónoma de Madrid Identifying genomic biomarkers for cancer treatment Doctoral Thesis submitted by: Sara Ruiz Pinto M.Sc. in Molecular Biomedicine from Universidad Autónoma de Madrid in Madrid B.Sc. in Biology from Universidad Complutense de Madrid in Madrid Thesis director: Dr. Anna González Neira Human Genotyping-CeGen Unit Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO) Dra. Anna González Neira, Jefa de la Unidad de Genotipado Humano-CeGen del Centro Nacional de Investigaciones Oncológicas (CNIO), como Directora CERTIFICA: Que Sara Ruiz Pinto, Licenciada en Biología por la Universidad Complutense de Madrid, ha realizado la presente Tesis Doctoral “Identifying genomic biomarkers for cancer treatment” y que a su juicio reúne plenamente todos los requisitos necesarios para optar al Grado de Doctor, a cuyos efectos será presentada en la Universidad Autónoma de Madrid, autorizando su presentación ante el Tribunal Calificador. Y para que así conste se extiende el presente certificado, Madrid, Enero 2017 VoBo de la Directora VoBo del Tutor Dra. Anna González Neira Dr. Sebastián Cerdán This Doctoral Thesis has been elaborated in the Human Genotyping-CeGen Unit at the Spanish National Cancer Research Centre (CNIO) in Madrid between 2012 and 2017 under the supervision of Dr. Anna González Neira. This work has been supported by the following grants and fellowships: Bancaja-Centre for Biomedical Network Research on Rare Diseases (CIBERER) ‘Becas Lanzadera’ (“Scholarship Shuttle”) fellowship, 2010-2011 Fundación Ramón Areces-Universidad Autónoma de Madrid M.Sc fellowship, 2010- 2011 Pediatric cancer research Project supported by Spanish Association Against Cancer (AECC), 2010-2013 Project PI12/00226 supported by Institute of Health Carlos III (ISCIII), 2013-2016 Severo Ochoa Excellence Programme (Project SEV-2011-191) PhD fellowship, 2014- 2017 A mis padres, a mi hermana y a Dani ACKNOWLEDGEMENTS Quisiera agradecer a todas las personas que han participado de una u otra manera en la realización de este trabajo de tesis doctoral comenzando por Anna González y terminando por el resto de los miembros, pasados y presentes, de la Unidad de Genotipado Humano-CeGen y del programa de Genética del Cáncer Humano del Centro Nacional de Investigaciones Oncológicas. ¡¡Ha sido un placer!! ¡¡Muchas gracias por acompañarme en este viaje!! En segundo lugar, pero no menos importante, muchas gracias a mis padres, a mi hermana y a Dani, a los que dedico este trabajo de tesis doctoral, porque lo más importante que tengo es vuestro afecto y vuestro apoyo incondicionales. ¡¡Muchas gracias!! ABSTRACT Abstract Patients vary widely in their response to medications. This is reflected in differences in treatment efficacy and toxicity and results in significant morbidity and mortality. The etiology of this observed variation is multifactorial, and can be explained in part by genetic factors. Gaining a better understanding of the relationship between human genetics and drug response is essential in cancer chemotherapy, as most chemotherapeutics have a narrow therapeutic window, and could lead to the development and adoption of personalized treatments. In this thesis we focused on the identification of germline genetic variants associated with treatment outcome in children diagnosed with Ewing sarcoma and risk of development of specific toxicities induced by the cytotoxic drug capecitabine (hand-foot syndrome) and by anthracyclines (chronic cardiotoxicity). Despite the effectiveness of current treatment protocols for Ewing sarcoma, the prognosis for patients with metastatic or refractory disease is dismal. The identification of genomic biomarkers of response and survival is therefore of major importance in order to optimize treatment for these patients. We studied the genetic variation across the genes involved in the transport and metabolism of drugs used in Ewing sarcoma. We identified and replicated associations with overall survival for three common variants located in the ABCC6, ABCB1 and CYP2C8 genes. Hand-foot syndrome is one of the most relevant dose-limiting adverse effects of capecitabine, experienced by more than 30% of patients and commonly leading to early discontinuation of capecitabine-based therapy. The few proven genetic markers of toxicity risk are variants involved in capecitabine biotransformation, but their predictive utility is uncertain. By combining genotyping-based genome-wide analysis and functional studies we identified a risk locus near the CDH4 gene, encoding R-cadherin, strongly associated with severe capecitabine-induced hand-foot syndrome occurrence and prompting changes in CDH4 gene expression, possibly through changes in chromatin topology. We also found that skin from patients who develop severe toxicity exhibited low levels of R-cadherin (highly expressed in the suprabasal granular layer of the epidermis) and involucrin (a component of the cornified envelope of the epidermis and essential for the skin barrier function) before capecitabine treatment. Anthracyclines, which are widely used chemotherapeutic drugs, can cause progressive and irreversible cardiac damage and fatal heart failure in children and in adult cancer patients; established risk factors have been proven insufficient to accurately stratify patients. We found novel associations for low-frequency coding variants in the GPR35 gene in pediatric oncology patients and in the ETFB and WISP1 genes in anthracycline-treated patients, independently of age at diagnosis. The studies performed as part of this thesis provide clear evidence that genetic variants could be used as predictors of drug efficacy and adverse drug reactions and could therefore be informative in the design of personalized cancer therapy. 17 RESUMEN Resumen Es bien conocida la existencia de importantes diferencias interindividuales en la respuesta a la mayoría de los medicamentos, pero dicha variabilidad es de especial relevancia en oncología, ya que el cáncer es una de las principales causas de morbilidad y mortalidad y puesto que los antineoplásicos presentan un índice terapéutico muy estrecho. Aunque dicha variabilidad puede ser atribuida a diferentes factores, la variación genética se postula como uno de los factores más importantes. En esta tesis doctoral nos hemos centrado en la identificación de variantes genéticas asociadas a respuesta tumoral, supervivencia y efectos adversos en pacientes oncológicos. A pesar de la eficacia de los tratamientos actuales para el sarcoma de Ewing, el pronóstico para aquellos pacientes con enfermedad metastásica y refractaria es desfavorable. Por tanto, la identificación de variantes genéticas predictivas y pronósticas resulta esencial para optimizar el tratamiento en dichos pacientes. Con este objetivo estudiamos variantes genéticas en aquellos genes implicados en el transporte y metabolismo de los fármacos más comúnmente utilizados en el tratamiento del sarcoma de Ewing e identificamos tres variantes comunes en los genes ABCC6, ABCB1 y CYP2C8 asociadas con la supervivencia de estos pacientes. El síndrome mano-pie es el más común de los afectos adversos producidos por la capecitabina, afectando a más de un 30% de los pacientes. Su aparición conlleva graves consecuencias clínicas ya que obliga a reducir la dosis o incluso a la suspensión del tratamiento. Los marcadores genéticos identificados hasta la fecha se encuentran involucrados en su totalidad en el proceso de biotransformación de la capecitabina y su utilidad predictiva es incierta. La combinación de un estudio de asociación del genoma completo junto con estudios funcionales nos ha permitido la identificación de un locus de susceptibilidad a este efecto adverso. Este locus regula la expresión del gen CDH4, probablemente mediante alteraciones en la topología de la cromatina. Además encontramos que aquellos pacientes que sufren una toxicidad más severa presentan en su piel reducidos niveles de la proteína que codifica CDH4, R-cadherina (altamente expresada en el estrato granuloso de la epidermis) y de involucrina (proteína del estrato cornificado esencial para la función de barrera de la epidermis). El tratamiento con antraciclinas produce efectos cardiotóxicos irreversibles e incluso fatales tanto en niños como en adultos y los factores de riesgo identificados hasta la fecha se han mostrado insuficientes para la estratificación de los pacientes. En esta tesis hemos encontrado nuevas variantes poco frecuentes asociadas a cardiotoxicidad en los genes GPR35 en pacientes oncológicos infantiles, y ETFB y WISP1 independientemente de la edad de diagnóstico. Todos los resultados obtenidos en esta tesis doctoral suponen una clara evidencia del importante papel que juega la variación genética en las diferencias interindividuales observadas tanto en la eficacia como en la toxicidad de los quimioterapéuticos y por tanto, podrían ser utilizados en el futuro en el diseño de una medicina individualizada en estos pacientes. 21 TABLE OF CONTENTS Table of contents ABSTRACT ............................................................................................................... 15 RESUMEN ............................................................................................................... 19 TABLE OF CONTENTS ..............................................................................................
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