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Le but de ce travail de thèse a été d’identifier par séquençage d’exomes, de nouveaux gènes de prédisposition dans 2 pathologies rares dont l’étiologie est peu connue. Le 1er projet a porté sur une famille à 3 cas de sarcomes, sans mutation du gène TP53. Nous avons identifié une mutation pathogénique du gène CDKN2A, dans les 3 cas. Le gène CDKN2A étant le gène majeur de prédisposition au mélanome, nous avons recherché parmi 3 collections différentes des cas de sarcomes associés à une mutation du gène CDKN2A. Nous avons identifié 8 cas de sarcomes indépendants, porteurs d’une mutation du gène CDKN2A et montré une perte d’hétérozygotie au niveau du site de la mutation constitutionnelle CDKN2A dans 5/7 cas, montrant ainsi une perte de fonction complète. Les sarcomes étant rares chez les porteurs de mutations CDKN2A, nous avons recherché des variants rares modificateurs potentiels, par séquençages d’exomes constitutionnels des 8 cas index, et identifié 3 variants du gène PDGFRA. Des études de modélisation ont montré que 2 de ces variants, pourraient avoir un impact sur la structure du domaine extracellulaire de la protéine PDGFRA. Nous avons ainsi démontré que le gène CDKN2A peut prédisposer aux sarcomes et identifié PDGFRA comme gène modificateur potentiel.Dans le second projet nous avons travaillé sur les mélanomes de l’enfant, d’apparence sporadique. Notre hypothèse de travail était que ces mélanomes surviennent suite à un accident génétique de novo. Nous avons analysé des exomes constitutionnels de 41 trios (enfant atteint et ses 2 parents sains). Nos analyses bio-informatiques ont montré l’existence de mutations de novo post-zygotiques de gènes impliqués dans le développement de la crête neurale ou le cancer, dans 5 cas. Les analyses plus complètes des exomes tumoraux sont en cours, ainsi que des études fonctionnelles des gènes et de leurs mutations, dans un modèle d’embryon de poulet. Ce travail permettra d’accroitre la compréhension des mécanismes moléculaires et cellulaires dérégulés dans ces maladies, ouvrant ainsi, de nouvelles perspectives thérapeutiques. / The aim of this thesis was to identify by sequencing of exomes new predisposing genes in 2 rare pathologies whose etiology is not well known.The first project involved a family with 3 cases of sarcomas, without mutation of TP53 gene. We identified a pathogenic mutation of the CDKN2A gene, in the 3 cases. Since CDKN2A gene is the major melanoma predisposing gene, we have searched in 3 different collections, sarcoma cases link to CDKN2A mutations. In total, we have identified 8 independent sarcomas cases, carrying a germline mutation of the CDKN2A gene and showed a loss of heterozygosity at the site of the constitutional mutation of CDKN2A in 5/7 cases, thus proving a complete loss of function. Since sarcomas are rare in carriers of CDKN2A mutations, we looked for potential modifying rare variants, by sequencing constitutional exomes of the 8 index cases, and identified 3 variants of the PDGFRA gene. Modeling studies have shown that 2 of these variants could have an impact on the structure of the extracellular domain of the PDGFRA protein. We have thus demonstrated that the CDKN2A gene can predispose to sarcomas and identified PDGFRA as a potential modifier gene. In the second project, we worked on childhood melanomas, of sporadic appearance. Our working hypothesis was that these melanomas occur as a result of a de novo genetic accident. We analyzed constitutional exomes of 41 trios (affected child and his 2 healthy parents). Our bioinformatics analyzes identified the existence of de novo post-zygotic mutations of genes involved in neural crest development or cancer, in 5 cases. More complete analyzes of tumor exomes are underway, as well as functional studies of genes and their mutations, in a chick embryo model.This work improves the understanding of molecular and cellular mechanisms that are deregulated in these diseases, thus opening up new therapeutic perspectives.

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京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第19632号 / 医科博第70号 / 新制||医科||5(附属図書館) / 32668 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 斎藤 通紀, 教授 小川 誠司, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13158号 / 論医博第2145号 / 新制||医||1029(附属図書館) / (主査)教授 川上 浩司, 教授 戸井 雅和, 教授 松田 秀一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Sarcoma cancer of the proximal femur is a bone tumor that develops near the hip joint. The most common method of treatment is limb salvage surgery (LLS), a highly invasive surgery that often leads to impaired movement including walking due to soft tissue resection. The current thesis focuses on 1) systematically reviewing current literature of functional outcomes after proximal femur LSS to determine if specific methods of muscle reattachment lead to better limb function, and 2) objectively analysing how reducing hip muscle strength impacts one’s ability to achieve healthy gait. Findings from the systematic review suggest using artificial mesh or ligaments for LLS may be a good alternative to allograft prosthesis composites and trochanter osteotomy, producing good functional outcomes with low rates of complications. It was also determined current literature is lacking objective quantitative analysis of patients’ limb function after surgery. Objective 2 was executed using instrumented gait analysis to record the gait kinematics, kinetics and EMG patterns of a patient who received LSS for proximal femur sarcoma. Data from the gait analysis was used to create a patient-specific musculoskeletal model. Healthy gait kinematics were applied to the model and specific hip muscle strengths were systematically reduced to simulate different surgical interventions. After an 85% reduction in gluteus medius and minimus muscle strength, healthy gait kinematics were not achieved. Reducing muscle strength of the gluteus medius and minimus together had a greater impact on the model’s ability to achieve healthy gait kinematics then when reduced individually. An understanding of how patient’s limb function is impacted after surgery can inform surgical technique, implant design and physiotherapy programs leading to better quality of life for patients after surgery. / Thesis / Master of Applied Science (MASc) / Hip reconstructive surgery as treatment for bone cancer is a highly invasive surgery that negatively impacts patients walking patterns and ultimately quality of life. The current thesis investigates existing literature to determine if specific, innovative surgical techniques lead to better functional results for patients after surgery. A three-dimensional model of a patient who had hip reconstruction surgery for bone cancer was created using quantitative analysis of their walking patterns. The model was manipulated to simulate surgical intervention for hip cancer treatment. The model findings suggest when specific hip muscles are substantially affected by surgery, patients walking patterns are negatively impacted. Understanding how surgical intervention impacts walking patterns can inform surgical technique, implant design and physiotherapy programs leading to better quality of life for patients after surgery.

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