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Follicular lymphoma (FL) is an attractive model for discovering biomarkers and elucidating mechanisms of tumour progression. We hypothesized that alterations in the expression of proteins with known roles in cancer biology and hematological cells might correlate with clinical outcome and thereby shed light on biological mechanisms. Sections from a tissue microarray (TMA) containing FL samples from 67 patients were immunostained for candidate biomarkers, including p53, p16INK4a, Bcl-2, Bcl-6, MUM1, PML, phospho-ERK, and p27Kip1. The Kaplan-Meier method and log-rank test were used to identify markers that correlate significantly (p<0.05) with overall survival (OS). The chi-squared or Fisher exact test were used to examine associations between histological markers and baseline clinical features, including the Follicular Lymphoma International Prognostic Index (FLIPI) score. Expression of p16INK4a or p53, or absent CD10 expression correlated with poor survival. Patients with p16INK4a-negative tumours had a median OS of 13.4 years compared to 8.3 years for those with p16INK4a-positive tumours (p=0.006). Expression of p16INK4a was significantly associated with low hemoglobin, elevated serum lactate dehydrogenase (LDH), high histological grade, high cell proliferation index, presence of associated diffuse large B-cell lymphoma (DLBCL) and high-risk FLIPI classification. Our observation of a positive association between p16INK4a expression and indicators of tumour aggressiveness is novel and perhaps surprising since loss of the INK4a tumour suppressor gene is one of the most frequently observed lesions in human cancers, including lymphoma. Expression of p16INK4a may be part of a cellular response to unidentified pro-mitotic mutations, such as deleterious mutations of the RB tumour suppressor gene, associated with more aggressive instances of FL. Immunostaining FL diagnostic biopsies for expression of p16INK4a may serve as an informative prognostic biomarker to aid clinicians managing FL patients. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-07-04 15:55:16.121

Treatment decision making (TDM) in oncology is complex. Understanding treatment information is essential for shared TDM. Research suggests many patients have low numeracy. This mixed methods study explored numeracy and experience with numbers in a sample of individuals diagnosed with follicular lymphoma. Participants completed questionnaires (N = 32) and interviews (N = 20) assessing numeracy, decisional conflict and regret, and number preference. Results suggest that mean objective numeracy was relatively high, and most reported high confidence in numerical ability. Most participants preferred to receive numbers during the TDM process. There was no relationship between numeracy and decision outcomes. Future research should investigate the use of numeracy measures in practice and the impact of patient preferences and beliefs on shared TDM.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL). FL is clinically designated as an indolent disease with a long median survival of 8-10 years. However, the clinical and biological behavior of FL shows considerable variability, with some patients showing aggressive disease progression and very short survival. Because defects in the regulation of apoptotic cell death are fundamental in FL pathogenesis, we hypothesized that deregulated expression of components of the pRb signaling pathway may promote cell proliferation, thereby complementing antecedent anti-apoptotic mutations and producing more aggressive disease. In the present study we undertook an immunohistochemical (IHC) evaluation of expression of key cell-cycle regulatory proteins in diagnostic biopsies from 127 cases of FL using formalin-fixed, paraffin-embedded tissues (FFPE) in tissue microarray (TMA) sections immunostained for p53, pRb, p16INK4A and cyclin D3. Data analysis revealed that increased abundance of p53 or p16INK4A is associated with reduced overall survival (OS) (p=0.005 and p=0.014 respectively), and with conventional pathological markers of tumour aggressiveness including high histologic grade. Encouraged by this remarkable finding of a counterintuitive association between p16INK4A expression and clinical outcome, we analyzed CDKN2A gene deletion and methylation, as these are the most frequent mechanisms of the CDKN2A gene inactivation in NHL including FL. We determined the deletion and methylation status of CDKN2A in 105 FL cases. Laser-capture microdissection was used to enrich the samples for lymphoma cells. CDKN2A was deleted in 9 cases and methylated in 22 cases. The 29 cases (28%) with CDKN2A deletion or methylation had decreased overall survival (OS) (p=0.046) in all cases and in cases treated with rituximab (p<0.001). Our findings indicate that deleterious alterations of CDKN2A are relatively prevalent in FL at diagnosis and can predict poor clinical outcome. In summary, our data reveal novel insights into the pathogenesis of FL and suggest a relationship between increased p16INK4A expression and CDKN2A deletion or methylation and unfavorable clinical outcome in FL. We hope that the work presented herein will provide a useful prognostic tool for predicting the prognosis and choosing optimal treatment approaches to help patients suffering from FL. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-03-12 23:49:44.541

O linfoma folicular é entidade clinicamente heterogênea, com carência de marcadores prognósticos que estratifiquem grupos de risco para otimização do manejo. É relativamente raro em pacientes abaixo de 40 anos. Os aspectos clínicos e patológicos desse tipo de linfoma, nessa faixa etária, assim como o comportamento biológico, são pouco conhecidos. No presente estudo, uma série de 208 pacientes entre 19-40 anos de idade foi, retrospectivamente, avaliada quanto aos achados anatomoclínicos e moleculares. Essas variáveis foram, então, correlacionadas com seguimento e sobrevida. A mediana de idade na apresentação foi de 35 anos, com leve predomínio no sexo feminino (56%). A maioria dos casos se manifestou como doença nodal (87%). Concomitância de linfoma folicular com linfoma difuso de grandes células B foi encontrada em 7 (3%) pacientes. Estudos imuno-histoquímicos revelaram expressão de CD10 (91%), BCL6 (97%), BCL2 (95%), MUM1/IRF4 (17%) e CD23 (25%). Rearranjos envolvendo os genes BCL2 e BCL6 foram encontrados em 74% e 20%, respectivamente. A sobrevida média geral estimada dos pacientes, em que foi possível o seguimento, foi de 13 anos. Presença de anemia, elevação da desidrogenase lática, acometimento de medula óssea, índice prognóstico internacional do linfoma folicular na faixa de alto risco, padrão de \"céu estrelado\", Ki-67 >= 50% e ausência do rearranjo do gene BCL2 e presença do BCL6 relacionaram-se diretamente com pior sobrevida geral. O estadiamento de Ann Arbor III/IV e MDM2 >=20% têm fortes indícios desta associação negativa com sobrevida geral. A combinação BCL2+ e BCL6- correlacionou-se com maior sobrevida média. O grau histológico determinou redução gradual da sobrevida, com semelhanças nas curvas de sobrevida entre os graus 1, 2 e 3A. Não houve diferença significativa para as curvas de sobrevida relacionando faixa etária, persistência da zona do manto, presença de áreas difusas, fibrose, expressão de CD10, BCL6 ou CD23, padrão de trama de células foliculares dendríticas ou clonalidade para cadeia leve de imunoglobulina. Esses achados revelaram que o linfoma folicular em adultos jovens apresenta similaridades com o linfoma folicular que ocorre em adultos mais velhos, incluindo a frequência de apresentação nos diversos sítios anatômicos, grau histológico e fatores prognósticos adversos / Follicular lymphoma is a clinically heterogeneous group of disease and therefore with a need of characterization of prognostic markers to stratify risk groups and to optimize clinical management. It is relatively rare in patients younger than 40 years, and the clinicopathologic characteristics and biological behavior in this age group are poorly understood. In the current study, samples from a cohort of 208 patients between 19-40 years of age were evaluated retrospectively with respect to clinical, histologic and molecular characteristics. These findings were then correlated with the follow up and the clinical outcome. The median age at presentation was 35 years with a slight female preponderance (56%). Most of the cases presented with nodal disease (87%). Concomitant follicular lymphoma and diffuse large B-cell lymphoma was observed in 7 (3%) patients. Immunohistological studies showed the expression in the following frequency: CD10 (91%), BCL6 (97%), BCL2 (95%), MUM1/IRF4 (12%), MDM2 (17%) and CD23 (25%). BCL2 and BCL6 rearrangements were present in 74%, and 20%, respectively. The estimated overall survival of patients was 13 years (mean). The presence of anemia, elevated lactose dehydrogenase, bone marrow involvement, high-risk follicular lymphoma international prognostic index, \"starry sky\" appearance, proliferative index >= 50%, absence of BCL2 rearrangement and presence of BCL6 rearrangement correlated with adverse overall outcome. Ann Arbor stage III/IV and MDM2 >= 20% correlated with high trend toward worse overall survival. The combination BCL2+ and BCL6- was associated with better overall survival. No impact on overall survival was observed related to age, persistence of mantle zone, presence of diffuse areas, fibrosis, expression. of CD10, BCL6 or CD23, follicular dendritic cells meshwork or clonality. These findings revealed that follicular lymphoma in young adults demonstrate similarities with that of older adults, including the frequency of presentation at various anatomic sites, grade, and adverse prognostic factors

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

O linfoma folicular é entidade clinicamente heterogênea, com carência de marcadores prognósticos que estratifiquem grupos de risco para otimização do manejo. É relativamente raro em pacientes abaixo de 40 anos. Os aspectos clínicos e patológicos desse tipo de linfoma, nessa faixa etária, assim como o comportamento biológico, são pouco conhecidos. No presente estudo, uma série de 208 pacientes entre 19-40 anos de idade foi, retrospectivamente, avaliada quanto aos achados anatomoclínicos e moleculares. Essas variáveis foram, então, correlacionadas com seguimento e sobrevida. A mediana de idade na apresentação foi de 35 anos, com leve predomínio no sexo feminino (56%). A maioria dos casos se manifestou como doença nodal (87%). Concomitância de linfoma folicular com linfoma difuso de grandes células B foi encontrada em 7 (3%) pacientes. Estudos imuno-histoquímicos revelaram expressão de CD10 (91%), BCL6 (97%), BCL2 (95%), MUM1/IRF4 (17%) e CD23 (25%). Rearranjos envolvendo os genes BCL2 e BCL6 foram encontrados em 74% e 20%, respectivamente. A sobrevida média geral estimada dos pacientes, em que foi possível o seguimento, foi de 13 anos. Presença de anemia, elevação da desidrogenase lática, acometimento de medula óssea, índice prognóstico internacional do linfoma folicular na faixa de alto risco, padrão de \"céu estrelado\", Ki-67 >= 50% e ausência do rearranjo do gene BCL2 e presença do BCL6 relacionaram-se diretamente com pior sobrevida geral. O estadiamento de Ann Arbor III/IV e MDM2 >=20% têm fortes indícios desta associação negativa com sobrevida geral. A combinação BCL2+ e BCL6- correlacionou-se com maior sobrevida média. O grau histológico determinou redução gradual da sobrevida, com semelhanças nas curvas de sobrevida entre os graus 1, 2 e 3A. Não houve diferença significativa para as curvas de sobrevida relacionando faixa etária, persistência da zona do manto, presença de áreas difusas, fibrose, expressão de CD10, BCL6 ou CD23, padrão de trama de células foliculares dendríticas ou clonalidade para cadeia leve de imunoglobulina. Esses achados revelaram que o linfoma folicular em adultos jovens apresenta similaridades com o linfoma folicular que ocorre em adultos mais velhos, incluindo a frequência de apresentação nos diversos sítios anatômicos, grau histológico e fatores prognósticos adversos / Follicular lymphoma is a clinically heterogeneous group of disease and therefore with a need of characterization of prognostic markers to stratify risk groups and to optimize clinical management. It is relatively rare in patients younger than 40 years, and the clinicopathologic characteristics and biological behavior in this age group are poorly understood. In the current study, samples from a cohort of 208 patients between 19-40 years of age were evaluated retrospectively with respect to clinical, histologic and molecular characteristics. These findings were then correlated with the follow up and the clinical outcome. The median age at presentation was 35 years with a slight female preponderance (56%). Most of the cases presented with nodal disease (87%). Concomitant follicular lymphoma and diffuse large B-cell lymphoma was observed in 7 (3%) patients. Immunohistological studies showed the expression in the following frequency: CD10 (91%), BCL6 (97%), BCL2 (95%), MUM1/IRF4 (12%), MDM2 (17%) and CD23 (25%). BCL2 and BCL6 rearrangements were present in 74%, and 20%, respectively. The estimated overall survival of patients was 13 years (mean). The presence of anemia, elevated lactose dehydrogenase, bone marrow involvement, high-risk follicular lymphoma international prognostic index, \"starry sky\" appearance, proliferative index >= 50%, absence of BCL2 rearrangement and presence of BCL6 rearrangement correlated with adverse overall outcome. Ann Arbor stage III/IV and MDM2 >= 20% correlated with high trend toward worse overall survival. The combination BCL2+ and BCL6- was associated with better overall survival. No impact on overall survival was observed related to age, persistence of mantle zone, presence of diffuse areas, fibrosis, expression. of CD10, BCL6 or CD23, follicular dendritic cells meshwork or clonality. These findings revealed that follicular lymphoma in young adults demonstrate similarities with that of older adults, including the frequency of presentation at various anatomic sites, grade, and adverse prognostic factors

Ce travail a eu pour objectif de proposer des modèles conjoints d'intensités de processus d'événements récurrents et d'un événement terminal dépendant. Nous montrons que l'analyse séparée de ces événements conduit à des biais d'estimation importants. C'est pourquoi il est nécessaire de prendre en compte les dépendances entre les différents événements d'intérêt. Nous avons choisi de modéliser ces dépendances en introduisant des effets aléatoires (ou fragilités) et de travailler sur la structure de dépendance. Ces effets aléatoires prennent en compte les dépendances entre événements, les dépendances inter-récurrences et l'hétérogénéité non-observée. Nous avons, en premier lieu, développé un modèle conjoint à fragilités pour un type d'événement récurrent et un événement terminal dépendant en introduisant deux effets aléatoires indépendants pour prendre en compte et distinguer la dépendance inter-récurrences et celle entre les risques d'événements récurrents et terminal. Ce modèle a été ajusté pour des données de patients atteints de lymphome folliculaire où les événements d'intérêt sont les rechutes et le décès. Le second modèle développé permet de modéliser conjointement deux types d'événements récurrents et un événement terminal dépendant en introduisant deux effets aléatoires corrélés et deux paramètres de flexibilités. Ce modèle s'avère adapté pour l'analyse des risques de récidives locorégionales, de récidives métastatiques et de décès chez des patientes atteintes de cancer du sein. Nous confirmons ainsi que le décès est lié aux récidives métastatiques mais pas aux récidives locorégionales tandis que les deux types de récidives sont liés. Cependant ces approches font l'hypothèse de proportionnalité des intensités conditionnellement aux fragilités, que nous allons tenter d'assouplir. Dans un troisième travail, nous proposons de modéliser un effet potentiellement dépendant du temps des covariables en utilisant des fonctions B-Splines. / This work aimed to propose joint models for recurrent events and a dependent terminal event. We show how separate analyses of these events could lead to important biases. That is why it seems necessary to take into account the dependencies between events of interest. We choose to model these dependencies through random effects (or frailties) and work on the dependence structure. These random effects account for dependencies between events, inter-dependence recurrences and unobserved heterogeneity. We first have developed a joint frailty model for one type of recurrent events and a dependent terminal event with two independent random effects to take into account and distinguish the inter-recurrence dependence and between recurrent events and terminal event. This model was applied to follicular lymphoma patient’s data where events of interest are relapses and death. The second proposed model is used to model jointly two types of recurrent events and a dependent terminal event by introducing two correlated random effects and two flexible parameters. This model is suitable for analysis of locoregional recurrences, metastatic recurrences and death for breast cancer patients. It confirms that the death is related to metastatic recurrence but not locoregional recurrence while both types of recurrences are related. However, these approaches do the assumption of proportional intensities conditionally on frailties, which we want to relax. In a third study, we propose to model potentially time-dependent regression coefficient using B-splines functions.

Le lymphome folliculaire (LF) représente le 2ème lymphome par ordre de fréquence et reste considéré à l’heure actuelle comme incurable. De nombreuses questions sur le processus de lymphomagénèse sont encore non résolues et il n’existe aucun marqueur génomique ou moléculaire unanimement reconnu permettant de prédire l’évolution des patients. Nos travaux de recherche s’inscrivent dans l’objectif de mieux comprendre l’impact des altérations moléculaires identifiées dans ces tumeurs, grâce à une approche intégrative visant à combiner des données génomiques, transcriptomiques et mutationnelles. Ce travail a permis de construire un score, basé sur l’expression d’un panel de gènes, prédictif du risque de progression de la maladie. Ce score a été confirmé sur une seconde cohorte de patients, validant son utilité potentielle en pratique clinique. Par ailleurs, nos résultats suggèrent que les cellules tumorales peuvent acquérir des propriétés évocatrices d’un profil de cellules souches et associées à un pronostic particulièrement défavorable. Une 2ème partie de notre travail a porté sur les altérations touchant le gène EZH2, muté chez 25% des patients. Nous avons démontré qu’un gain génomique au niveau du locus EZH2 pouvait également avoir des conséquences sur le profil transcriptomique et un impact pronostique, soulignant l’importance de prendre en compte l’ensemble des anomalies touchant ce gène. Enfin, nous rapportons qu’un polymorphisme constitutionnel situé dans ce gène est associé au risque de progression des patients traités par un anticorps anti-CD20. L’ensemble de ces résultats apporte un éclairage nouveau sur la biologie du LF et peut contribuer à améliorer la prise en charge des patients / Follicular Lymphoma (FL) is the 2nd most frequent lymphoma subtype and is usually considered incurable with current strategies. Several questions regarding the lymphomagenesis process are still pending, and no molecular or genomic marker has been unanimously recognized yet to predict outcome. We performed an integrative analysis combining genomic, transcriptomic and mutational data in the view to bringing new highlights in the molecular alterations acting in FL. Based on gene-expression profiling data we developed a model able to predict progression-free survival in FL patients. We confirmed its predictive value in another cohort of patients, thereby allowing its potential use in clinical practice. Furthermore, our results highlight that some tumors show a stem-cell-like gene-expression profile that was associated with highly unfavorable outcome. In the second part of our work, we focused on alterations of the gene EZH2. Although mutations have been reported in 25% of FL patients, we questioned whether genomic gains at EZH2 locus could also contribute to lymphomagenesis. We showed that such gain may impact the transcriptional profile and have a prognostic significance, thus highlighting the crucial interest of determining both kinds of alterations. Finally, we report that a germ-line polyporphism in the EZH2 gene was significantly associated with progression-free survival in patients treated by anti-CD20 therapy. Taken together, these results bring new highlights on FL biology and may help to improve the clinical management of FL patients