Background: When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation-negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation-positive to actual mutation-negative. This study was designed to explore cancer risk perception and the experience of being a mutation-negative woman within a known BRCA1/2 mutation-positive family. Methods: We employed a qualitative descriptive design and convened a sample of 13 women who contributed in-depth, semi-structured telephone interviews (audio-recorded and transcribed verbatim) and performed qualitative content analysis with NVivo 2.0 software. Results: Six major content areas emerged from interview data: (i) rationale for initial involvement in the breast imaging study, (ii) rationale for continued participation, (iii) experience of living in a multiple-case family, (iv) risk perception: the personal meaning of mutation-negative status, (v) opinions regarding cancer aetiology and (vi) communication patterns between mutation-negative and mutation-positive family members. Conclusions: Living in a hereditary breast and ovarian cancer family is a complex experience that affects cognitive, emotional and social functioning. Our findings indicate that mutation-negative women may have unmet psychosocial needs that must be addressed by health-care professionals, particularly in the primary-care setting following genetic disclosure of a potentially reassuring result regarding their lack of the very high cancer risks associated with BRCA1/2 mutations.

Les thrombocytoses correspondent à une élévation du taux de plaquettes au-delà de 450x109/L et sont soit réactionnelles dans la plupart des cas, soit primitives quand il existe une altération génétique sur la voie de la production plaquettaire. Dans ce dernier cas il est habituel de distinguer les thrombocytoses sporadiques des thrombocytoses familiales, qui partagent néanmoins un mécanisme physiopathologique commun à l’image de la mutation MPLS505N résultant en une activation constitutive du récepteur. En effet les thrombocytémies essentielles (TE), les plus fréquentes, présentent une mutation activatrice dans 85% des cas soit de JAK2, de CALR ou MPL. Les thrombocytoses héréditaires quant à elles peuvent être la conséquence de mutations de MPL, de JAK2 ou de la TPO. Nous avons étudié dans un premier temps la mutation MPLP106L décrite chez une famille saoudienne mais dont le mécanisme physiopathologique aboutissant à la thrombocytose était mal compris. En effet les sujets homozygotes présentent une thrombocytose importante et de manière paradoxale un taux de TPO élevé. Nous avons pu montrer qu’il s’agit d’un récepteur fonctionnel sans autonomie de croissance mais qu’il existe un défaut de trafic cellulaire, MPL restant bloqué dans le réticulum endoplasmique et étant adressé faiblement à la membrane. Néanmoins l’expression membranaire de MPL est moins diminuée à la surface des cellules immatures par rapport aux cellules matures expliquant un découplage entre la fonction de prolifération (mégacaryocytes) et de clearance de la TPO (plaquettes). Nous avons également étudié les TE triples négatives pouvant correspondre potentiellement à des mutations de MPL liées à un défaut de trafic cellulaire comme pour MPLP106L. Grâce à un séquençage à haut débit de l’exome entier, nous avons pu mettre en évidence de nouvelles mutations récurrentes comme MPLS204P ou Y591N qui sont des mutations faiblement activatrices ne donnant pas de croissance autonome mais n’altérant pas le trafic cellulaire et nécessitant la présence éventuellement d’autres mutations pour déclencher une thrombocytose. / Thrombocytosis is defined as a platelet count exceeding 450x109/L and generally either is a reactive process or is caused by genetic alteration on the way of platelet production. In the latter case sporadic thrombocytosis are usually distinguished from familial thrombocytosis, the boundaries between these two cases becoming less sharp since the mutation first described in familial thrombocytosis (MPLS505N) is also found in sporadic cases. Essential thrombocythemia (ET), the most frequent, sporadic thrombocytosis have an activating mutation in 85% of cases in either JAK2, MPL or CALR genes. Hereditary thrombocytosis may be the result of mutations of MPL, JAK2 or TPO. We studied initially MPLP106L already described in a Saudi family in which the pathophysiologic mechanism leading to thrombocytosis was misunderstood. Indeed homozygous patients exhibit significant thrombocytosis and paradoxically high TPO plasma level. We have shown that MPLP106L is a functional receptor without spontaneous growth but with a trafficking defect and a low cell surface expression. Nevertheless membrane expression of MPL is less reduced on immature cell surface compared to mature cells, explaining an uncoupling between proliferation (megakaryocyte precursors) and TPO clearance (platelets) functions. We also studied triple negative ET, to find potentially MPL mutations linked to a trafficking defect like MPLP106L. Thanks to Whole Exome Sequencing we were able to decipher new MPL mutations as MPLS204P or Y591N, which are weakly activating mutations without autonomous growth and the absence of trafficking defect and requiring the presence of other mutations in most cases to trigger thrombocytosis.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Genetic Counselling Johannesburg, 2013 / Five to ten percent of both breast and ovarian cancer cases are attributable to dominantly inherited mutations in genes that predispose to cancer, with a large proportion caused by mutations in the breast and ovarian cancer predisposing genes BRCA1 and BRCA2. Testing for these inherited cancers is indicated for individuals identified as being at high risk, or moderate to high risk, of having a cancer syndrome based on their family history of breast and/or ovarian cancer. Screening for high-risk individuals through services such as genetic counselling, has the potential to improve outcomes for these individuals and lower mortality rates. This study focused on individuals who attended genetic counselling for breast and/or ovarian cancer at the Genetic Counselling Clinics of the Division of Human Genetics, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg from 2001 to 2010. The study was divided into a file review on 218 counsellees and a telephonic interview of 50 counsellees. Focusing on breast and/or ovarian cancer, the study aimed to review who attends genetic counselling and why; who is offered genetic testing; what testing is offered and performed and; who pays for the testing, as well as gain a better understanding of how the service is received by counsellees. The study found that the majority of counsellees are white females, at a high risk of inherited breast and/or ovarian cancer, attend the genetic counselling session alone and are self-referred. There is an under representation of the black and coloured populations and an over representation of the Ashkenazi Jewish population in the cohort. The study‟s findings showed that a main motivator for individuals attending genetic counselling was for BRCA mutation testing, with the majority of testing offered being nationally based testing. The study also demonstrated that the service is generally well received and counsellees reported having a positive experience. Overall, the study pointed to the general lack of understanding and public awareness of genetic counselling, with suggestions to market to both the general population and to other medical professionals in order to reach more high risk individuals. On a practical level, a follow up service was suggested to ensure counsellees adhered to screening measures, informing counsellees on changes to testing protocols and identifying family members who may be at an increased risk of inherited breast and/or ovarian cancer.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23759号 / 医博第4805号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 万代 昌紀, 教授 松村 由美, 教授 古川 壽亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Objetivo: Até 10% dos casos de câncer de mama estão associados com uma síndrome genética de predisposição ao câncer. A identificação de possíveis portadores dessas síndromes e o consequente encaminhamento para aconselhamento genético permitem a adoção de estratégias direcionadas de prevenção e rastreamento capazes de diminuir morbidade e mortalidade. O objetivo do presente estudo foi avaliar a proporção de pacientes com câncer de mama atendidos no Hospital Universitário de Santa Maria (HUSM) que necessitariam ser encaminhados para avaliação genética. Métodos: Pacientes com câncer de mama que iniciaram tratamento oncológico no HUSM durante o ano de 2014 foram considerados elegíveis. Uma entrevista foi conduzida com cada paciente para coleta de dados e exame físico dirigido. O questionário FSH-7 (Family Story Screening 7) e os critérios do NCCN (National Comprehensive Cancer Network) foram utilizados para identificar os pacientes que deveriam ser encaminhados para avaliação genética. Estes pacientes foram então avaliados quanto à indicação de teste genético - de acordo com as recomendações do NCCN para teste genético – e à probabilidade de mutações nos genes BRCA1 e BRCA2 através de modelos de predição de risco (BOADICEA, Penn II, sistema de escore de Manchester e tabelas da Myriad). Resultados: Dentre os 114 participantes do estudo, 65 (57%) preenchiam critérios de encaminhamento para avaliação genética de acordo com as diretrizes do NCCN. O questionário FHS-7 apresentou uma sensibilidade de 90% para identificar estes pacientes, com uma especificidade de 85%. A presença de história pessoal ou familiar de câncer de mama antes dos 50 anos foi o critério mais comum para indicar avaliação genética. Em relação aos testes genéticos, 52 pacientes (45%) deveriam ser testados para mutações nos genes BRCA1 e BRCA2 e 4 pacientes (3,5%) possuíam indicação de teste para mutações em TP53, de acordo com as recomendações do NCCN. Utilizando os modelos de predição de risco, 10,2% a 57,1% dos pacientes apresentavam uma probabilidade ≥ 10% de mutações em BRCA1 ou BRCA2. Conclusão: Este estudo revelou que a maioria dos pacientes com câncer de mama atendidos no HUSM possui indicação de encaminhamento para avaliação genética. A utilização de um questionário simples e rápido poderia identificar 90% destes pacientes. / Objective: Up to 10% of breast cancers are associated with a hereditary cancer syndrome. The identification of possible carriers of these syndromes and the subsequent referral for genetic counselling allow the adoption of tailored screening and prevention strategies capable of reducing morbidity and mortality. The aim of this study is to assess the proportion of patients with breast cancer treated at the University Hospital of Santa Maria (HUSM) that would need to be referred for genetic evaluation. Methods: Breast cancer patients who began cancer treatment at HUSM during the year 2014 were eligible. An interview was conducted with each patient for data collection and targeted physical examination. The FSH-7 (Family Story Screening 7) questionnaire and the NCCN (National Comprehensive Cancer Network) criteria were used to identify patients who should be referred for genetic evaluation. Then these patients were assessed for genetic testing criteria - according to the NCCN recommendations for genetic testing - and the likelihood of BRCA1 and BRCA2 mutations through risk prediction models (BOADICEA, Penn II, Manchester score system and Myriad tables). Results: Among the 114 study participants, 65 (57%) meet referral criteria for genetic evaluation according to the NCCN guidelines. The FHS-7 questionnaire showed a sensitivity of 90% to identify such patients with a specificity of 85%. The presence of personal or family history of breast cancer before age 50 was the most common criteria to indicate genetic evaluation. With respect to genetic testing, 52 patients (45%) should be tested for BRCA1 and BRCA2 mutations and 4 patients (3.5%) had test indication for TP53 mutations in accordance with the recommendations of the NCCN. Using risk prediction models, 10.2% to 57.1% of patients had a BRCA1 or BRCA2 mutations probability ≥ 10%. Conclusion: This study showed that most of the patients with breast cancer treated at HUSM have referral indication for genetic evaluation. The use of a fast and simple questionnaire could identify 90% of these patients.