RESUMO
In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency. SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.
Assuntos
Neoplasias da Mama , Classe I de Fosfatidilinositol 3-Quinases , Receptor alfa de Estrogênio , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Proteína Supressora de Tumor p53 , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/etnologia , Receptor alfa de Estrogênio/genética , Proteína Supressora de Tumor p53/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Pessoa de Meia-Idade , População Branca/genética , Predisposição Genética para Doença/genética , Adulto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Current treatments for people with obesity emphasise the need for person-centred approaches that consider complex biopsychosocial factors and value the lived experience of people when attempting to lose weight. METHODS: Narrative interviews (n = 20) were conducted with people living with obesity to explore the causes of their weight gain and their expectations and engagement with treatment at a Weight Management Clinic. A mixed inductive and deductive qualitative analysis identified utterances that represented psychological constructs used to understand self-appraisal and health behaviour. A narrative analysis was used to situate these findings in the context of a participant's life story. RESULTS: Locus of control was a dominant construct evidenced through a person's attributional style and self-efficacy. Transcripts represented a heightened sense of self-understanding and shifts in control, and styles of attribution and efficacy resulted in either stasis or self-actualisation. The Stages of Change model could be applied to narratives to ascertain a patient's motivation to access treatment. Importantly, narrative interviews also allowed for the consideration of how a person's systemic context influenced their weight. CONCLUSION: Narrative interaction supports both self- and shared understandings of the causes and consequences of obesity for individuals, in a non-blaming or shaming manner. It provides an opportunity to enhance engagement through tailored, person-centred treatments.
RESUMO
Background: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. Methods: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC. Results: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons. Conclusions: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.