Unhealthy Lifestyle Patterns Are Prevalent In Unaffected Brca Mutation Carriers & Are Associated With Increased Oxidative Stress And Telomere Length Alterations

The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication.The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication. Citation Format: McGarrigle SA, Guinan EM, Hussey J, O9Sullivan J, Boyle T, Hanhauser Y, Al-azawi D, Kennedy MJ, Gallagher DJ, Connolly EM. Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers u0026 are associated with increased oxidative stress and telomere length alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-02.