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Background: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for BRCA1/2 founder mutation screening in U.S. Ashkenazi-Jewish women. Methods: BRCA1/2 carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). Results: Identifying 90% of BRCA1/2 founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women. Conclusions: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities. Impact: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.

Background: Li Fraumeni Syndrome (LFS) is an autosomal dominant cancer predisposition syndrome in which about 90% of individuals develop cancer by age 60. Approximately 70% of individuals with LFS have germline TP53 mutation. We hypothesized that this high level of cancer risk may be associated with increased emotional distress, cancer risk perceptions and cancer worry in individuals from LFS families. Methods: Data from 276 adult (≥18 years old) TP53 mutation carriers (TP53+), mutation negative (TP53-) and untested (UT) participants enrolled in an IRB-approved study at the Clinical Genetics Branch, NCI were obtained between January 2011 and June 2014.. Using questionnaires at baseline, we assessed emotional distress (global distress, somatization, anxiety and depression) as measured by the BSI-18, cancer risk perceptions (comparative: scores 1-5; 1 = much less than other people your age to 5 = much more than other people your age and absolute: 10-point scale; 1 = no chance; 5 = may or may not; 10 = almost certainly) and cancer worry scales (frequency of cancer thoughts, interference with mood and daily activity, scores 1-4; = not at all or rarely to 4 = several times a day). Results: TP53+ estimated their comparative lifetime risk of cancer as higher than TP53- and UT; [4.9 (SD = 0.5) vs. 3.8 (SD = 1) and 3.2 (SD = 1.3) p Conclusions: Participants in the LFSS do not demonstrate high levels of emotional distress. TP53+ appropriately identify their comparative and absolute cancer risk as high, but have levels of cancer worry that appears to be only slightly affecting their mood or ability to perform daily activities. Future research will focus on longitudinal changes in risk perception, cancer worry and emotional well-being while enrolled in a cancer screening study. Citation Format: Jennifer T. Loud, Renee C. Bremer, Rosamma Decastro, June A. Peters, Phuong L. Mai, Sharon A. Savage. Psychosocial functioning in research participants at enrollment in a Li-Fraumeni syndrome study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3473.

Introduction: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome causing a range of cancers across the lifespan. About 70% of families meeting classical LFS criteria have detectable germline mutations in the TP53 gene, vs 40% of those classified as Li-Fraumeni-like (LFL). The psychological, social, and behavioral issues faced by individuals with LFS/LFL and their relatives comprise an important, but under-studied, topic. Methods: Ours is a prospective, cohort study of LFS/LFL. Enrollees are invited to participate in epidemiologic and lifestyle questionnaires, clinical evaluations, genetic counseling and testing if indicated, molecular research, cancer screening and psychosocial assessments, and, of adults, standardized, self-report, psychological assessments. Those attending clinic also have in-person interview and social assessments. Results: Two of the first five families we saw illustrate a wide range of psychosocial issues, which emerged during the social assessment and family interview.Family 1 included two adolescents with histories of osteosarcoma, and their unaffected father. Their biological mother had died a decade earlier from a different type of cancer and their father had remarried. The adolescent female proband was struggling with internal conflict, overwhelmed with trying to balance pleasing her family with the developmentally appropriate task of gaining independence. The younger male proband focused on short-term goals, seemingly finding the cancer risk personally irrelevant. The father worried about raising his children in a highly secular environment, and about how to manage their medical needs. The proband of Family 2 is a 37-year-old woman who had already survived 4 primary cancers, seen with her 2 unaffected, mutation-positive children and her mother. She was divorced from the children's father and raised them as a single mom for several years with the help of her mother until re-marrying. Pertinent psychosocial issues included an emotional and practical cut-off between the biological parents, resulting in the mother's struggle to manage her children's healthcare needs and communicate with them about their risk independent of their father, who preferred not to be involved in the medical system. Additionally, the mother's strong sense of independence created a communication barrier between her and her own mother, who felt shut out of her daughter's emotional experience despite wanting to provide support. Conclusions: There is great breadth of needs in families with LFS/LFL. Understanding the psychological, social, and behavioral issues as they are manifest in the context of LFS will help guide our efforts aimed at alleviating the psychosocial morbidity associated with this syndrome. We recommend that families receive ongoing psychosocial evaluation as an integral part of their medical management, preferable by multi-disciplinary teams. Citation Format: June A. Peters, Lindsey M. Hoskins, Phuong L. Mai, Farzana Walcott, Renee Bremer, Sharon A. Savage. Li-Fraumeni syndrome: Clinical experience with family psycho-social issues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1383. doi:10.1158/1538-7445.AM2013-1383