Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort.

Importance: Establishment of an optimal cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with Li-Fraumeni syndrome, a rare, highly penetrant cancer predisposition syndrome. Objective: To determine the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid whole-body magnetic resonance imaging (MRI) and laboratory measurements. Design, Setting, and Participants: Baseline evaluation of a prospective cancer screening study was conducted from June 1, 2012, to July 30, 2016, at the National Cancer Institute, National Institutes of Health (an academic research facility). Participants included 116 individuals with Li-Fraumeni syndrome with a germline TP53 pathogenic variant who were aged 3 years or older at the time of baseline screening and had not received active cancer therapy at least 6 months prior to screening. Main Outcomes and Measures: Detection of prevalent cancer with multimodal screening techniques and the need for additional evaluation. Results: Of the 116 study participants, 77 (66.4%) were female; median age was 37.6 years (range, 3-68 years). Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers [ductal carcinoma in situ]); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer in our cohort. Conclusions and Relevance: This study describes the establishment and feasibility of an intensive cancer surveillance protocol for individuals with Li-Fraumeni syndrome. Prevalent cancers were detected at an early stage with baseline whole-body, brain, and breast MRI. Prospective screening of the participants is under way.

Analysis of p53 tumor suppressor gene in families with multiple glioma patients.

The high incidence of gliomas in Li-Fraumeni families and the high frequency of somatic p53 mutations in sporadic glial tumors have raised the possibility that germline p53 mutations could play an important role in familial aggregation of gliomas. In the present study, 18 families with two or more gliomas were screened for germline p53 mutation. The families were identified through questionnaires sent to 369 consecutive glioma patients operated at Tampere University Hospital during 1983-1994. In these families, a family history of cancer was verified through the Finnish Cancer Registry. Interestingly, the questionnaires reveled only 15 of 57 cancers (index gliomas excluded) retrieved through the Cancer Registry. None of the 18 families fufilled the criteria for classic Li-Fraumeni syndrome. Immunostaining analysis of p53 protein accumulation suggested that alterations of the p53 gene are as common in familial as in sporadic gliomas. Sequencing analysis of exons 4-10 of the p53 gene revealed no germline mutations in any of the 18 families. Thus, although occasional glioma families carrying germline p53 mutations have been identified in earlier studies, systematic evaluation of familial glioma patients suggests that the p53 gene is not a common susceptibility gene in case of familial gliomas. The p53 tumor suppressor gene seems to have a similar role in the tumorigenesis of most familial and sporadic gliomas.