Jacquelyn Powers

Supplementary Table S1: Reported cases of individuals with germline hypomorphic TP53 variants

In individuals with classic Li-Fraumeni syndrome (LFS) due to a loss-of-function pathogenic germline variant in TP53, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adrenal cortical carcinomas, brain tumors, and leukemia. In adults with classic LFS, in addition to the classical malignancies, breast cancers and other cancers develop at earlier ages of onset compared with individuals without LFS. Increased genetic testing is identifying a higher frequency of germline TP53 variants with conflicting interpretations in clinical databases, some of which are likely hypomorphic or of atypical penetrance. Studies of these hypomorphic TP53 variants reveal differential retention or loss of the myriad of p53 tumor-suppressive functions. Many individuals with hypomorphic TP53 variants develop cancer, including both canonical and common types, though at later ages compared with classic LFS. Therefore, further study is needed to understand the most critical tumor suppressive functions of p53, as are data-driven clinical guidelines for the management of cancer risk. Herein, we review models of TP53 variant classification, focusing on strategies to identify hypomorphic TP53 variants. We go on to review the biology and clinical phenotypes of TP53 hypomorphic variants that have detailed reports of their effects on p53 tumor-suppressive functions. Using this framework, we propose possible modifications to the standard LFS screening protocol for individuals with hypomorphic TP53 variants that should be studied in prospective clinical trials.

In individuals with classic Li Fraumeni Syndrome (LFS) due to a loss of function pathogenic germline variant in TP53, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adrenal cortical carcinomas, brain tumors and leukemia. In adults with classic LFS, in addition to the classical malignancies, breast cancers and other cancers develop at earlier ages of onset compared to individuals without LFS. Increased genetic testing is identifying a higher frequency of germline TP53 variants with conflicting interpretations in clinical databases, some of which are likely hypomorphic, or of atypical penetrance. Studies of these hypomorphic TP53 variants reveal differential retention or loss of the myriad of p53 tumor suppressive functions. Many individuals with hypomorphic TP53 variants develop cancer, including both canonical and common types, though at later ages as compared to classic LFS. Therefore, further study is needed to understand the most critical tumor suppressive functions of p53 as are data-driven clinical guidelines for management of cancer risk. Herein, we review models of TP53 variant classification focusing on strategies to identify hypomorphic TP53 variants. We go on to review the biology and clinical phenotypes of TP53 hypomorphic variants that have detailed reports of their effects on p53 tumor suppressive functions. Using this framework, we propose possible modifications to the standard LFS screening protocol for individuals with hypomorphic TP53 variants that should be studied in prospective clinical trials.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%–4% initial, 6%–10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes.Prevention Relevance:The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.