Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant cancer predisposition syndrome, associated with germline mutations in the TP53 gene and a variety of histologically different tumours, of which early-onset breast cancer, sarcomas and brain tumours tend to occur most frequently. In this study, we report on sarcoma incidence in the LFS population in the Netherlands, based on data of the Netherlands Cancer Institute (NCI), the national referral centre for LFS.
The cohort consisted of all subjects with a confirmed pathogenic TP53 germline mutation included in the screening program at the NCI between October 2011 and October 2020. Patient and tumour characteristics, family history and type of TP53 mutation were collected from patient files. All malignancies in the medical history of the screened subjects, including those diagnosed before participation in the screening program, were included in the analysis.
In 119 TP53 mutation carriers, 29 sarcomas, 16 soft tissue and 13 bone sarcomas, were detected in 28 patients (24.0% of all malignancies). Sarcoma was the second most frequently diagnosed malignancy, after breast cancer. Osteosarcoma was most common (9 cases, 5 in males, median age at time of diagnosis (AAD) 18 years (range 11-41)), followed by rhabdomyosarcoma (6 cases, 2 in males, median AAD 5 years (range 2-44)) and leiomyosarcoma (5 cases, 3 in males, median AAD 57 years (range 27-71)). Other subtypes had 2 cases or less. Sarcoma subtypes were evenly divided across mutation variant groups. 4 of 9 osteosarcomas were located in either mandibula or maxilla. Of these 4 patients (2 male, 2 female), median AAD was 24.5 years (range 18-36).
We found a high incidence of osteosarcomas of the jaw at a relatively young age in the national screening cohort of TP53 mutation carriers in the Netherlands. Several case reports suggest a connection between LFS and this rare location for osteosarcoma, although a series as seen in our screening cohort has not been reported yet. Further exploration of associations between TP53 genotype and phenotypic features, such as sarcoma subtypes, requires international collaboration with larger LFS cohorts.
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G.S. Sonke: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Roche. W.T.A. Van Der Graaf: Financial Interests, Institutional, Other, Consultancy: Springworks; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Other, Sarcoma Council Panel: GSK. All other authors have declared no conflicts of interest.