Abstract 4159: Gonadal mosaicism in a family with TP53-associated Li-Fraumeni syndrome
Authors: Khincha Payal P. , Jones Kristine , Teshome Kedest , Hicks Belynda , Mai Phuong L. , Savage Sharon A. 
Published: August 2019

Abstract
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome with exceptionally high lifetime cancer risks, caused primarily by germline pathogenic variants in TP53. Sarcomas, pre-menopausal breast cancer, brain tumors and adrenocortical carcinomas are the ‘core’ LFS cancers among a multitude of other cancers that can occur. Individuals with LFS are also at risk of developing multiple primary cancers over their lifetime. Clinical criteria have been established to denote LFS and ‘Li-Fraumeni like’ (LFL) families to facilitate genetic testing for TP53. De novo pathogenic germline variants in TP53 are estimated to cause between 7-25% of LFS. Gonadal mosaicism is an alternate explanation for presumed de novo variants and is yet to be described in LFS.
We present a proband who developed WHO grade II astrocytoma at age 18 years, who had a deceased brother with osteosarcoma diagnosed at age 13 years, and a healthy older sibling. The only other cancer history was leukemia at age 62 years in the paternal grandmother, who also had polycythemia vera. The family meets Eele’s criteria for LFL. The proband’s germline genetic testing revealed a heterozygous TP53 c.743G&gt;A p.R248Q pathogenic variant. Subsequent clinical genetic testing of the parents failed to reveal the variant, and the proband was presumed to have a de novo variant. Given the characteristic LFS-associated cancers in the brothers, we investigated further and identified the same TP53 pathogenic variant in the brother’s osteosarcoma tissue and pathology-confirmed benign liver tissue. TP53 sequencing of the brother’s tumor did not show loss of heterozygosity. Parental relationships to the proband and brother were confirmed through STR-based identifiler profiling. Ultra-deep sequencing (&gt;50,000x) of DNA derived from the parents’ blood, saliva and father’s benign colon polyp did not identify the variant, thus ruling out somatic mosaicism in the parents. We were unable to test gonadal tissues from the parents. In the setting of two siblings with the same pathogenic variant in TP53 which is absent in both parents, this family presents a case of assumed gonadal mosaicism resulting from a post-zygotic event.
The possibility of gonadal mosaicism presents complexity in genetic counselling of families with inherited disorders, and a conundrum in syndromes such as TP53-associated LFS where the presumed de novo rate is high and cancer risks are significantly elevated. The presented family suggests that further investigation of individuals with presumed de novo variation, especially in the setting of suspicious family cancer history, is required to accurately identify family members at-risk.
Citation Format: Payal P. Khincha, Kristine Jones, Kedest Teshome, Belynda Hicks, Phuong L. Mai, Sharon A. Savage. Gonadal mosaicism in a family with TP53-associated Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4159.