Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne.

Purpose: Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li-Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.

Methods: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.

Results: TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.

Conclusion: The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC-HBOC criteria for genetic testing.