TP53 mutations in the subgroup of BRCA-negative breast cancer families – a clinical challenge

Background:

TP53 germline mutations are associated with the Li-Fraumeni syndrome, an autosomal dominant cancer syndrome, which predisposes to a wide spectrum of malignancies. For the diagnosis of LFS the classic LFS or the Chompret criteria must be met. TP53 mutations have been rarely reported in the context of hereditary breast and ovarian cancer (HBOC). However, the prevalence in this target group is unknown and medical counseling remains challenging, especially concerning the large-scale screening protocol including annual whole body MRI that is implemented for LFS families.

This study aims to further characterize the prevalence and spectrum of germline TP53 mutations in BRCA-negative HBOC families.

Method:

Gene panel testing was conducted on 2,273 patients with breast cancer whose families fulfilled the HBOC inclusion criteria and who were screened negative for pathogenic BRCA-mutations.

Results:

Pathogenic variants in TP53 were present in 11 (0.5%), unclear variants in 22 (1%) of the breast cancer patients. Considering tumor biology, mutation carriers presented following distribution: 28%TNBC, 36%Her2pos, 36%HRpos Her2neg. Interestingly, two patients with breast cancer had a pathogenic TP53 missense mutation and did not fulfill the LFS/Chompret critieria. The corresponding pedigrees did not present any other cancer associated with LFS. We assume that this subgroup must differentiate from the classic LFS families regarding clinical manifestation. Concerning the profound screening protocol, which is associated with an enormously psychological discomfort, we suggest that the surveillance program needs to be adapted for this subgroup.

However more data is required to further characterize this special subgroup of TP53-mutation carriers in HBOC-families.