Abstract
Simple SummaryTP53 variants detected in blood represent a main genetic cause of breast cancers occurring before 31 years of age. TP53 being included in most of the cancer gene panels, patients with breast cancer are offered germline TP53 testing, independently of the age of tumour onset and familial history. Interpretation of TP53 variants is remarkably complex, and detection of a germline disease-causing TP53 variant in a breast cancer patient has drastic medical consequences: radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided. In her family, variant carriers should be offered annual follow-up, including whole-body MRI. Therefore, we consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and that the decision of TP53 testing should not be systematic but based on the age of tumour onset, type of breast cancer, personal and familial history of cancer.Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first- or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.
Highlights
The development of cancer multi-gene panels has resulted in an exponential increase of TP53 testing in patients with breast cancers, as TP53 is included in most of the commercial or academic cancer gene panels
A high nuclear grade is observed in the majority of the invasive carcinoma and ductal carcinoma in situ (DCIS) cases associated with germline TP53 variants, and most of the invasive carcinoma are of mSBR
* A germline disease-causing TP53 variant should be considered as “high risk” in childhood if the index case has developed a childhood cancer; or childhood cancers have been observed within the family, or this variant has already been detected in other families with childhood cancers, or this variant corresponds to a dominant-negative missense variant. ** The first scan should be conducted with I.V
Summary
The development of cancer multi-gene panels has resulted in an exponential increase of TP53 testing in patients with breast cancers, as TP53 is included in most of the commercial or academic cancer gene panels. Thirty years after the characterization of LFS molecular basis, testing children with malignancies or adult females with very early-onset breast cancers without the aspect of family history has shown that familial history of cancer is not mandatory to identify a germline disease-causing TP53 variant [5,6,7,8,9,10,11,12]. This is explained by the fact that de novo TP53 variants are not uncommon and penetrance of the variants is incomplete [10,11,12,13]. We review here the complexity both of TP53 variant interpretation and cancer risk estimation in variant carriers and the medical consequences of germline disease-causing TP53 variant identification in breast cancer patients
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