The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer


Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.



Li-Fraumeni syndrome


Next-generation sequencing


Hereditary breast and ovarian cancer syndrome




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This work was funded by IPO-Porto Research Center. MP is a Post-Doctoral fellow from Fundação para a Ciência e a Tecnologia (FCT: SFRH/BPD/113014/2015). PP is a Post-Doctoral fellow supported by FCT and the Research Center of IPO-Porto (UID/DTP/00776/POCI-01-0145-FEDER-006868). JG is a PhD student fellow from Fundação para a Ciência e a Tecnologia (FCT: SFRH/BD/138670/2018). The funding bodies did not have a role in the design of the study; collection, analysis, and interpretation of data; and in writing the manuscript.

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CE performed laboratory experiments, analyzed and interpreted data, and wrote the manuscript. MRT conceptualized the project. RS, CL, NC, PL, MF, ABS and JS provided biological samples and patient data. PP contributed to bioinformatic analysis. CP and JV oversaw laboratory and analytical experiments. AP, MP, CS, JG and SL performed some laboratory experiments. All authors read and approved the final manuscript.

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Correspondence to Manuel R. Teixeira.

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Escudeiro, C., Pinto, C., Vieira, J. et al. The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer. Familial Cancer (2020).

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  • HER2-positive breast cancer
  • TP53 germline variants
  • Li-fraumeni syndrome
  • Next-generation sequencing