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.

乳腺癌是与生殖系TP53变异相关的 Li-Fraumeni 综合征中最常见的事件。一些研究表明，Li-Fraumeni 综合征女性的乳腺癌通常是 HER2 阳性的，这表明年轻女性的HER2扩增或过度表达可能是检测TP53基因种系变异的有用标准。我们通过 Sanger 测序或下一代测序评估了149 名诊断为 40 岁之前的 HER2 阳性乳腺癌女性中胚系TP53变异的流行率。HER2扩增模式是在来自患者的乳腺癌子集中使用双探针 FISH 进行评估的带有种系TP53与非携带者的变异相比。在接受测试的 149 名女性中，三名呈现有害的TP53种系变异 (2%)，一名患者在 31 岁时被诊断出，另外两名患者分别在 29/33 和 28/32 岁时被诊断出患有双侧乳腺癌。在 31 岁或更年轻时诊断出第一次乳腺癌的 36 名患者中，有 36 名 (8.3%) 表现出致病性TP53变异。此外，所有TP53有害变异携带者的一级亲属在 45 岁或更年轻时被诊断出患有不同的早发性癌症（通常不属于 Li-Fraumeni 综合征肿瘤谱）。在TP53 的乳腺癌中发现了更高水平的HER2扩增致病变异携带者多于非携带者。有害生殖系TP53变异占早发性 HER2 阳性乳腺癌的一小部分，但这些似乎具有更高的HER2扩增率。本研究中发现的所有TP53致病性变异携带者均在 31 岁或更年轻时诊断出首例乳腺癌，并且其一级亲属患有早发性癌症。需要进一步的研究来阐明早发性乳腺癌患者的 HER2 状态，结合其他个人和/或家族癌症病史，是否有助于更新TP53检测标准。