Given that the large population of young breast cancer patients remains a substantial health burden for China and the limited data available for TP53 PVs of that population, we investigated the germline TP53 PVs with data derived from 1492 patients with early-onset breast cancer unselected for family history to inform efficient strategies for genetic testing. To our knowledge, this is the largest study to date that provides insight into the prevalence and clinical characteristics of TP53 PVs in early-onset breast cancer in China.

Seven patients were found to be carriers of TP53 PVs with mutation rates of 0.47% in this study, which was lower than 1.0% reported by Sheng et al. in the corresponding age subgroups of another large unselected breast cancer cohort in China11, but slightly higher than the rate of 0.31% in UK19 and 0.40% in America20. Additionally, given the rare mutation frequency of 0.47% among our early-onset breast cancer cohort, the onset age contributed limited to TP53 gene testing.

One of the variants detected in this study is TP53 1009 C > T (p.R337C), a pathogenic or likely pathogenic variant commonly associated with LFS. It should be noted that this variant differs from p.R337H (TP53 1010 G > A)17, a variant that has been identified in 12.1% of patients diagnosed with breast cancer at or before age 45, regardless of their family history of cancer. The p.R337H is identified as a founder mutation in the Brazilian population, representing 70.3% of all TP53 PVs in Brazil21. However, no recurrent variants were found in our study. Although the identification of founder mutations allows targeted detection of single mutations and saves testing costs, current research has not found any founder mutations in the Chinese population.

Among the variations detected in this study, p.R175H is a hotspot of TP53 PVs among breast cancer and LFS patients in both Western and Asian populations11,22. Specifically, while codons 248 and 273 are acknowledged TP53 hotspots11,16,22, with p.R248Q, p.R248W, and p.R273H mutations frequently reported, our cohort uniquely identified p.R248P mutations within these codons, and p.R273C has not been previously reported in breast cancer patients. Additionally, p.R248P, p.I251F had not been identified in breast tumors before and are also being reported for the first time as germline mutations. The p.G266R mutation was identified as a somatic mutation in breast tumor specimens in a Japanese study23, and it has not been previously reported as a germline mutation. Our research findings revealed the specific TP53 PVs in Chinese patients with early-onset breast cancer and reflected the necessity of investigating diverse populations to better understand unique genetic variations.

In previous studies, the frequencies of TP53 PVs among patients aged 30 years or younger were ranging from <2%–8%16,18,24,25,26. In our study, the mutation rate of TP53 PVs in the corresponding population was 1.9%, which is found to be significantly higher than the frequency in breast cancer patients aged 31–40 years (p = 0.01). The comparison underscored the higher propensity for TP53 PVs in the patients with younger age.

Some previous studies have found a significant association between TP53 PVs and bilateral breast cancer9,11,20,27, leading to the recommendation of bilateral mastectomy for affected patients28,29. Furthermore, Couch et al. reported that TP53 PVs were only associated with a family history of ovarian cancer, but not with a family history of breast cancer in a larger nationwide sample of unselected breast cancer20. Conversely, Siraj et al. did not observe any association between TP53 PVs and family history of breast cancer or any cancer among early onset Middle Eastern breast cancer patients27. In our current study, we did not find a significant association between TP53 PVs and personal history of bilateral breast cancer or family history of breast cancer and/or ovarian cancer. This suggests that these two factors may not be appropriate decision criteria for TP53 genetic testing in younger patients.

Sheng et al. indicated that breast cancer patients with germline TP53 mutations have a poorer prognosis compared to non-carriers11. Additionally, TP53 carriers are at an increased risk of developing radiation-induced secondary malignancies after adjuvant radiotherapy25,28. Consequently, mastectomy may be more appropriable for TP53 carriers to avoid the need for radiotherapy following breast-conserving surgery. The decision to use radiotherapy post-mastectomy also warrants careful consideration. The European Reference Network for Genetic Tumour Risk Prediction (GENTURIS) guidelines emphasize the importance of identifying TP53 carriers before the initiation of treatment to potentially avoid radiotherapy in carriers30. Moreover, asymptomatic carriers in the families of TP53 mutation patients face a significantly increased risk of cancer, necessitating regular surveillance, particularly in pediatric carriers25,29. Therefore, the identification of TP53 carriers among breast cancer patients not only aids in optimizing treatment strategies for patients but also enhances cancer surveillance in at-risk family members.

In clinical practice, BRCA1/2 gene testing is recommended for young breast cancer patients, with emphasis on testing for HER2-negative patients because it accounts for the majority of BRCA1/2 PVs. However, the majority of TP53 carriers were HER2-positive patients (71.4%) in our study, consistent with 67%–83% from previous studies31,32. Consistent with the majority of previous studies, our research found a significant association between TP53 mutations and HER2-positive status31,32,33. Compared to HER2-negative disease, patients with HER2-positive status have a significantly higher frequency of TP53 PVs (1.2%) in the whole cohort, similar to the 1.4%-1.5% found in previous studies of early-onset patients6,33. In addition, we observed that the prevalence of TP53 PVs in HER2-positive patients aged 35 years or younger was 2.3%, which is approximately 13 times higher than that of the remaining cohort after adjustment for family history and personal history of bilateral breast cancer. Although the prevalence of TP53 PVs can be as high as 4.4% in HER2-positive patients aged 30 years or younger, it should be highlighted that 40% of TP53 PVs occurred in patients between age 31 and 35 years old, which should not be omitted. Consequently, our findings recommend that TP53 genetic testing could serve as a crucial supplement for HER2-positive patients with early-onset, particularly in patients younger than 35 years old.

There are some limitations to our study. First, although this study has the largest sample size of patients with early-onset breast cancer to date, the rare mutation rate of breast cancer susceptibility genes led to a limited number of identified carriers, potentially reducing the statistical power of our analyses. Therefore, the results should be interpreted with caution. Additionally, this study focused on Chinese patients with early-onset breast cancer. Due to the regional and ethnic specificity of genetic mutations, the TP53 mutation spectrum observed in this cohort may not be generalizable to other populations, and further validation is needed. Second, although we collected LFS-related family history for individuals carrying TP53 mutations, we did not collect such information for all study participants, which may have limited our ability to comprehensively evaluate the association between TP53 mutations and LFS-associated malignancies. Third, long-term follow-up was not available for all individuals, and the survival data were immature. Previous studies have reported that TP53 carriers have a high rate of ipsilateral breast tumor recurrence after breast-conserving surgery18. Therefore, further prognostic analysis is necessary to estimate the impact of different treatment options on survival in PV carriers and non-carriers, so as to offer optimal management for carriers. Finnally, this study did not include a control group of young individuals who are not affected by breast cancer, limiting our ability to evaluate the risk for the development of early breast cancer in young carriers of TP53 PVs.

In conclusion, we demonstrated that the prevalence of TP53 PVs were 0.47% in the largest early-onset breast cancer cohort in China. TP53 PVs are significantly associated with younger age at diagnosis and HER2-positive status. Multivariate logistic regression results indicated that the prevalence of TP53 PVs was significantly increased in HER2-positive patients with a diagnosis age of 35 or younger; thus, we emphasized that target TP53 genetic testing needs to be considered in that population.