Abstract:

Objective To explore the germline mutation frequency of genetic susceptibility genes and clinical characteristics in early-onset breast cancer （onset age ≤35 years） in China. Methods Clinical information and peripheral blood of 150 patients aged 35 and younger diagnosed with breast cancer in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from January 1, 2015 to December 31, 2019 were collected. Then DNA was extracted to detect germline mutations in breast cancer susceptibility gene （BRCA）1, BRCA2, ataxia telangiectasia mutated （ATM）, partner and localizer of BRCA2 （PALB2）, tumor protein 53 （TP53） and cell cycle checkpoint kinase 2 （CHEK2） genes. Mutations were interpreted as pathogenic, likely pathogenic, uncertain significance, likely benign and benign according to the classification criteria and guidelines for genetic variation. Patients were divided into mutation group （n=18） and non-mutation group （n=132） according to the presence or absence of pathogenic or probable pathogenic germline mutations, and the χ² test was used to analyze the relationships between genetic susceptibility gene mutations and clinicopathological characteristics. Results Eighteen pathogenic or likely pathogenic germline mutations were detected in 150 patients with early-onset breast cancer, for an overall mutation frequency of 12.0%. Among them, there were 8 （5.3%） BRCA2 mutation, 7 （4.7%） BRCA1 mutation, 1 （0.7%） PALB2 mutation, and 2 （1.3%） TP53 mutation. There were no pathogenic or likely pathogenic variants in ATM and CHEK2 genes. The mutation type was dominated by frameshift mutation （9/18, 50.0%）, followed by nonsense mutation （7/18, 38.9%）, missense mutation （1/18, 5.6%） and splice acceptor mutation（1/18,5.6%）. Among the molecular subtypes of 18 mutation carriers, 9 cases were Luminal B, 6 cases were triple negative breast cancer （TNBC）, 2 cases were Luminal A, and only 1 case was human epidermal growth factor receptor-2 （HER-2） amplification. Among them, 8 BRCA2 mutation carriers were Luminal type, and 6 of 7 BRCA1 mutation carriers were TNBC type. There were no statistical differences in family history of breast cancer （P=0.343）, estrogen receptor （ER） status （χ²=0.16, P=0.688）, HER-2 status （χ²=2.89, P=0.089）, molecular subtype （χ²=1.99, P=0.575）, and initial diagnosis TNM stage （χ²=2.49, P=0.115） between the mutation group and the non-mutation group. Conclusion The patients with early-onset breast cancer have high frequency of germline mutations. It is recommended that patients with early-onset breast cancer undergo genetic counseling and multigene testing.

Key words: Breast neoplasms, Early-onset, Heredity, Susceptibility genes