To investigate the characteristics of gene mutations and homologous recombination repair (HRR)-related gene mutations in different molecular subtypes of breast cancer.

According to the inclusion and exclusion criteria, 139 patients who were pathologically diagnosed with breast cancer and tested for somatic or/and germline mutations of 1021 tumor-related genes in the Daping Hospital of Army Medical University from March 2017 to March 2021 was included for a retrospective study. Based on the results of genetic testing, the somatic single nucleotide variants (SNV), copy number variants (CNV) and germline SNV in patients with five molecular subtypes were compared, and the mutation characteristics of HRR-related genes were also analyzed. Comparison among multiple groups was performed using χ² test, and Fisher's exact test and Bonferroni correction were used for pairwise comparison.

Among 139 patients, 108 patients were tested for somatic mutations and 139 patients were tested for germline mutations; there were 42 patients with luminal A subtype, 25 luminal B subtype (HER-2 negative), 11 luminal B subtype (HER-2 positive), 26 HER-2 overexpression subtype, 30 triple negative subtype and 5 unknown subtype. Among the 103 patients with clear molecular subtype and gene mutation detection, the five genes with the highest SNV mutation frequency were as follow: TP53 (57.3%, 59/103), PIK3CA (43.7%, 45/103), MLL3 (12.6%, 13/103), GATA3 (9.7%, 10/103) and MAP3K1 (8.7%, 9/103). The SNV mutation frequencies of TP53 and PIK3CA showed a significant difference among breast cancer patients with different molecular subtypes (χ²=16.617, 16.434, both P=0.002). Compared with luminal A subtype, TP53 mutation frequency was significantly higher in HER-2 overexpression subtype (P=0.004). Compared with luminal A and luminal B (HER-2 positive) subtypes, PIK3CA mutation frequency was significantly lower in triple negative subtype (P=0.006, 0.005). The ten genes with the highest CNV amplification frequency were as follow: ERBB2 (27.2%, 28/103), CDK12 (16.5%, 17/103), MYC (14.6%, 15/103), CCND1 (11.6%, 12/103)), FGF19 (8.7%, 9/103), FGF3 (8.7%, 9/103), FGF4 (8.7%, 9/103), SPOP (5.8%, 6/103), FGFR1 (5.8%, 6/103) and MCL1 (5.8%, 6/103). The amplification frequencies of ERBB2, CDK12 and SPOP showed a significant difference among breast cancer patients with different molecular subtypes (χ²=69.996, 38.192, 14.859, all P<0.050). Pairwise comparison results showed that ERBB2 amplification was significantly enriched in luminal B subtype (HER-2 positive) and HER-2 overexpression subtype [compared with luminal A subtype, P=0.001, <0.001; compared with luminal B subtype (HER-2 negative), P=0.007, <0.001; compared with triple negative subtype, P=0.005, <0.001]; compared with luminal A, luminal B (HER-2 negative) and TNBC subtypes, CDK12 amplification frequency was significantly higher in HER-2 overexpression subtype (P<0.001, <0.001, P=0.004); CDK12 amplification frequency in luminal B (HER-2 positive) subtype was significantly higher than that in luminal B (HER-2 negative) subtype (P=0.040). The germline gene mutation analysis showed that the top two genes with the highest germline mutation frequency were BRCA2 and BRCA1 [10.4% (14/134), 6.0% (8/134)]. Among the 36 HRR-related genes, the amplification frequency of CDK12 showed a significant difference among different molecular subtypes (χ²=38.192, P=0.001).

Breast cancer patients with different molecular subtypes have different gene mutation characteristics. Among them, the mutation frequency of TP53, PIK3CA, SNV and the amplification frequency of ERBB2, CDK12 and SPOP are significantly different among five molecular subtypes.