Ching-Shui Huang ^1 2, Chih-Yi Liu ³, Tzu-Pin Lu ⁴, Chi-Jung Huang ^5 6, Jen-Hwey Chiu ^7 8, Ling-Ming Tseng ^8 9, Chi-Cheng Huang ^9 10

Affiliations

1. Division of General Surgery, Department of Surgery, Cathay General Hospital, Taipei 106, Taiwan.
2. School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
3. Department of Pathology, Cathay General Hospital Sijhih, New Taipei 221, Taiwan.
4. Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei 110, Taiwan.
5. Department of Medical Research, Cathay General Hospital, Taipei 106, Taiwan.
6. National Defense Medical Center, Department of Biochemistry, Taipei 114, Taiwan.
7. Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11121, Taiwan.
8. School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
9. Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei 1121, Taiwan.
10. School of Public Health, College of Public Health, National Taiwan University, Taipei 100, Taiwan.

ABSTRACT

Breast cancer is the most common female malignancy in Taiwan, while conventional clinical and pathological factors fail to provide full explanation for prognostic heterogeneity. The aim of the study was to evaluate the feasibility of targeted sequencing combined with concurrent genes signature to identify somatic mutations with clinical significance. The extended concurrent genes signature was based on the coherent patterns between genomic and transcriptional alterations. Targeted sequencing of 61 Taiwanese breast cancers revealed 1036 variants, including 76 pathogenic and 545 likely pathogenic variants based on the ACMG classification. The most frequently mutated genes were NOTCH, BRCA1, AR, ERBB2, FANCA, ATM, and BRCA2 and the most common pathogenic deletions were FGFR1, ATM, and WT1, while BRCA1 (rs1799965), FGFR2 (missense), and BRCA1 (rs1799949) were recurrent pathogenic SNPs. In addition, 38 breast cancers were predicted into 12 high-risk and 26 low-risk cases based on the extended concurrent genes signature, while the pathogenic PIK3CA variant (rs121913279) was significantly mutated between groups. Two deleterious SH3GLB2 mutations were further revealed by multivariate Cox’s regression (hazard ratios: 29.4 and 16.1). In addition, we identified several significantly mutated or pathogenic variants associated with differentially expressed signature genes. The feasibility of targeted sequencing in combination with concurrent genes risk stratification was ascertained. Future study to validate clinical applicability and evaluate potential actionability for Taiwanese breast cancers should be initiated.

Keywords: Taiwan; actionable mutations; breast cancer; concurrent genes; risk stratification; targeted sequencing.

>J Pers Med. 2021 Jun 28;11(7):613. doi: 10.3390/jpm11070613.